complement. complement pathways: classical pathway alternative pathway lectin pathway
TRANSCRIPT
Complement Complement
Complement pathways:
Classical pathway Alternative pathway Lectin pathway
Complement proteinsClassical pathway C1q C1r C1s C4 C2Alternative pathway D C3 BLectin pathway MBL MASP-1 MASP-2Membrane attack complex(MAC) C5 C6 C7 C8 C9Membrane regulatory proteins CD55 CD46 CD59
Soluble regulatory proteins Positive regulation Properdin Negative regulation C1-INH C4-bp Factor H Factor I Carboxypeptidase S protein ClusterinReceptors CR1 CR2 CR3 CR4 C1qR C5aR C3aR
Comparison of the classical and alternative complement pathways
Antigen/antibodyComplexes(adaptive) C3
microorganisms
Classical pathway Alternative pathway(innate)
C3bC3a
C5-C9Terminal sequences
plays a central role in complement activation
C3
Classical C3 convertases C1q/C1r/C1s C5 convertasesC4 C4b+C2 C4b2a C4a C4b2a3b C3 C3a C5 C5bLectin C3bBbC3b C5a C6MBP/MASP-1 C5b6/MASP2 C7 C3a C3bBbP C5b67 C3 C3b P,B,D C8C3(H2O)+B C3(H2O)Bb C5b678 D C9Alternative Ba C5b6789
Complement pathway
Complement pathway activators
Classical pathway IgM-containing immune complexes IgG-containing immune complexes Mannose-binding lectin(MBL) C-reactive protein(CRP) Serum amyloid P(SAP) Myocardial damage products Membranes of apoptotic cells C4 nephritic factor (C4Nef) Myelin
Alternative pathway Tickover Amplification from classical pathway C3b fixation Repeating polysaccharides Endotoxin Virally infected cells(measles,influenza,Epstein-Barr virus) IgA-containing immune complexes Some Ig light Chains C3 nephritic factor(C3Nef) Cobra venom factor(CVF) Zymosan(yeast cell wall)
Lectin pathway Repeating simple sugars
Complement-fixing potential of antibodies
Classical pathway:
IgM>IgG3>IgG1>IgG2>>IgG4
IgA can activate the alternative pathway
IgE will activate complement only in unusual circumstances
Structural and functional homologs in activation
pathways
C2 and factor BC1q and mannose-binding lectin(MBL)C1r/C1s and MASP-1/MASP-2C3/C4/C5C6/C7/C8/C9
Complement regulatory proteins
and primary locations
Fluid phaseC1-INHFactor IFactor HC4b-binding protein (C4-bp)S protein(vitronectin)SP-40,40(clusterin)Carboxypeptidase
Cell membraneDecay-accelerating factor(DAF,CD55)Membrane cofactor protein(MCP,CD46)CD59Membrane C3-proteinasesMatrixDecorin
Complement pathway regulatory mechanisms and examples of
each
Protease inhibitors
C1r:C1-INHC1s:C1INH
Complement pathway regulatory mechanisms and examples of
eachProteases
C4aC3a Carboxypeptidase InactivatedC5a
Complement pathway regulatory mechanisms and examples of
eachDecay-acceleration DAF,C4-bp,CR1 C2aC4b2a C4b
DAF,H,CR1 BbC3bBb C3b
Complement pathway regulatory mechanisms and examples of
eachCofactor activity Factor IC3b C3bi MCP,H,CR1
FactorIC4b C4bi MCP,C4-bp,CR1
Complement pathway regulatory mechanisms and examples of
eachInhibition of assembly
C1:DecorinC5b-C7:S proteinC5b-C7:SP-40,40C5b-C9:CD59C9polymerization:CD59
Complement receptors
C1q receptorComplement receptor 1(CR1)Complement receptor 2(CR2)Complement receptor 3(CR3)Complement receptor 4(CR4)C5a,C3a and C4a receptors
Anaphylatoxins and disease
Target Smooth muscle Mast cells Blood capillary wall Vascular endothelium Leukocytes
Platelets Immune response
