complement and complement deficiency

COMPLEMENT AND COMPLEMENT DEFICIENCY

Boonthorn

4 September 2009

OUTLINE Complement pathway activation

Classical pathway Alternative pathway Lectin activation pathway Membrane attack complex

Complement receptors and biological functions

Regulation of complement activation Disorders associated with complement

deficiency Management of complement deficiencies

COMPLEMENT SYSTEM

Important part of innate immune system Major effector mechanism of humoral immunity Named by Jules Bordet ( 1919 , Nobel Prize ) Group of serum protein ( normally

inactive ) ,activated through sequential protease- based step (under particular condition )

Complement activator, Complement regulatory protein and Complement receptor

FUNCTIONS OF COMPLEMENT. THE MAJOR FUNCTIONS OF THE COMPLEMENT SYSTEM IN HOST DEFENSE ARE SHOWN. CELL-BOUND C3B IS AN OPSONIN THAT PROMOTES PHAGOCYTOSIS OF COATED CELLS (A); THE PROTEOLYTIC PRODUCTS C5A, C3A, AND (TO A LESSER EXTENT) C4A STIMULATE LEUKOCYTE RECRUITMENT AND INFLAMMATION (B); AND THE MAC LYSES CELLS (C).

PATHWAYS OF COMPLEMENT ACTIVATION

3 major pathways of complement activation classical pathway : activated by Ab bound to Ag alternative pathway : activated on microbial cell

surfaces in the absence of antibody lectin pathway : activated by plasma lectin that

binds to mannose residues on microbes central event in complement activation is

proteolysis of C3 to generate biologically active products and subsequent covalent attachment of C3b to microbial cell surfaces or to Ab bound to Ag

Abbas et.al.Cellular&Molecular immunology 6th edition

OVERVIEW OF THE COMPLEMENT PATHWAYS INDICATING COMPONENTS REQUIRED FOR RECOGNITION, ENZYMATICALLY ACTIVE COMPONENTS AND COMPLEXES, MAJOR OPSONIC, INFLAMMATORY AND MEMBRANOLYTIC

PRODUCTS.

Rich et al.Clinical immunology principle and practice. third edition.

THE EARLY STEPS OF COMPLEMENT ACTIVATION BY THE ALTERNATIVE AND CLASSICAL PATHWAYS. THE ALTERNATIVE PATHWAY IS ACTIVATED BY C3B BINDING TO VARIOUS ACTIVATING SURFACES, SUCH AS MICROBIAL CELL WALLS, THE CLASSICAL PATHWAY IS INITIATED BY C1 BINDING TO ANTIGEN-ANTIBODY COMPLEXES, AND THE LECTIN PATHWAY IS ACTIVATED BY BINDING OF A PLASMA LECTIN TO MICROBES. THE C3B THAT IS GENERATED BY THE ACTION OF THE C3 CONVERTASE BINDS TO THE MICROBIAL CELL SURFACE OR THE ANTIBODY AND BECOMES A COMPONENT OF THE ENZYME THAT CLEAVES C5 (C5 CONVERTASE) AND INITIATES THE LATE STEPS OF COMPLEMENT ACTIVATION. THE LATE STEPS OF ALL THREE PATHWAYS ARE THE SAME (NOT SHOWN HERE), AND COMPLEMENT ACTIVATED BY ALL THREE PATHWAYS SERVES THE SAME FUNCTIONS

ALTERNATIVE PATHWAY

Activation : proteolysis of C3 C3 tickover C3b , binding site for factor B covalently tethered

to surface of microbial or host cell Bound factor B cleaved by factor D (serine

protease) C3 convertase : C3bBb Properdin bind to and stabilize C3bBb complex C5 convertase : C3bBb3b


INTERNAL THIOESTER BONDS OF C3 MOLECULES. A SCHEMATIC VIEW OF THE INTERNAL THIOESTER GROUPS IN C3 AND THEIR ROLE IN FORMING COVALENT BONDS WITH OTHER MOLECULES IS SHOWN. PROTEOLYTIC CLEAVAGE OF THE Α CHAIN OF C3 CONVERTS IT INTO A METASTABLE FORM IN WHICH THE INTERNAL THIOESTER BONDS ARE EXPOSED AND SUSCEPTIBLE TO NUCLEOPHILIC ATTACK BY OXYGEN (AS SHOWN) OR NITROGEN ATOMS. THE RESULT IS THE FORMATION OF COVALENT BONDS WITH PROTEINS OR CARBOHYDRATES ON THE CELL SURFACES. C4 IS STRUCTURALLY HOMOLOGOUS TO C3 AND HAS AN IDENTICAL THIOESTER GROUP.

