2. 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

3. 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)

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

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

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

7. C4b Mg ++ C4a Ca ++ C1r C1s C1q C2 C2b a C2 a _____ C4b2a is C3 convertase

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

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

10. Components of the lytic pathway C6 C9C9 C8 C7 C5

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

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

13. Lytic pathway: insertion of lytic complex into cell membrane C5 b C6 C7 C8 C9C9 C9C9 C9C9 C9C9 C9C9 C9C9 C9C9 C9C9 C9C9

14. 13 Biological Activities of Classical Pathway Components ComponentBiological Activity C2bProkinin; cleaved by plasmin to yield kinin, which results in edema C3aAnaphylotoxin; can activate basophils and mast cells to degranulate resulting in increased vascular permeability and contraction of smooth muscle cells, which may lead to anaphylaxis C3bOpsonin Activation of phagocytic cells C4aAnaphylaotoxin C4bOpsonin

15. Components of the alternative pathway C3 B D P

16. Spontaneous C3 activation C3 H2OH2O i B D Generation of C3 convertase C3iBb complex has a very short half life b C3 C3a b

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

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

19. C3a BbBb C3b BbBb BbBb C3a C3-activation the amplification loop C3b

20. C3a BbBb C3b BbBb BbBb C3a C3-activation the amplification loop C3b

21. C5-convertase of the two pathways C3b BbBb C5-convertase of the Alternative Pathway C4b C2a C3b C5-convertase of the Classical and lectin Pathways

22. Biological effects of C5a

23. ProductBiological EffectsRegulation Biological properties of C-activation products 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

24. ProductBiological EffectsRegulation Biological properties of C-activation products 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) C5b67protein-Schemotaxis, attaches to other membranes

25. Opsonization and phagocytosis