the complement system sections from chapter 2 and 11 in parham’s book
TRANSCRIPT
THE COMPLEMENT SYSTEM
Sections from chapter 2 and 11 in Parhamrsquos book
The complement system is a set of about 30 soluble proteins constitutively produced by the liver that are found in the blood lymph and extracellular fluids and act against extracellular pathogens
Complement activation proceeds by a cascade of enzymatic reactions (proteases) in which each protease cleaves and activates the next enzyme in the pathway
Complement system
THE CENTRAL COMPONENT OF THE THE CENTRAL COMPONENT OF THE COMPLEMENT SYSTEMCOMPLEMENT SYSTEM
C3C3CGEQCGEQ
One of the proteins present at the highest concentration in serum One of the proteins present at the highest concentration in serum 12mgml12mgml
CLEAVAGE SITE
((33 900900 000000 000000 000000 000 000 moleculesmoleculesmlml))
InflammationInflammation
C3aC3a C3bC3b
CGEQCGEQ
C3C3CGEQCGEQ RROHOH
BaBacctteriumerium
CGEQCGEQ
RROHOHRROO
RROHOH
RROO
CGEQCGEQ
RROHOHRROHOH
Cell
BindingBinding
THE CENTRAL COMPONENT OF THE THE CENTRAL COMPONENT OF THE COMPLEMENT SYSTEM COMPLEMENT SYSTEM
Complement fixation-Complement fixation- Covalent binding of C3b to the pathogensrsquo surfaceCovalent binding of C3b to the pathogensrsquo surface
The alternative pathway
The alternative soluble C3 convertase
The alternative C3 convertase C3bBb
AMPLIFICATION OF THE COMPLEMENT CASCADE
inactive
precursorslimited
proteolysis
activating surfaceenzyme
Regulation of the complement system
Positive regulation
Negative regulation
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
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- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
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- Slide 47
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- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
The complement system is a set of about 30 soluble proteins constitutively produced by the liver that are found in the blood lymph and extracellular fluids and act against extracellular pathogens
Complement activation proceeds by a cascade of enzymatic reactions (proteases) in which each protease cleaves and activates the next enzyme in the pathway
Complement system
THE CENTRAL COMPONENT OF THE THE CENTRAL COMPONENT OF THE COMPLEMENT SYSTEMCOMPLEMENT SYSTEM
C3C3CGEQCGEQ
One of the proteins present at the highest concentration in serum One of the proteins present at the highest concentration in serum 12mgml12mgml
CLEAVAGE SITE
((33 900900 000000 000000 000000 000 000 moleculesmoleculesmlml))
InflammationInflammation
C3aC3a C3bC3b
CGEQCGEQ
C3C3CGEQCGEQ RROHOH
BaBacctteriumerium
CGEQCGEQ
RROHOHRROO
RROHOH
RROO
CGEQCGEQ
RROHOHRROHOH
Cell
BindingBinding
THE CENTRAL COMPONENT OF THE THE CENTRAL COMPONENT OF THE COMPLEMENT SYSTEM COMPLEMENT SYSTEM
Complement fixation-Complement fixation- Covalent binding of C3b to the pathogensrsquo surfaceCovalent binding of C3b to the pathogensrsquo surface
The alternative pathway
The alternative soluble C3 convertase
The alternative C3 convertase C3bBb
AMPLIFICATION OF THE COMPLEMENT CASCADE
inactive
precursorslimited
proteolysis
activating surfaceenzyme
Regulation of the complement system
Positive regulation
Negative regulation
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
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- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
THE CENTRAL COMPONENT OF THE THE CENTRAL COMPONENT OF THE COMPLEMENT SYSTEMCOMPLEMENT SYSTEM
C3C3CGEQCGEQ
One of the proteins present at the highest concentration in serum One of the proteins present at the highest concentration in serum 12mgml12mgml
CLEAVAGE SITE
((33 900900 000000 000000 000000 000 000 moleculesmoleculesmlml))
InflammationInflammation
C3aC3a C3bC3b
CGEQCGEQ
C3C3CGEQCGEQ RROHOH
BaBacctteriumerium
CGEQCGEQ
RROHOHRROO
RROHOH
RROO
CGEQCGEQ
RROHOHRROHOH
Cell
BindingBinding
THE CENTRAL COMPONENT OF THE THE CENTRAL COMPONENT OF THE COMPLEMENT SYSTEM COMPLEMENT SYSTEM
Complement fixation-Complement fixation- Covalent binding of C3b to the pathogensrsquo surfaceCovalent binding of C3b to the pathogensrsquo surface
The alternative pathway
The alternative soluble C3 convertase
The alternative C3 convertase C3bBb
AMPLIFICATION OF THE COMPLEMENT CASCADE
inactive
precursorslimited
proteolysis
activating surfaceenzyme
Regulation of the complement system
Positive regulation
Negative regulation
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 19
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
InflammationInflammation
C3aC3a C3bC3b
CGEQCGEQ
C3C3CGEQCGEQ RROHOH
BaBacctteriumerium
CGEQCGEQ
RROHOHRROO
RROHOH
RROO
CGEQCGEQ
RROHOHRROHOH
Cell
BindingBinding
THE CENTRAL COMPONENT OF THE THE CENTRAL COMPONENT OF THE COMPLEMENT SYSTEM COMPLEMENT SYSTEM
