Complement and Rheumatoid Arthritis

Complement pathways:  Classical pathway  Alternative pathway  Lectin pathway Complement proteins  Classical pathway C1q C1r C1s C4 C2  Alternative pathway D C3 B  Lectin pathway MBL MASP-1 MASP-2  Membrane attack complex(MAC) C5 C6 C7 C8 C9  Membrane regulatory proteins CD55 CD46 CD59 Soluble regulatory proteins Positive regulation Properdin Negative regulation C1-INH C4-bp Factor H Factor I Carboxypeptidase S protein Clusterin Receptors CR1 CR2 CR3 CR4 C1qR C5aR C3aR Comparison of the classical and alternative complement pathways Antigen/antibody Complexes (adaptive) microorganisms C3 Alternative pathway (innate) Classical pathway C3a C3b C5-C9 Terminal sequences C3 plays a central role in complement activation Classical C1q/C1r/C1s C4 C4b+C2 C4a Lectin MBP/MASP-1 /MASP2 C3a C3bBbP C3 C3b P,B,D C3(H2O)+B C3(H2O)Bb D Alternative Ba C3 convertases C5 convertases C4b2a C4b2a3b C3 C3a C5 C5b C3bBbC3b C5a C5b6 C5b67 C6 C7 C8 C5b678 C9 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 B C1q and mannose-binding lectin(MBL) C1r/C1s and MASP-1/MASP-2 C3/C4/C5 C6/C7/C8/C9 Complement regulatory proteins and primary locations  Fluid phase  C1-INH  Factor I  Factor H  C4b-binding protein (C4-bp)  S protein(vitronectin)  SP-40,40(clusterin)  Carboxypeptidase Cell membrane Decay-accelerating factor(DAF,CD55) Membrane cofactor protein(MCP,CD46) CD59 Membrane C3-proteinases Matrix Decorin Complement pathway regulatory mechanisms and examples of each Protease inhibitors C1r:C1-INH C1s:C1INH Complement pathway regulatory mechanisms and examples of each Proteases C4a C3a C5a Carboxypeptidase Inactivated Complement pathway regulatory mechanisms and examples of each Decay-acceleration DAF,C4-bp,CR1 C4b2a DAF,H,CR1 C3bBb C3b C4b Bb C2a Complement pathway regulatory mechanisms and examples of each Cofactor activity Factor I  C3b MCP,H,CR1 FactorI  C4b C4bi C3bi MCP,C4-bp,CR1 Complement pathway regulatory mechanisms and examples of each Inhibition of assembly C1:Decorin C5b-C7:S protein C5b-C7:SP-40,40 C5b-C9:CD59 C9polymerization:CD59 Complement receptors C1q receptor Complement 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  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  Platelets  Immune response Complement as an effector pathway in disease Vasculitis and immune complex diseases Rheumatologic disease Pulmonary disease Renal disease Platelet diseases Hemolytic disease Myocardial disease Blood vessels disease Cutaneous disease Systemic lupus erythematosus(SLE) Reproduction and pregnancy Myositis Neurologic disease Vasculitis and immune complex diseases Polyarteritis nodosa(PAN) Hypersensitivity vasculitis Henoch-Schonlein purpura(HSP) Rheumatoid vasculitis Systemic lupus erythematosus(SLE) Rheumatologic disease Rheumatoid arthritis SLE Osteoarthritis Reiter’s syndrome Gout 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 angina Myocardial infarction Reperfusion injury Renal disease(Glomerulonephritis) Classification of glomerulonephritis Deposited Immunoglobulin Complement components Primary glomerulonephritis IgA GN Minimal change GN Idiopathic membranous GN Membranoproliferative GN-I Membranoproliferative GN-II Poststereptococcal GN Focal GN IgA(IgG) IgM IgG (IgG) IgM IgG(IgM,IgA) IgM IgA IgG(IgM) C3,P,H,C5b-9 (C1q,C4),C3,C5b-9 C3,P,B,C5-9 C3,P,C5-9 C3,P,C5-9 C1q,(C3),C5-9 C3,P,C5-9 C3,C5-9 Secondary GN Henoch-Schonlein purpura Systemic lupus erythematosus Goodpasture syndrome IgG,IgM,IgA C3,C4,C1q,C5-9 Blood vessels disease Atherosclerosis Cutaneous disease SLE Phototoxic reactions Autoimmune bullos diseases Acne Psoriasis Systemic lupus erythematosus Reproduction and pregnancy Antibody-mediated infertility Recurrent fetal loss Myositis Dermatomyositis Neurologic disease Multiple sclerosis SLE Guillian-Barre syndrome Alzheimer’s disease Transplantation Xenotransplant rejection 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 states Component C1 C4 C2 Mode of inheritance ACD ACD ACD Primary disease associations Autoimmune>>infection Autoimmune>>infection Autoimmune>>infection Classical pathway Lectin pathway MBL ACD Infection>>autoimmune _ MASP1/MASP NA 2 Alternative pathway Factor B Factor D Properdin NA ACD X-linked _ Infection Infection>>autoimmune Shared components C3 C5 C6-9 ACD ACD ACD Infection>>autoimmune Infection>>autoimmune Infection>>autoimmune Summary of complement deficiency states Component Mode of inheritance NA Acq Primary disease association _ Autoimmune and Immune complex Receptors C1qR CR1/CR2 CR3/CR4 C5aR C3aR C1-INH DAF MCP CD59 Factor H C4-bp ACD NA NA AD ACD(Inab)Acq(PNH) NA Acq ACD ACD Leukocyte adhesion disease _ _ HAE PNH _ PNH Infection~autoimmune Autoimmune~infection Regulatory proteins FactorI ACD Infection~autoimmune