The document discusses the complement system, which was discovered in 1894 and plays an important role in host defense against pathogens. It summarizes the key proteins in the complement pathways, including the classical, lectin, and alternative pathways. It also describes the biological activities of complement activation products and how deficiencies in specific complement components can increase susceptibility to certain infections.

1. Complement

2. Complement: History Discovered in 1894 by Bordet It represents lytic activity of fresh serum Its lytic activity destroyed when heated at 56C for 30 min

3. Complement functions Host benefit: opsonization to enhance phagocytosis phagocyte attraction and activation lysis of bacteria and infected cells regulation of antibody responses clearance of immune complexes clearance of apoptotic cells Host detriment: Inflammation, anaphylaxis

4. Proteins of the complement system (nomenclature) C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9 factors B, D, H and I, properdin (P) mannose binding lectin (MBL), MBL associated serine proteases (MASP-1 MASP-2) C1 inhibitor (C1-INH, serpin), C4-binding protein (C4-BP), decay accelerating factor (DAF), Complement receptor 1 (CR1), protein-S (vitronectin)

5. Definitions C-activation : alteration of C proteins such that they interact with the next component C-fixation : utilization of C by Ag-Ab complexes Hemolytic units (CH50) : dilution of serum which lyses 50% of a standardized suspension of Ab-coated r.b.c C-inactivation : denaturation (usually by heat) of an early C-component resulting in loss of hemolytic activity Convertase/esterase : altered C-protein which acts as a proteolytic enzyme for another C-component

6. Activation product of complement proteins (nomenclature) When enzymatically cleaved, the larger moiety , binds to the activation complex or membrane and the smaller peptide is released in the microenvironment Letter “b” is usually added to the larger, membrane-binding, peptide and “a” to the smaller peptide ( e.g. , C3b/C3a, C4b/C4a, C5b/C5a), EXCEPT C2 (the larger, membrane-binding moiety is C2a; the smaller one is C2b) Activated component are usually over-lined: e.g. C1qrs

7. Pathways of complement activation CLASSICAL PATHWAY ALTERNATIVE PATHWAY LECTIN PATHWAY activation of C5 LYTIC ATTACK PATHWAY antibody dependent antibody independent Activation of C3 and generation of C5 convertase

8. Components of the Classical Pathway C4 C2 C3 C1 complex Ca ++ C1r C1s C1q

9. Classical Pathway Generation of C3-convertase C4 Ca ++ C1r C1s C1q C4a b

10. Classical Pathway Generation of C3-convertase C4b Mg ++ C4a C2 _____ C4b2a is C3 convertase Ca ++ C1r C1s C1q C2b a C2 a

11. Classical Pathway Generation of C5-convertase C4b Mg ++ C4a C2b C3 ________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway Ca ++ C1r C1s C1q C2 a C3a b

12. Biological Activities of Classical Pathway Components Opsonin C4b Anaphylaotoxin C4a Opsonin Activation of phagocytic cells C3b Anaphylotoxin; can activate basophils and mast cells to degranulate resulting in increased vascular permeability and contraction of smooth muscle cells, which may lead to anaphylaxis C3a Prokinin; cleaved by plasmin to yield kinin, which results in edema C2b Biological Activity Component

13. Control of Classical Pathway Components C4 binding protein (C4-BP) and Factor I; C4-BP facilitates degradation of C4b by Factor I; C4-BP also prevents the association of C2a with C4b thus blocking formation of C3 convertase C4b C3a-INH C4a Factors H and I; Factor H facilitates the degradation of C3b by Factor I C3b C3a-inactivator (C3a-INA; Carboxypeptidase B) C3a C1-inhibitor (C1-INH); dissociates C1r and C1s from C1q All Regulation Component

14. C1-inhibitor deficiency: hereditary angioedema

15. Components of mannose-binding lectin pathway C4 C2 MASP1 MASP2 MBL

16. Mannose-binding lectin pathway C4 C2 _____ C4b2a is C3 convertase; it will lead to the generation of C5 convertase MASP1 MASP2 MBL C4b C4a C4b C2b C2a C2a

17. Components of the alternative pathway C3 B D P

18. Spontaneous C3 activation C3 H 2 O B D Generation of C3 convertase C3iBb complex has a very short half life C3 i b C3a b