Complement fixation-Complement fixation- Covalent binding of C3b to the pathogensrsquo surfaceCovalent binding of C3b to the pathogensrsquo surface
The alternative pathway
The alternative soluble C3 convertase
The alternative C3 convertase C3bBb
AMPLIFICATION OF THE COMPLEMENT CASCADE
inactive
precursorslimited
proteolysis
activating surfaceenzyme
Regulation of the complement system
Positive regulation
Negative regulation
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
THE CENTRAL COMPONENT OF THE THE CENTRAL COMPONENT OF THE COMPLEMENT SYSTEM COMPLEMENT SYSTEM
Complement fixation-Complement fixation- Covalent binding of C3b to the pathogensrsquo surfaceCovalent binding of C3b to the pathogensrsquo surface
The alternative pathway
The alternative soluble C3 convertase
The alternative C3 convertase C3bBb
AMPLIFICATION OF THE COMPLEMENT CASCADE
inactive
precursorslimited
proteolysis
activating surfaceenzyme
Regulation of the complement system
Positive regulation
Negative regulation
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 23
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- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
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- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Complement fixation-Complement fixation- Covalent binding of C3b to the pathogensrsquo surfaceCovalent binding of C3b to the pathogensrsquo surface
The alternative pathway
The alternative soluble C3 convertase
The alternative C3 convertase C3bBb
AMPLIFICATION OF THE COMPLEMENT CASCADE
inactive
precursorslimited
proteolysis
activating surfaceenzyme
Regulation of the complement system
Positive regulation
Negative regulation
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
The alternative pathway
The alternative soluble C3 convertase
The alternative C3 convertase C3bBb
AMPLIFICATION OF THE COMPLEMENT CASCADE
inactive
precursorslimited
proteolysis
activating surfaceenzyme
Regulation of the complement system
Positive regulation
Negative regulation
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
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- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
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- Slide 45
- Slide 46
- Slide 47
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- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
The alternative C3 convertase C3bBb
AMPLIFICATION OF THE COMPLEMENT CASCADE
inactive
precursorslimited
proteolysis
activating surfaceenzyme
Regulation of the complement system
Positive regulation
Negative regulation
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
AMPLIFICATION OF THE COMPLEMENT CASCADE
inactive
precursorslimited
proteolysis
activating surfaceenzyme
Regulation of the complement system
Positive regulation
Negative regulation
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
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- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Regulation of the complement system
Positive regulation
Negative regulation
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Negative regulatory proteins on human cells protecting them from
complement-mediated attack
MCP binds to sialic acid on the surface of human cells and prevents
the complement activation
DAF and MCP
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
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- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectoseNeuraminNeuraminic acidic acid ((SSialic acid)ialic acid)
ProkarProkariotic cellsiotic cells
SSialic acidialic acid
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
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- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
The classical pathway
Collagen bdquolegsrdquo
Gobular bdquoheadsrdquo
THE C1 COMPLEXTHE C1 COMPLEX
C1qR binding by PhagocytesCleavage of C4 and C2 components
Binding the Fc part of an antibody
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
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- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Immunoglobulin Fragments StructureFunction Relationships
antigen binding
complement binding site
placental transfer
binding to Fc receptors
C1 component lsquoheadsrsquo
Association between native and adaptive immunityOnly the antigen-linked antibodies are able to associate to complement
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
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- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
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- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Low affinity binding to the C-terminal of an antibody
Multiple interactions with immune complexes