THE ALTERNATIVE PATHWAY OF COMPLEMENT ACTIVATION. SOLUBLE C3 IN PLASMA UNDERGOES SLOW SPONTANEOUS HYDROLYSIS OF ITS INTERNAL THIOESTER BOND, WHICH LEADS TO THE FORMATION OF A FLUID-PHASE C3 CONVERTASE (NOT SHOWN) AND THE GENERATION OF C3B. IF THE C3B IS DEPOSITED ON THE SURFACES OF MICROBES, IT BINDS FACTOR B AND FORMS THE ALTERNATIVE PATHWAY C3 CONVERTASE. THIS CONVERTASE CLEAVES C3 TO PRODUCE MORE C3B, WHICH BINDS TO THE MICROBIAL SURFACE AND PARTICIPATES IN THE FORMATION OF A C5 CONVERTASE. THE C5 CONVERTASE CLEAVES C5 TO GENERATE C5B, THE INITIATING EVENT IN THE LATE STEPS OF COMPLEMENT ACTIVATION

CLASSICAL PATHWAY

Activate :IgM>IgG3>IgG1>IgG2>>IgG4 C1 : large, multimeric, protein complex

C1q binding site in Cμ3 (IgM),Cγ2 (IgG) domain through its globular head group

C1r, C1s subunits are proteases Activated C1s cleaves C4, to generate C4b C2, complexes with C4b and cleaved by C1s to

generate soluble C2a and larger C2b fragment C3 convertase : C4b2b C5 convertase : C4b2b3b C5a : potent inflammatory activity C5b initiate formation of MAC


STRUCTURE OF C1. C1Q CONSISTS OF SIX IDENTICAL SUBUNITS ARRANGED TO FORM A CENTRAL CORE AND SYMMETRICALLY PROJECTING RADIAL ARMS. THE GLOBULAR HEADS AT THE END OF EACH ARM, DESIGNATED H, ARE THE CONTACT REGIONS FOR IMMUNOGLOBULIN. C1R AND C1S FORM A TETRAMER COMPOSED OF TWO C1R AND TWO C1S MOLECULES. THE ENDS OF C1R AND C1S CONTAIN THE CATALYTIC DOMAINS OF THESE PROTEINS. ONE C1R2S2 TETRAMER WRAPS AROUND THE RADIAL ARMS OF THE C1Q COMPLEX IN A MANNER THAT JUXTAPOSES THE CATALYTIC DOMAINS OF C1R AND C1S.

C1 BINDING TO THE FC PORTIONS OF IGM AND IGG. C1 MUST BIND TO TWO OR MORE FC PORTIONS TO INITIATE THE COMPLEMENT CASCADE. THE FC PORTIONS OF SOLUBLE PENTAMERIC IGM ARE NOT ACCESSIBLE TO C1 (A). AFTER IGM BINDS TO SURFACE-BOUND ANTIGENS, IT UNDERGOES A SHAPE CHANGE THAT PERMITS C1 BINDING AND ACTIVATION (B). SOLUBLE IGG MOLECULES WILL ALSO NOT ACTIVATE C1 BECAUSE EACH IGG HAS ONLY ONE FC REGION (C), BUT AFTER BINDING TO CELL SURFACE ANTIGENS, ADJACENT IGG FC PORTIONS CAN BIND AND ACTIVATE C1 (D).

THE CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION. ANTIGEN-ANTIBODY COMPLEXES THAT ACTIVATE THE CLASSICAL PATHWAY MAY BE SOLUBLE, FIXED ON THE SURFACE OF CELLS (AS SHOWN), OR DEPOSITED ON EXTRACELLULAR MATRICES. THE CLASSICAL PATHWAY IS INITIATED BY THE BINDING OF C1 TO ANTIGEN-COMPLEXED ANTIBODY MOLECULES, WHICH LEADS TO THE PRODUCTION OF C3 AND C5 CONVERTASES ATTACHED TO THE SURFACES WHERE THE ANTIBODY WAS DEPOSITED. THE C5 CONVERTASE CLEAVES C5 TO BEGIN THE LATE STEPS OF COMPLEMENT ACTIVATION.