19. C3-activation the amplification loop B D If spontaneously-generated C3b is not degraded C3 b C3b C3a b

20. C3-activation the amplification loop C3a B D C3 B b C3b b C3b C3a b

21. C3-activation the amplification loop C3a C3a C3 B D B b C3b C3b B b b b C3a C3b

22. C3-activation the amplification loop C3a C3a C3a B b C3b B b B b C3b C3b C3b

23. C3-activation the amplification loop C3a C3a C3a B b C3b B b B b C3b C3b

24. Control of spontaneous C3 activation via DAF DAF prevents the binding of factor B to C3b B C3b Autologous cell membrane DAF CR1

25. Control of spontaneous C3 activation via DAF DAF dislodges C3b-bound factor Bb B b b C3b Autologous cell membrane DAF CR1 B b

26. Control of spontaneous C3 activation via CR1 Autologous cell membrane H I I DAF C3b C3b B b iC3b B b iC3b CR1 DAF CR1

27. Degradation of spontaneously produced C3b C3b C3b iC3b iC3b I I C3dg C3dg C3c C3c

28. C3b stabilization and C5 activation C3 B D P This is stable C5 convertase of the alternative pathway C3b C3b finds an activator (protector) membrane C3a b b

29. C3b regulation on self and activator surfaces C3b

30. C5-convertase of the two pathways C3b B b C3b C5-convertase of the Alternative Pathway C5-convertase of the Classical and lectin Pathways C4b C2a C3b

31. Generation of C5 convertase leads to the activation of the Lytic pathway Lytic pathway

32. Components of the lytic pathway C6 C 9 C5 C8 C7

33. Lytic pathway C5-activation C5 C3b C2 a C4b b C5a

34. Lytic pathway assembly of the lytic complex C6 C5 b C7

35. Lytic pathway: insertion of lytic complex into cell membrane C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9 C5 b C6 C7 C8

36. Biological effects of C5a

37. Biological properties of C-activation products Product Biological Effects Regulation C2b (prokinin) edema C1-INH C3a (anaphylatoxin) mast cell degranulation; enhanced vascular permeability; anaphylaxis carboxy-peptidase- B (C3-INA)

38. Biological properties of C-activation products Product Biological Effects Regulation as C3, but less potent (C3-INA) C4a (anaphylatoxin) opsonization; phagocytosis C4b (opsonin) C4-BP, factor I C3b (opsonin) opsonization; phagocyte activation factors H & I

39. Biological properties of C-activation products Product Biological Effects Regulation anaphylactic as C3, but much more potent; attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release C5a ( chemotactic factor ) carboxy-peptidase-B (C3-INA) C5b67 protein-S chemotaxis, attaches to other membranes

40. Complement Deficiencies and Disease Classical Pathway Opsonization of immune complexes help keep them soluble, deficiency results in increased precipitation in tissues and inflammation Predisposition to SLE C1, C2, C4 Overproduction of C2b (prokinin) Hereditary Angioedema C1INH Mechanism Disease Pathway Component

41. Complement Deficiencies and Disease Lectin Pathway Inability to initiate lectin pathway Susceptibility to bacterial infections in infants or immunosuppressed MBL Mechanism Disease Pathway Component

42. Complement Deficiencies and Disease Alternative Pathway Inability to attack the outer membrane of Gram-negative bacteria Susceptibility to Gram-negative infections C5, C6, C7 C8, or C9 Lack of opsonization and inability to utilize the membrane attack pathway Susceptibility to bacterial infections C3 Lack of sufficient opsonization of bacteria Susceptibility to pyogenic (pus-forming) bacterial infections Factors B or D Mechanism Disease Pathway/Component

43. Complement Deficiencies and Disease Alternative Pathway cont. Uncontrolled activation of C3 via alternative pathway resulting in depletion of C3 C3 deficiency and susceptibility to bacterial infections Factors H or I Lack of opsonization of bacteria Susceptibility meningococcal meningitis Properdin (X-linked) Mechanism Disease Pathway Component

44. Opsonization and phagocytosis

45. C1qrs breakdown C 1 I nh C1r C1s C1q C1r C1s