Kulkarni and Afshar-Kharghan Alternative Pathway Pathogen surface C3 C3b FactorB+FactorD+properdin FACTOR H DAF CR-1 C3 C3b,Bb C3b Common Pathway Lectin Pathway Pathogen surface MBL MASP1/2 C3a C3a C3b,C3b,Bb C3b,C4b,C2b C5a C5b C5b,6 C5b,6,7 C5b,6,7,8 C6 C7 C8 (C9)n CD59 C5b,6,7,8,(9)in (Membrane Attack Complex) Classic Pathway Antigen-antibody complex C2 C4 C3 C3b C2a C4b C4b.C2b C1NH DAF C4bBP C1qrs C1q + C1r + C1s Figure 1 Activation pathways of the complement system and complement regulatory proteins.Three pathways of activation of the complement system (the classical, alternative and lectin pathways), their convergence on a common pathway, and the components of each pathway are depicted.The effect of different complement regulatory proteins is shown as dashed lines. Abbreviations: MBL, mannan-binding lectin; MASP1/2, MBL-associated serine protease 1 and 2; C1INH, C1 inhibitor; C4bBP, C4b binding protein, DAF, decay accelerating factor, CR-1, complement receptor 1. Cummings et al 2007; Oksjoki et al 2007). The central convergence point of all three pathways is the formation of a C3 convertase on the surface of a particular cell. With the formation of a functioning C3 convertase, complement is able to carry out its effector functions (Figure 2). In the classical pathway, C1q, one of the subunits of C1, ﬁrst binds to the Fc domains of antibodies attached to their antigen. Another subunit of C1, C1r, cleaves and activates the third subunit of C1, C1s. Activated C1s cleaves C4 and C2 to form C4b and C2b, respectively, which then combine to form the C3 convertase of the classical complement pathway (Figure 1). Similarly, in the lectin pathway, cleavage of C4 and C2 allow formation of the C3 convertase. In the alternative pathway, C3 is spontaneously cleaved to C3a and C3b. C3b covalently binds to cell surfaces and with the help of factor B (FB) and factor D (FD) can form the C3bBb complex, which is the alternative pathway’s C3 convertase (Figure 1). The function of the C3 convertase in all three pathways is to further cleave C3, producing C3a, one of the two major 672 anaphylatoxins of the complement system, and C3b, a potent opsonin. Binding of several C3b molecules to cells and other debris marks them for phagocytosis by macrophages. Propagation of complement activation by the C3 convertase results in the generation of a C5 convertase on cell surfaces. The function of the C5 convertase is to cleave C5 to C5a and C5b. C5a is the other anaphylatoxin and is much more potent than C3a. As anaphylatoxins, C3a and C5a are able to recruit neutrophils to areas of inﬂammation and damage. C5b is subsequently able to bind to C6, C7, C8, and C9 to form the membrane attack complex (MAC or C5b-9 complex). The C5b-9 complex is able to disrupt the phospholipid bilayer of the cell membrane, leading to loss of cellular homeostasis and eventual cell death (Figure 2). Thus, the three main functions of the complement system are opsonization of pathogens or other molecules, which targets them for eventual destruction, augmentation of inﬂammation by the recruitment of inﬂammatory cells via the anaphylatoxins C3a and C5a, and direct killing of cells by the formation of MACs (Figure 2). Biologics:Targets & Therapy 2008:2(4)