LECTIN PATHWAY

Activation : D-mannose,GlcNAc ( microbial polysaccharides )

Binding to circulating lectins, eg. Mannose -binding lectin (MBL), or to N-acetylglucosamine recognizing lectins (ficolins ) collectin family and structurally resemble C1q

MASPs eg. MASP-1, 2, and 3 (tetrameric complex similar to C1r and C1s )

MASP-1 cleave C3 MASP-2 cleave C4 and C2 C3 convertase : MASP-1 C5 convertase : C4b2b3b Abbas et.al.Cellular&Molecular immunology 6th edition

ACTIVATION OF THE LECTIN PATHWAY. THE LECTIN ACTIVATION PATHWAY IS ENGAGED BY PATHOGEN OLIGOSACCHARIDES (BLACK DIAMONDS ) AND LEADS TO A C3 CONVERTASE WHICH IS IDENTICAL TO THAT OF THE CLASSICAL PATHWAY. MBL SERVES AS THE RECOGNITION DOMAIN OF THE COMPLEX ,WHILE MASP1 AND MASP ARE SIMILAR IN FUNCTION TO C1R AND C1S

Middleton’s allergy:principles and practice. 7th edition.

MEMBRANE ATTACK COMPLEX

Cleavage of C5 into C5a and C5b. C5 (structurally homologous to C3 and C4, lacks

internal thioester bond ) C5b initiates formation of MAC (complex of C5b,

C6, C7, C8 and multiple C9 molecules ) binds to C6, and C7 , recruits C8 and complex penetrates more deeply into the membrane.

C9, a pore-forming molecule with homology to perforin. The complex of C5b678 forms a nidus for C9 binding and polymerization

Penetrates membrane bilayers to form pores Disrupt the osmotic barrier, leading to swelling

and lysis of susceptible cellsAbbas et.al.Cellular&Molecular immunology 6th edition

LATE STEPS OF COMPLEMENT ACTIVATION AND FORMATION OF THE MAC. CELL-ASSOCIATED C5 CONVERTASE CLEAVES C5 AND GENERATES C5B, WHICH BECOMES BOUND TO THE CONVERTASE. C6 AND C7 BIND SEQUENTIALLY, AND THE C5B,6,7 COMPLEX BECOMES DIRECTLY INSERTED INTO THE LIPID BILAYER OF THE PLASMA MEMBRANE, FOLLOWED BY STABLE INSERTION OF C8. UP TO 15 C9 MOLECULES MAY THEN POLYMERIZE AROUND THE COMPLEX TO FORM THE MAC, WHICH CREATES PORES IN THE MEMBRANE AND INDUCES CELL LYSIS. C5A RELEASED ON PROTEOLYSIS OF C5 STIMULATES INFLAMMATION.

A. COMPLEMENT LESIONS IN ERYTHROCYTE MEMBRANES ARE SHOWN IN THIS ELECTRON MICROGRAPH. THE LESIONS CONSIST OF HOLES APPROXIMATELY 100 Å IN DIAMETER THAT ARE FORMED BY POLY-C9 TUBULAR COMPLEXES. B. FOR COMPARISON, MEMBRANE LESIONS INDUCED ON A TARGET CELL BY A CLONED CTL LINE ARE SHOWN IN THIS ELECTRON MICROGRAPH. THE LESIONS APPEAR MORPHOLOGICALLY SIMILAR TO COMPLEMENT-MEDIATED LESIONS, EXCEPT FOR A LARGER INTERNAL DIAMETER (160 Å). CTL- AND NK CELL-INDUCED MEMBRANE LESIONS ARE FORMED BY TUBULAR COMPLEXES OF A POLYMERIZED PROTEIN (PERFORIN), WHICH IS HOMOLOGOUS TO C9 C. A MODEL OF THE SUBUNIT ARRANGEMENT OF THE MAC IS SHOWN. THE TRANSMEMBRANE REGION CONSISTS OF 12 TO 15 C9 MOLECULES ARRANGED AS A TUBULE, IN ADDITION TO SINGLE MOLECULES OF C6, C7, AND C8 Α AND Γ CHAINS. THE C5BΑ, C5Bẞ, AND C8ẞ CHAINS FORM AN APPENDAGE THAT PROJECTS ABOVE THE TRANSMEMBRANE PORE.