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
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- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
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- Slide 43
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- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
The classical C3 convertase C4bC2a
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
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- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
CRP binds to phosphocholine component of the lipopolisaccharides in bacterial and fungal cell wall but not to phosphocholine component
of phospholipids on human cell membranes
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES C-reactive protein
CRP levels can increase up to 1000-fold during an acute-phase response
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
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- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
One of the major function of C1 INHIBITORC1q binds to IgM on
bacterial surfaceC1q binds to at least two IgG
molecules on bacterial surface
Binding of C1q to Ig activates C1r which cleaves and activates the serine protease C1s
C1INH dissociates C1r and C1s from the active C1 complex
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
The Mannose-binding Lectin pathway
bull Binds Mannose-containing carbohydrates of bacteria fungi protozoans and viruses
bull Similar to C1q protein in triggering a complement cascade
bull MASP-1 and 2 have common gene ancestors with C1r and C1s
bull A member of the Collectin family
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
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- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
EEukariotic cellsukariotic cells
GluGluccooseseaminamineeMannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid(sialic acid)(sialic acid)
MannoseMannose
ProkarProkariotic cellsiotic cells
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
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- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
ACUTE-PHASE RESPONSEINCREASES THE SUPPLY OF
INNATE IMMUNITY MOLECULES Mannose-binding lectin
MBL levels can increase up to 1000-fold during an acute-phase response
SP-A and SP-D belong to the collectin family as well opsonyzing
pathogens in the lung
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Local inflammatory responses can be induced by the small complement fragments C3a C4a and especially C5a
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
BBaacctterieriumum
ccomplementomplement r reecceptorseptors
mmaaccrorophagephage
Opsonization
C3b
ExCR1 CR3 CR4
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Membrane attack complex (MAC)
C3bBbC3b = alternative C5 convertase
Or
C4bC2aC3 = classical C5 convertase
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
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- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
The membrane-attack complex assembles to generate a pore in the lipid bilayer membrane
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
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- Slide 45
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- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
MAC in the cell membrane
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
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- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
CD59 prevents assembly of terminal complement components into a membrane pore
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
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- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
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- Slide 40
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Diseases caused by deficiencies in the complement pathways
Complement protein
Effects of deficiency
C1 C2 C4 Immune-complex diseases
C3 Susceptibility to a wide range of pyogenic infections
C5-C9 Susceptibility to Neisseria
Factor D Properdin Susceptibility to capsulated bacteria and Neisseria but no Immune-complex disease
Factor I Similar to C3 deficiency
DAF CD59 Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria (PNH)
C1INH Hereditery angioneurotic edema (HANE)
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Immune complex diseases
Early components of the classical pathway (C1-C4) are necessary for the elimination of immune complexes Attachment of the complement
components to the soluble immune complexes allows them to be transported or ingested and degraded by CR-bearing cells
Deficiencies in these components lead to the accumulation of immune complexes in the blood lymph and extracellular fluid and their
