1. Complement

2. Complement pathways: Classical pathway Alternative pathway Lectin pathway

3. 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

4. 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

5. Comparison of the classical and alternative complement pathways Antigen/antibody Complexes (adaptive) C3 microorganisms Classical pathway Alternative pathway (innate) C3bC3a C5-C9 Terminal sequences

6. plays a central role in complement activation C3

7. Classical C3 convertases C1q/C1r/C1s C5 convertases C4 C4b+C2 C4b2a C4a C4b2a3b C3 C3a C5 C5b Lectin C3bBbC3b C5a C6 MBP/MASP-1 C5b6 /MASP2 C7 C3a C3bBbP C5b67 C3 C3b P,B,D C8 C3(H2O)+B C3(H2O)Bb C5b678 D C9 Alternative Ba C5b6789 Complement pathway

8. 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

9. 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

10. 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

11. 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

12. 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

13. Cell membrane Decay-accelerating factor(DAF,CD55) Membrane cofactor protein(MCP,CD46) CD59 Membrane C3-proteinases Matrix Decorin

14. Complement pathway regulatory mechanisms and examples of each Protease inhibitors C1r:C1-INH C1s:C1INH

15. Complement pathway regulatory mechanisms and examples of each Proteases C4a C3a Carboxypeptidase Inactivated C5a

16. Complement pathway regulatory mechanisms and examples of each Decay-acceleration DAF,C4-bp,CR1 C2a C4b2a C4b DAF,H,CR1 Bb C3bBb C3b

17. Complement pathway regulatory mechanisms and examples of each Cofactor activity Factor I C3b C3bi MCP,H,CR1 FactorI C4b C4bi MCP,C4-bp,CR1

18. 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

19. 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

20. 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

21. 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

22. Vasculitis and immune complex diseases Polyarteritis nodosa(PAN) Hypersensitivity vasculitis Henoch-Schonlein purpura(HSP) Rheumatoid vasculitis Systemic lupus erythematosus(SLE)

23. Rheumatologic disease Rheumatoid arthritis SLE Osteoarthritis Reiter’s syndrome Gout

24. Pulmonary disease Acute respiratory distress syndrome SLE

25. Platelet diseases Idiopathic thrombocytopenic purpura (ITP)

26. Hemolytic disease Paroxysmal nocturnal hemoglobinuria (PNH) Hemolytic-uremic syndrome (HUS)

27. Myocardial disease Unstable angina Myocardial infarction Reperfusion injury

28. Renal disease(Glomerulonephritis) Classification of glomerulonephritis Deposited ImmunoglobulinComplement 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 IgMC3,P,C5-9 Poststereptococcal GN IgG(IgM,IgA)C3,P,C5-9 Focal GN IgMC1q,(C3),C5-9 Secondary GN Henoch-Schonlein purpura IgAC3,P,C5-9 Systemic lupus erythematosusIgG(IgM)C3,C5-9 Goodpasture syndrome IgG,IgM,IgAC3,C4,C1q,C5-9

29. Atherosclerosis Blood vessels disease

30. Cutaneous disease SLE Phototoxic reactions Autoimmune bullos diseases Acne Psoriasis

31. Systemic lupus erythematosus

32. Reproduction and pregnancy Antibody-mediated infertility Recurrent fetal loss

33. Myositis Dermatomyositis

34. Neurologic disease Multiple sclerosis SLE Guillian-Barre syndrome Alzheimer’s disease

35. Xenotransplant rejection Transplantation Allotransplant rejection

36. 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

37. Complement deficiencies

38. Clinical presentation of complement deficiencies Infection Autoimmune disease

39. Summary of complement deficiency states ComponentMode of inheritancePrimary disease associations Classical pathway C1ACDAutoimmune>>infection C4ACDAutoimmune>>infection C2ACDAutoimmune>>infection Lectin pathway MBLACDInfection>>autoimmune MASP1/MASP 2 NA_ Alternative pathway Factor BNA_ Factor DACDInfection ProperdinX-linkedInfection>>autoimmune Shared components C3ACDInfection>>autoimmune C5ACDInfection>>autoimmune C6-9ACDInfection>>autoimmune

40. Summary of complement deficiency states ComponentMode of inheritancePrimary disease association Receptors C1qRNA_ CR1/CR2AcqAutoimmune and Immune complex CR3/CR4ACDLeukocyte adhesion disease C5aRNA_ C3aRNA_ Regulatory proteins C1-INHADHAE DAFACD(Inab)Acq(PNH)PNH MCPNA_ CD59AcqPNH Factor HACDInfection~autoimmune C4-bpACDAutoimmune~infection FactorIACDInfection~autoimmune