Structure of the MAC in cell membranes

RECEPTORS FOR COMPLEMENT PROTEINS

CR1 or CD35 : On erythrocyte,neutrophil,monocyte,eosinophil,T and B

cell Bind C3b,C4b and promote phagocytosis Opsonization ,activate phagocyte when Fc receptor

engaged by Ab coated particle clearance of immune complexes from circulation Regulator of complement activation

CR2 or CD21 : On B lymphocyte, FDC Bind C3d,C3dg and iC3b enhancing B cell activation ( CR2,CD19,TAPA-1 orCD81) promote trapping of Ag-Ab complexes in germinal centers

(FDC) Receptor for EBV virus


RECEPTORS FOR COMPLEMENT PROTEINS

CR3, CD11bCD18 or Mac-1 : On neutrophil,mononuclear phagocyte,mast cell,

NK cell Bind iC3b promote phagocyotsis,ICAM-1 promote

attachment to endothelium CR4, p150/95, CD11cCD18 :

on dendritic cells binds iC3b function probably similar to Mac-1


RECEPTORS FOR COMPLEMENT PROTEINS The complement receptor of the

immunoglobulin family (CRIg) on macrophages ( Kupffer cells ) integral membrane protein bind C3b and iC3b clearance of opsonized bacteria and other blood-

borne pathogens SIGN-R1

C-type lectin on marginal zone macrophage recognizes pneumococcal polysaccharides bind C1q, activation of classical complement

pathway in an antibody-independent manner opsonization and clearance of pneumococci


REGULATION OF COMPLEMENT ACTIVATION

C1 inhibitor Regulators of the C3 and C5 convertases

Factor I Soluble regulatory proteins; C4b-binding protein

and factor H Membrane regulatory proteins, CD55 (DAF),

CD46 (MCP), CD35 (CR1) Properdin

Regulators of the MAC Soluble MAC inhibitors; S protein, and clusterin Membrane MAC inhibitor; CD59


C1 INHIBITOR

C1 inhibitor (C1-INH) serine proteinase inhibitor (serpin) , SERPING1 binds to activated C1r and C1s, limit classical

pathway activation. inhibits MASP-1 and 2, kallikrein, factor XIa, XIIa

and plasmin of the lectin pathway and the contact, coagulation, and fibrinolytic systems.

( Autosimal dominant ) inherited deficiency of C1-INH is basis of hereditary angioedema , plasma level of C1 inh<20-30% of normal


SERPIN INHIBITORY MECHANISM. ACTIVE SERPIN (PINK) IS CHARACTERIZED BY A 5-STRANDED B-SHEET (B-SHEET A, CYAN) AND AN EXPOSED REACTIVE CENTRE LOOP (RCL, GREEN)PRESENTING THE P1 RESIDUE TO THE ACTIVE SITE OF THE TARGET PROTEASE (GOLD)(A). THE INITIAL STEP IS THE BINDING OF FREE PROTEASE AND ACTIVE SERPIN RCL (B). SUBSEQUENTLY, THE PROTEASE CLEAVES THE RCL. RCL CLEAVAGE TRIGGERS A PROFOUND CONFORMATIONAL CHANGE WITHIN THE SERPIN MOLECULE: THE RCL DOWNSTREAM OF THE SCISSILE BOND INSERTS BETWEENSTRANDS 3 AND 5 OF B-SHEET A AS STRAND 4, WHILE THE PROTEASE IS TRANSLOCATED TO THE OPPOSITE POLE OF THE INHIBITOR MOLECULE AND DEFORMED, RESULTING IN ENZYME INHIBITION BY ACTIVE-SITE DISTORTION (C).THEREFORE, PROTEASE-SERPIN ACYL-ENZYME COMPLEX FORMATION CAN BE VIEWED GENERALLY AS BIOLOGICALLY IRREVERSIBLE.

