Classical Complement Cascade

The complement cascade activation and function. The complement system consists of a large number of inactive components (zymogens) that are activated in a cascade-like manner to exert its biological effects in the innate immune system. Binding of complement zymogens to a membrane surface results in structural modifications, proteolytic cleavage, and the assembly into active enzyme complexes (convertases), which can then activate downstream substrates in a cascade-like fashion as shown. The complement cascade can be initiated by three major pathways: The classical pathway is induced when C1q interacts with antibodies or one of its many binding partners, such as serum pentraxins, polyanions (DNA, RNA, and lipopolysaccharides), or apoptotic cells. The C1q tail region of C1q binds proteases C1r and C1s to form the C1 complex. Binding of the C1q complex to an antibody/receptor on the cell surface induces a conformational change in the C1q molecule, which leads to activation of an autocatalytic enzymatic activity in C1r; C1r then cleaves C1s to generate the active serine protease. Once activated, C1s cleaves C4 and C2 to generate the C3 convertase, C3b2b, which in turn cleaves C3 and activates downstream cascade components. The lectin pathway is triggered by the binding of mannose binding lectin (MBL) to mannose residues on the cell surface. This activates the MBL-associated proteases mannose binding lectin serine protease 1 (MASP1) and MASP2, which then cleave C4 to generate the C4 convertase, C4b2b. The alternative pathway is spontaneously and continuously activated (via spontaneous C3 hydrolysis), which serves to amplify the cascade triggered by classical and lectin pathways. All three cascades converge on the major complement component, C3. Cleavage of C3 generates the anaphylactic peptide C3a and the opsonin C3b. Opsonization with C3b/iC3b leads to elimination of target structures by phagocytes that express C3 receptors (i.e., C3R/Cd11b). C3b later joins with C4b2a (the C3 convertase) to form the C5 convertase (C4b2a3b complex) that generates the anaphylatoxin C5a, which binds to C5a receptors (C5aR) on phagocytic/effector cells. Robust activation of complement can trigger activation of the terminal complement cascade, resulting in cell lysis through the insertion of the pore-forming C5b-C9 complex into the membrane, termed membrane attack complex (MAC). (Stephan et al., Annu. Rev. Neurosci. 2012)