deposition in tissues Damage is caused by the deposition itself and by the activation of phagocytes causing inflammation
These may include Pyogenic infections Systemic Lupus Erythematosus
Vasculitis Glomerulonephritis
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acqired clonal mutation of PIG-A gene no GPI enchor proteins on RBCs No expression of the complement regulatory proteins CD59 and DAF on these RBCs episodes of complement-mediated RBCs lysis hemolytic anemia
Symptoms include Anemia (tiredness shortness of breath palpitations)Hemoglobin in the urine40 develope thrombosis
Therapy include Anti-C5-Mab transfusion immunosuppression and BM transplantation
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Hereditary Angioneuretic Adema (HANE)
Deficiency in C1INH complement regulatory protein The C1INH is a serine protease inhibitor that regulates the C1 complex and complement activation as well as inhibiting proteins in the coagulation cascade
Symptoms include swellings of skin gut and respiratory tracts serious acute abdomenal pain vomiting
Therapy include C1INH from donor blood Androgens and other bradykinin inactivators
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Supplementary materials
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
C1Inh C1-inhibitor (serine-protease inhibitor can affect in many steps)
Factor H inhibits C3-convertase of alternative pathway co-factor of
factor I cleaves C4b and C3b
Properdin stabilizes convertases of alternative pathway
DAF Decay Accelerating Factor
MCP Membrane Cofactor Protein
CD59 inhibits the linking of C9 and C8
Major regulating factors of complement system
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 16
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- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
DAFC1Inh
Properdin
positive feedback
Factor I
CR1 MCPC4bp
C-peptase N
Factor I
Fact-H CR1 MCPDAF
CD59
HRF
S-protein
-2macrogl
LECTIN PATHWAY
Regulation of complement system
membrane protein
soluble molecule
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Complement receptors
Name Ligand ExpressionCR1 CD35
C3bgtC4b iC3b RBC MoMOslash Gr B
Act-T FDC
CR2CD21 CD21L
C3d C3dg iC3b
EBV IFN CD23
B activated T FDC
CR3CD11bCD18
iC3bgt C3dg C3d
ICAM-1 LPS fibrinogen
MoMOslash Gr NK
CR4CD11cCD18
iC3b C3dg C3d
Fibriogen
MoMOslash Gr NK
C3aR C3a M B Gr MoMOslash Trombocites simaizom Neur
C5aR C5a des-Arg-C5a M B MoMOslash Trombocytes SMC Neur
C1qR C1q collagen part B NGr MoMOslash endothel
C1qRp C1q Phagocytes
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Slide 23
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- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
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- Slide 41
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Antigen-antibodycomplex
Mannose Pathogen surface
C1q C1r C1s
Serin protease
C4 C2
MBLMASP-1MASP-2
Serin proteaseC4 C2
C3
B D
COMPLEMENT SYSTEM
CLASSICAL PATHWAY MB-LECTIN PATHWAY ALTERNATIVE PATHWAY
C3 CONVERTASEC4a
C3a C5a
Inflammatory peptid mediators
Phagocyte recruitment
C3b
OpsonizationBinding to phagocyte CRImmune complex removal
Terminal C5b ndash C9
MACPathogencell
lysis
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Deficiencies of complement system ndash cascade molecules
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Deficiencies of complement system ndash regulatory molecules receptors
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Hereditary angioneurotic edema (HANE)(hereditary C1INH defect)
bull 17-year old boy - severe abdominal pain (frequent sharp spasms vomiting)
bull appendectomia normal appendix
bull similar symptoms occured repeatedly earlier in his life with watery diarrhea
bull family history of prior illness
bull immunologistrsquos suspicion hereditary angioneurotic edema
bull level of C1INH 16 of the normal mean
bull daily doses of Winstrol (stanozolol) ndash marked diminution in the frequency and
severity of symptoms
bull purified C1INH intravenously became avaible by the time
Main symptomsbull swellings of skin guts respiratory tractsbull serious acute abdomenal pain vomiting bull larynx swelling ndash may cause death
Treatment bull iv C1INHbull kallikrein and bradykinin receptor antagonists
Child with symptomes of HANE
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Complement receptors
- Slide 32
- Membrane attack complex (MAC)
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Slide 43
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
-
Pathogenesis of hereditary angioneurotic edema
bull bradykinin and C2-kinin
enhance the permeability of
postcapillar venules
by contraction of endothel
bull holes in the venule walls
bull edema formation
bull C1 is always active without