Trends in Molecular Medicine Vol.15 No.2

REGULATION OF C1 ACTIVITY BY C1 INH. C1 INH DISPLACES C1R2S2 FROM C1Q AND TERMINATES CLASSICAL PATHWAY ACTIVATION

REGULATORS OF THE C3 AND C5 CONVERTASES

C3b bound by membrane cofactor protein ( MCP ,CD46), CR1, decay-accelerating factor (DAF), factor H

C4b bound by DAF, CR1, C4-binding protein (C4BP)

competitively inhibit binding of other components of C3 convertase, eg. Bb (alternative pathway ) and C2b ( classical pathway ) , blocking further progression of the complement cascade

Factor H inhibits binding of only Bb to C3b Abbas et.al.Cellular&Molecular immunology 6th edition

THE REGULATION OF THE CLASSICAL PATHWAY. THE CLASSICAL ACTIVATION PATHWAY IS SHOWN WITH THE RELEVANT REGULATORY PROTEINS SHOWN IN THE GRAY HEXAGONS. C4 BP DENOTES C4 BINDING PROTEIN


THE REGULATION OF THE ALTERNATIVE PATHWAY. THE ALTERNATIVE ACTIVATION PATHWAY IS SHOWN WITH THE RELEVANT REGULATORY PROTEINS SHOWN IN GRAY HEXAGONS. C3BBB IS STABILIZED BY PROPERDIN.


INHIBITION OF THE FORMATION OF C3 CONVERTASES. SEVERAL MEMBRANE PROTEINS PRESENT ON NORMAL CELLS DISPLACE EITHER C2B FROM THE CLASSICAL PATHWAY C3 CONVERTASE (A) OR BB FROM THE ALTERNATIVE PATHWAY C3 CONVERTASE (B) AND STOP COMPLEMENT ACTIVATION.

REGULATORS OF THE C3 AND C5 CONVERTASES

DAF glycophosphatidylinositol-linked membrane protein on endothelial cells and erythrocytes. If deficiency , Causes paroxysmal nocturnal

hemoglobinuria. unusual feature , acquired mutation in defective

gene ,in hematopoietic stem cells. factor I

plasma serine protease degrade cell-associated C3b active only in presence of regulatory proteins MCP, factor H, C4BP, and CR1 serve as cofactors cause dissociation of C3b (and C4b)-containing

complexes Generates iC3b, C3d, and C3dg, recognized by

receptors on phagocytes and B lymphocytesAbbas et.al.Cellular&Molecular immunology 6th edition

FACTOR I-MEDIATED CLEAVAGE OF C3B. IN THE PRESENCE OF CELL MEMBRANE-BOUND COFACTORS (MCP OR CR1), PLASMA FACTOR I PROTEOLYTICALLY CLEAVES C3B ATTACHED TO CELL SURFACES, LEAVING AN INACTIVE FORM OF C3B (IC3B). FACTOR H AND C4-BINDING PROTEIN CAN ALSO SERVE AS COFACTORS FOR FACTOR I-MEDIATED CLEAVAGE OF C3B. THE SAME PROCESS IS INVOLVED IN THE PROTEOLYSIS OF C4.

REGULATION OF FORMATION OF THE MAC

CD59 Membrane protein inhibit formation of the MAC glycophosphatidylinositol-linked protein

expressed on many cell types. incorporate into assembling MACs after the

membrane insertion of C5b-8, thereby inhibiting the subsequent addition of C9 molecules

present on normal host cells, where it limits MAC formation, but it is not present on microbes

S protein binding to soluble C5b,6,7 complexes Prevent insertion into cell membranes near the

site where the complement cascade was initiated Abbas et.al.Cellular&Molecular immunology 6th edition

REGULATION OF FORMATION OF THE MAC. THE MAC IS FORMED ON CELL SURFACES AS AN END RESULT OF COMPLEMENT ACTIVATION. THE MEMBRANE PROTEIN CD59 AND S PROTEIN IN THE PLASMA INHIBIT FORMATION OF THE MAC.