Effect Contraction Histamine release Increase in vascular permeability Increased adhesiveness for leukocytes Adhesion,aggregation,chemotaxis,release
of lysosomal enzymes,generation of oxygen radicals
Aggregation,release of serotonin C3a:suppression C5a:enhancement
Complement as an effector pathway in disease
Vasculitis and immune complex diseasesRheumatologic diseasePulmonary disease Renal diseasePlatelet diseasesHemolytic diseaseMyocardial diseaseBlood vessels diseaseCutaneous diseaseSystemic lupus erythematosus(SLE)Reproduction and pregnancyMyositis Neurologic disease
Vasculitis and immune complex diseases
Polyarteritis nodosa(PAN)Hypersensitivity vasculitisHenoch-Schonlein purpura(HSP)Rheumatoid vasculitisSystemic lupus erythematosus(SLE)
Rheumatologic disease
Rheumatoid arthritisSLEOsteoarthritisReiter’s syndromeGout
Pulmonary disease
Acute respiratory distress syndrome
SLE
Platelet diseases
Idiopathic thrombocytopenic purpura
(ITP)
Hemolytic disease
Paroxysmal nocturnal hemoglobinuria
(PNH)Hemolytic-uremic syndrome
(HUS)
Myocardial disease
Unstable anginaMyocardial infarctionReperfusion injury
Renal disease(Glomerulonephritis)Classification of glomerulonephritis
Deposited
Immunoglobulin Complement components
Primary glomerulonephritis
IgA GN IgA(IgG) C3,P,H,C5b-9
Minimal change GN IgM -
Idiopathic membranous GN IgG (C1q,C4),C3,C5b-9
Membranoproliferative GN-I (IgG) C3,P,B,C5-9
Membranoproliferative GN-II IgM C3,P,C5-9
Poststereptococcal GN IgG(IgM,IgA) C3,P,C5-9
Focal GN IgM C1q,(C3),C5-9
Secondary GN
Henoch-Schonlein purpura IgA C3,P,C5-9
Systemic lupus erythematosus IgG(IgM) C3,C5-9
Goodpasture syndrome IgG,IgM,IgA C3,C4,C1q,C5-9
Atherosclerosis
Blood vessels disease
Cutaneous disease
SLEPhototoxic reactionsAutoimmune bullos diseasesAcnePsoriasis
Systemic lupus erythematosus
Reproduction and pregnancy
Antibody-mediated infertilityRecurrent fetal loss
Myositis
Dermatomyositis
Neurologic disease
Multiple sclerosisSLEGuillian-Barre syndromeAlzheimer’s disease
Xenotransplant rejection
Transplantation
Allotransplant rejection
Diseases in which complement inhibitors will probably be effective
Some forms of vasculitis Rheumatoid arthritis ARDS SLE Many types of renal diseases ITP Hemolytic anemia Myocardial infarction Neurologic disease Ischemia-reperfusion injury Antiphospholipid syndrome Recurrent immune-mediated fetal loss Ab-mediated cutaneous disease Xenotransplant rejection
Complement deficiencies
Clinical presentation of complement deficiencies
Infection
Autoimmune disease
Summary of complement deficiency statesComponent Mode of inheritance Primary disease associations
Classical pathway
C1 ACD Autoimmune>>infection
C4 ACD Autoimmune>>infection
C2 ACD Autoimmune>>infection
Lectin pathway
MBL ACD Infection>>autoimmune
MASP1/MASP2
NA _
Alternative pathway
Factor B NA _
Factor D ACD Infection
Properdin X-linked Infection>>autoimmune
Shared components
C3 ACD Infection>>autoimmune
C5 ACD Infection>>autoimmune
C6-9 ACD Infection>>autoimmune
Summary of complement deficiency statesComponent Mode of inheritance Primary disease association
Receptors
C1qR NA _
CR1/CR2 Acq Autoimmune and Immune complex
CR3/CR4 ACD Leukocyte adhesion disease
C5aR NA _
C3aR NA _
Regulatory proteins
C1-INH AD HAE
DAF ACD(Inab)Acq(PNH) PNH
MCP NA _
CD59 Acq PNH
Factor H ACD Infection~autoimmune
C4-bp ACD Autoimmune~infection
FactorI ACD Infection~autoimmune