activating surface because
plasmine is always active
Inhibition by C1INH in many stepsactivation of XII factor
activation of kallikrein
activation ofproactivator
cleveage of kininogento generate bradykinin
vasoactive peptide
activation of C1
cleveage of plasminogen
to generate plasmin
cleveage of C2 to generate C2a
cleveage of C2a to generate C2-kinin
vasoactivepeptide
Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
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- Complement receptors
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- Membrane attack complex (MAC)
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- Paroxysmal nocturnal hemoglobinuria (PNH)
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Questions hereditary angioneurotic edema
1 Activation of complement system results in the release of histamine and chemokines which normally produce pain heat and itching Why is the edema fluid in HANE free of cellular components and why does the swelling not itch
- In HANE C4b and C2b both generated free in plasma because plasmine always actives the C1- There are not an activating surface so C4b are not able to bind to a surface so it is rapidly inactivated The concentration of C4b and C2b are relatively low no C3C5 convertase is formed C3 and C5 are not cleaved and C3a and C5a are not generated After the complement activation histamine do not release which is caused by C3a Without C5a there is no cell recruitmentBUT there are C2a-kinin and bradykinin which cause edema
2 Which complement component levels will be decreased Why
C2 and C4 because of the continous cleavage by activated C1
4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
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- Complement receptors
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- Membrane attack complex (MAC)
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
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4 What about the levels of the terminal components
The unregulated activation of the early components does not lead to the formation
of the C3C5 convertase so the terminal components are not abnormally activated
5 Despite the complement deficiency in patients with HANE they are not
unduly susceptible to infection Why not
The alternative pathway of complement activation is intact and these are
compensated for by the potent amplification step from the alternative pathway
6 How might you decide the background of the laryngeal edema
(HANO or anaphylactic reaction)
If the laryngeal edema is anaphylactic it will respond to epinephrine
If it is due to HANO it will not C1INH needed
Questionshereditary angioneurotic edema
3 Would you expect the alternative pathway components to be low normal or elevated
C1 plays no part in the alternative pathway This pathway is not affected
bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Complement receptors
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- Membrane attack complex (MAC)
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
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bull Acqired clonal mutation of PIG-A gene ndash no GPI-enchored proteins in the the cell membrane
bull CD59 (upper pic) and CD55 complement regulatory proteins
bull No CD59 andor CD55 PNH patients are highly susceptible to complement-mediated lysis (lower pics)
bull Eleveted levels of TF derived from complement-damaged leukocytes
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
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- Complement receptors
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- Membrane attack complex (MAC)
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
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Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
bull Haemolytic anaemia and associated symptoms
bull Haemoglobin and its products in the urine
bull Thrombosis in brain veins mesentheric veins vv hepaticae (Budd-Chiari-syndrome)
bull transformation to acut myelogenous leukemia (AML) aplastic anaemia myelodisplastic syndrome (MDS)
bull Specific th eculizumab (Soliris - anti-C5 monoclonal antibody)
bull Curative th bone marrow transplantation
bull Alternative th steroids (general immunosuppression)
bull Anticoagulants sc heparin po kumarin
bull Iron replacement
bull Transfusion (filtered-irradiated blood)
- PowerPoint Presentation
- Slide 2
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- Complement receptors
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- Membrane attack complex (MAC)
- Slide 34
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- Paroxysmal nocturnal hemoglobinuria (PNH)
- Paroxysmal nocturnal hemoglobinuria (PNH) symptoms and therapy
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