COMPLEMENT DEFICIENCIES

Genetic deficiencies in classical pathway components

Deficiencies in components of the alternative pathway

Mutation of the gene encoding the mannose-binding lectin (MBL)

Deficiencies in the terminal complement components

Deficiencies in complement regulatory proteins

Deficiencies in complement receptorsAbbas et.al.Cellular&Molecular immunology 6th edition

GENETIC DEFICIENCIES IN CLASSICAL PATHWAY COMPONENTS

Deficiency Chromosomal location

Number of cases reported

Clinical features, diagnostic strategy

C1q 1p36.12 10–100 SLE, infections, CH50 near 0

C1r/s 12p13 10–100 SLE, infections, CH50 near 0

C4 6p21.3 10–100 SLE, infections, CH50 near 0

C2 6p21.3 Many SLE, infections, some asymptomatic, CH50 near 0

C3 19p13.3-13.2 10–100 Infections frequent and severe, glomerulonephritis, CH50 near 0



C1q deficiency Present with early onset SLE , anti-dsDNA less

common ,more severe disease , less steroid responsive

Strongest known genetic risk factor for lupus C4 deficiency

C4A deficiency , risk factor for SLE (less severity than sufficient complement) early onset SLE , anti-dsDNA less common ,

C4B deficiency, with invasive bacterial disease



C2 deficiency most common of the inherited classical

complement component deficiencies in Caucasians

most common cause of death : sepsis most common organisms :S. pneumoniae and H.

influenzae C3 deficiency

rarest of the four early component deficiencies most severe phenotype Membranoproliferative glomerulonephritis neutrophil dysfunction (abscesses), humoral

deficiencies (sinopulmonary disease), and complement deficiencies (sepsis, meningitis). Middleton’s allergy:principles and practice. 7th edition.

DEFICIENCIES IN COMPONENTS OF THE ALTERNATIVE PATHWAY




C3 19p13.3-13.2 10–100 Infections frequent and severe, glomerulonephritis, CH50 near 0

Factor D 19p13.3 <10 Neisseria, AH50 near 0

Factor B 6p21.3 <10 Neisseria, AH50 near 0

Properdin Xp11.3-11.23 >100 Neisseria, AH50 diminished


DEFICIENCIES IN COMPONENTS OF THE ALTERNATIVE PATHWAY

FACTOR B DEFICIENCY single case has been reported

( meningococcemia ) FACTOR D DEFICIENCY

Neisserial infections are the most common manifestation

PROPERDIN DEFICIENCY X-linked complement deficiency one of the more common complement

deficiencies and occurs largely in Caucasians one or more episodes of meningococcal disease high fatality rate in contrast to terminal

complement component deficienciesMiddleton’s allergy:principles and practice. 7th edition.

MUTATION OF THE GENE ENCODING THE MANNOSE-BINDING LECTIN (MBL)Deficiency Chromosomal

locationNumber of cases reported


MBL 10q11.2-21 Millions Most asymptomatic, infections, SLE, CH50 normal, MBL assay required


GUPTA et al.Indian J Med Res 127, May 2008, pp 431-440

MUTATION OF THE GENE ENCODING THE MANNOSE-BINDING LECTIN (MBL)

MBL DEFICIENCY therapy Plasma derived MBL is now being produced by

Co-operative Research Centre for Vaccine Technology (CRC-VT)

on phase I safety, tolerability and pharmacokinetics

MBL replacement therapy used in 3 situations. where MBL deficiency leads to increased

susceptibility of infection, increase resistance to that infection

In acute infection,may enhance the resolution of the disease

Used to alter the natural history of chronic disease

GUPTA et al.Indian J Med Res 127, May 2008, pp 431-440

DEFICIENCIES IN THE TERMINAL COMPLEMENT COMPONENTS




C5 9q33 10–100 Neisseria, CH50 near 0

C6 5p13 >100 Neisseria, CH50 near 0

C7 5p13 >100 Neisseria, CH50 near 0

C8 1p32, 9q34.3 >100 Neisseria, CH50 near 0

C9 Many Neisseria, CH50 diminished


DEFICIENCIES IN COMPLEMENT REGULATORY PROTEINS




Factor I 4q25 10–100 Neisseria, HUS, C3 may be diminished, many require mutation analysis

Factor H 1q32 10–100 Neisseria, HUS, C3 may be diminished, many require mutation analysis

MCP 1q32 <10 HUS, mutation analysis required

C1 inhibitor 11q12-13.1 Many Angioedema, C1 antigen and functional levels

CD59 11p13 <10 Paroxysmal nocturnal hemoglobinuria, flow cytometry


C1 INHIBITOR DEFICIENCY

Hereditary angioedema mildly increased susceptibility to infection increased risk of SLE Recurrent episodes of angioedema,

involvement of airway in absence of anaphylaxis, abdominal episodes, a positive family history, or angioedema arising after trauma

Type I deficiency ,most common (85%) of inherited cases

Type II deficiency normal production ,but dysfunctional protein Middleton’s allergy:principles and practice. 7th edition.

