Figure 2.

Overview of the complement system. Created with BioRender.com. MBL, mannan-binding lectin; MASP, mannan-binding lectin serine protease; C4BP, C4b-binding protein; DAF, decay-accelerating factor; MCP, membrane cofactor protein; CR1, complement receptor 1; MAC, membrane attack complex; C3aR, C3a receptor; C5aR, C5a receptor; PMN, primary membranous nephropathy; PLA2R, M-type phospholipase A2 receptor 1; THSD7A, thrombospondin type-1 domain-containing protein 7A. The complement system consists of 3 pathways: classical pathway, lectin pathway and alternative pathway, which can be conceptually understood using 4A’s: attachment, activation, amplification, and attack (steps of complement activation in bold text below). In the classical pathway, complement C1q attaches to the Fc receptor of antigen-bound antibodies (IgG1, IgG3 and IgM in humans, and IgG2a and IgG2b in rodents). The lectin pathway is similar to the classical pathway where lectins (such as ficolins, MBLs or collectins) attach to carbohydrates on pathogens, activating MASP-1 and MASP-2 (analogous to C1r and C1s of the classical pathway), which cleave C4 and C2 to form C3 convertase (C4b2b). In the alternative pathway, small amounts of C3 are spontaneously activated (“C3 tickover”) due to a labile thioester bond, forming a C3b fragment that binds to factor B (B), which in turn is cleaved by factor D (D) to form the alternative pathway C3 convertase (C3bBb) that is stabilised by properdin (P), forming C3bBbP. Regardless of the pathway of activation, C3 convertase cleaves C3 into C3a and C3b, which amplifies alternative pathway activation whereby further factor B binds to C3b forming more C3 convertase. Apart from amplifying C3 convertase formation, C3b also acts as an opsonin and binds to C3 convertase to form C5 convertase (C4b2b3b and C3bBbC3bP), which cleaves C5 into C5a and C5b. C3a and C5a act as potent anaphylatoxins via their respective receptors (C3aR and C5aR). Complement attack is initiated by C5b sequentially binding C6, C7, C8, and C9 to form the MAC (C5b-9), which causes transmembrane pores that cause osmotic cell lysis or sublethal cell injury, activating internal cellular processes. The complement system is tightly regulated by proteins present in plasma (fluid-phase) and on cell surfaces including the podocyte (solid-phase). Fluid-phase regulators include C1q inhibitor (binds C1r/C1s and MASP-1/MASP-2 to prevent classical and lectin pathway activation), C4BP (binds C4b to prevent formation of the classical/lectin pathway C3 convertase), factor H (binds C3b to prevent formation of the alternative pathway C3 convertase), factor I (cofactor for factor H and MCP, which both inhibit C3 convertase formation), vitronectin (binds the C5b-7 complex to prevent MAC formation) and clusterin (binds C7, C8, C9 to prevent MAC formation). Solid-phase regulators include DAF (dissociates C2b from C4b and Bb from C3b to inactivate C3 convertase), MCP (binds C3b and C4b to prevent C3 convertase formation), CR1 (binds C3b and C4b to prevent C3 convertase formation) and CD59 (binds C8 and C9 to prevent MAC formation).