Antigenic Surface C1r and C1s Enzymes Associate with C1q to form C1 CH 2 Conformational Change C1r 2 - C1s 2 C1q Ca 2+ Fig. 9.1 C1 activation by an antibody duplet formed by binding to the corresponding antigen C1q Stalk and Stem regions C1q Globular Heads

Fig. 9.2 Conversion of C4 followed by covalent deposition of C4b on the antigenic surface. Antigenic Surface C1r 2 C1s 2 C4 C4b Short-lived Active Binding Site C4 C4b C4a C1q C4a C4b

Fig. 9.3 Formation of C4b2a complex (C3 convertase) on the antigenic surface. Although activated C1s (within the macromolecular C1 complex) can activate any C2 molecule that it contacts, the cleavage of C2 adjacent to a membrane- bound C4b increases the probability of generating bound C4b2a complexes on that foreign membrane. Antigenic Surface C1r 2 C1s 2 C2 C4b C2 C1q C4b C2a C2b C2 a C4b C2a

C3b Native C3 C4b2aC3b becomes covalently bound to the antigenic surface C3a C3a is released Antigenic Surface Host Phagocytes attach to these newly exposed regions on the successfully deposited C4b and C3b. C4b C2a C3a Fig. 9.4 C3 activation by C4b2a enzyme complex (C3 convertase) results in the split of C3 into two fragments. While C3b remains associated with C4b2a, C3a is released into the fluid phase (top). Sites on the deposited C4b and C3b are now exposed and recognized by phagocytic cell receptors (bottom).

Fig. 9.5 Binding of C4b and C3 fragments to antibody-antigen complexes results in dissolution of those immune complexes. Removal and inactivation of C1 occur as C4b and C3b deposit on the Fab (CH1) of IgG1 and on the antigenic determinants and thereby disrupt the immune complexes, which in turn cause a loosening of the C1qr 2 s 2 complex and allows entrance of C1-Inhibitor. C1-Inhibitor binds and inactivates C1r and C1s and then attempts to remove the inactivated C1r and C1s. However, when low levels of deposited IgG are present, the entire C1qr 2 s 2 complex is removed by the action of C1-Inhibitor. Antigenic Surface C3c C3d C3b Release of C1 iC3b C1 Inhibitor C3b Dissolution of Immune Complexes Release of Ab Factor I C3b C4b C2a iC3b C4b C2a Factor I

SSSS S S  chain C3  chain C3d C3g Tissue protease or plasmin C3dg C3c SS Factor I again C3c goes into the fluid phase SSSS S S iC3b Factor I with co-factor H or CR1 or MCP SSSS S S C3b C3 Convertase C4bC2a or C3bBb C3a SSSS C3b becomes covalently bound to the antigen The speed of the breakdown (catabolism) of deposited C3b depends on the nature of the substance onto which C3b covalently binds. Note that C3b, and its breakdown products iC3b, C3dg and C3d are covalently bound to the antigen. Fig. 9.7 Diagrammatic summary of the different steps involved in the breakdown of C3

C4b, C3b, iC3b, C3dg, C3d Immune Adherence Enhanced Phagocytosis C3a, C5a Anaphylotoxins Chemotactic Factors Classical Pathway Activation by Antigen-Antibody Complexes Fig.9.9 The sequence of complement activation pathways. C1 C4 C2 C3 C5 C6 C7 C8 C9 Amplification Loop - Alternative Pathway: Bound C3b, Factor B, Factor D Membrane Attack Complex ( ) Lectin Pathway Mannan Binding Lectin (MBL) or F icolins and proenzymes MBL-associated serine proteases (MASPs) bind directly to microbial structures Membrane damage