C1 INHIBITOR DEFICIENCY

main manifestations of C1 inhibitor deficiency are recurrent episodes of submucosal or subcutaneous edema

severity of episodes do not correlate with laboratory features

extremities, face, or genitalia are most often involved

The most feared type of angioedema is that involving the airway

angioedema typically progresses for 1–2 days and resolves in another 2–3 days. Common precipitants are illness, hormonal fluctuations, trauma, and stressMiddleton’s allergy:principles and practice. 7th edition.

Contact system

PATHOGENESIS OF ANGIOEDEMA DUE TO C1-INH DEFICIENCY. IN HAE, THE DEFICIENCY OF C1-INH IS DUE TO A MUTATION IN THE C1-INH GENE, WHICH IMPAIRS C1-INH SYNTHESIS OR FUNCTION. IN AAE, C1-INH DEFICIENCY IS DUE TO THE CLEAVAGE OF C1-INH BY AUTOANTIBODIES OR TO ITS CONSUMPTION BY NEOPLASTIC, MAINLY LYMPHOPROLIFERATIVE, TISSUE. REDUCED C1-INH PLASMA LEVELS RESULT IN HYPERACTIVATION OF THE CLASSICAL COMPLEMENT PATHWAY WITH INCREASED CONSUMPTION OF C1-INH AND FURTHER REDUCTION OF ITS PLASMA LEVEL. IMPAIRED INHIBITION OF ACTIVATED FACTOR XII (FXIIA) AND KALLIKREIN, AS A RESULT OF A LACK OF THEIR PRINCIPAL INHIBITOR C1-INH, ENABLES CLEAVAGE OF HIGH MOLECULAR WEIGHT KININOGEN (HK) BY KALLIKREIN AND RELEASE OF BRADYKININ, WHICH BINDS TO ITS B2 RECEPTORS, CAUSING EDEMA

Tissue permeabilityvasodilatation

ACQUIRED C1 INHIBITOR DEFICIENCY

clinically indistinguishable from inherited that the age of onset is after 30 years The laboratory features are similar to those

of hereditary C1 inhibitor deficiency except that C1q levels are diminished in these patients

B cell malignancies and monoclonal gammopathies are the most common


Trends in Molecular Medicine Vol.15 No.2

CD59 DEFICIENCY AND PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

PNH : recurrent episodes of hemoglobinuria due to

intravascular hemolysis Thrombosis occurs for unknown reasons aplastic anemia due to acquired somatic mutations of PIG-A or

PIG-M in a clone of bone marrow progenitor cells These protein products are required for GPI-

anchored proteins and C8-binding protein, DAF and CD59 are all GPI-anchored proteins which protect hematopoietic cells from complement-mediated lysis

DAF deficiency does not have a hemolytic phenotype

CD59 is more important Middleton’s allergy:principles and practice. 7th edition.

DEFICIENCIES IN COMPLEMENT RECEPTORS




CR3/CR4 16p11.2 >100 Leukocyte adhesion deficiency, very severe systemic infections, lack of pus, flow cytometry


CR3/CR4 DEFICIENCY

β2-integrin deficiency is leukocyte adhesion deficiency type I (LAD type I)

Mutations in the common chain (CD18) LAD type I is very serious disorder with high

mortality rate Very high resting wbc counts, frequent

necrotic skin infections without pus formation, delayed separation of umbilical cord, and assorted other serious bacterial and fungal infections

bone marrow transplantation is recommended ( severe case )


CONCLUSION

Middleton’s allergy:principles and practice. 7th edition

J ALLERGY CLIN IMMUNOL . APRIL 2004

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complement and complement deficiency

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