Figure 2.

The complement pathway. The classical pathway is activated through antibody/antigen recognition by C1q in complex with C1r and C1s. The proteases C1r and C1s cleave C4 and C2 to generate the C3 convertase C4b2a regulated by complement receptor 1 (CR1), C4 binding protein (C4BP), decay accelerating factor (DAF), membrane cofactor protein (MCP), and factor I (FI). The lectin pathway is triggered by binding of mannose-binding lectin (MBL) or ficolins (FCN) to carbohydrate epitopes on targets. The MBL-associated serine proteases (MASPs) then cleave C4 and C2 to generate the C3-convertase as in the classical pathway. C1-inhibitor (C1INH) functions as a regulator to prevent excessive activation of both classical and lectin pathways. The alternative pathway is better considered as an amplification loop. C3b binds factor B (FB) to form C3bB. FB is cleaved by Factor D (FD) to form the C3bBb C3-convertase stabilized by properdin (P). This process is regulated by CR1, FI, factor H (FH), DAF and MCP. At this point the pathways converge—both C3-convertases cleave C3 to generate the anaphylatoxin C3a, and more C3b that binds to form the C5-convertases (C4b2a3b and C3bBb3b) that cleave C5 into C5a and C5b. C3a and C5a are potent anaphylatoxins that act through their respective receptors (C3aR, C5aR1, C5L2, and C5aR2) to recruit immune cells. C5b binds C6, C7, C8 (inhibited by vitronectin and clusterin) and multiple copies of C9 (inhibited by CD59) to form the lytic membrane attack complex (MAC). C3b opsonizes targets for phagocytosis and B-cell activation; C3b decays to iC3b then C3dg catalyzed by FI in the presence of cofactors (CR1, MCP, FH, C4BP).