The complement system can be activated through three major pathways: classical, lectin, and alternative. Initiation of the classical pathway occurs when C1q, in complex with C1r and C1s serine proteases (the C1 complex), binds to the Fc region of complement-fixing antibodies (generally IgG1 and IgM) attached to pathogenic surfaces.
Autocatalytic activation of C1r and C1s in turn cleaves C4 and C2 into larger (C4b, C2a) and smaller (C4a, C2b) fragments. The larger fragments associate to form C4bC2a on pathogenic surfaces, and the complex gains the ability to cleave C3 and is termed the C3 convertase. Generation of the C3 convertase, which cleaves C3 into the anaphylatoxin C3a and the opsonin C3b, is the point at which all complement activation cascades converge.
When C3 is cleaved into C3b, it exposes an internal thioester bond that allows stable covalent binding of C3b to hydroxyl groups on proximate carbohydrates and proteins. This activity underpins the entire complement system by effectively 'tagging' microorganisms as foreign, leading to further complement activation on and around the opsonized surface and terminating in the production of anaphylatoxins and assembly of the membrane attack complex/MAC.
Due to the destructive potential of complement activation, especially in light of the potent feedback amplification ability of the alternative pathway, complement activities need to be confined to appropriate pathogenic surfaces, and generation of potent effectors needs to be tightly regulated to prevent collateral damage to healthy host tissues.
Therefore, many steps involved in complement activation are checked by inhibitors so that the final system represents an intricate, homeostatic balance between the efficient detection and destruction of pathogens and the minimization of bystander tissue damage. Complement system regulation occurs predominantly at two steps within the cascades, at the level of the convertases, both in their assembly and in their enzymatic activity, and during assembly of the membrane attack complex/MAC.
Upon generation of C4b and C3b fragments (through upstream complement activation) and their covalent linkage to cellular surfaces, they experience one of the two fates. The first, which prevents these molecules from forming active convertases, is the catabolism of C3b and C4b via the constitutively active serine protease Factor I which can cleave C3b and C4b into inactive fragments, such as iC3b, C3c, and C3dg.
To prevent nonspecific C3b degradation, for instance in the case of proper complement activation, Factor I requires cofactors for its proteolytic activity. These cofactors include membrane cofactor protein (MCP; CD46), complement receptor 1 (CR1), and Factor H which are either intrinsic membrane proteins on host cells or have various mechanisms to ensure preferential cofactor activity on host surfaces, and thereby limit complement activation in these contexts and prevent bystander tissue damage
Complement activation, regardless of the pathway, converges on the generation of three broad effector pathways that serve to enable the complement to fulfill its physiological imperatives in host defense: (1) direct lysis of targeted surfaces by way of the membrane attack complex/MAC assembly, (2) alerting and priming the immune system by way of the generation of potent proinflammatory anaphylatoxins, and (3) opsonization and clearance of target surfaces by way of the complement opsonins (C4b, C3b, C3bi) and engagement of CRs on phagocytic cells, such as macrophages and neutrophils.
MAC assembly is germinated when C3b, following its deposition on cell surfaces, associates with C3 convertases of all three pathways to form the C5 convertases; C4bC2aC3b (classical and lectin pathways) and C3bBbC3b (alternative pathway).
C5 convertases are the staging points for the terminal complement activation and cleave C5 into anaphylatoxins C5a and C5b. C5b liberation exposes a binding site for C6, and the subsequent C5bC6 binds reversibly to the targeted surfaces and forms the molecular foundation for the MAC.
C7 associates with C5bC6, creating C5b-7, which is integrated into the phospholipid membrane bilayer and induces the membrane insertion of C8α and C8β, forming unstable pores. C9 binds to C8α and initiates polymerization of multiple C9 molecules to form stable inserted pores with a maximum diameter of 10 nm (up to 13 C9 molecules).
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2. Cooper N R. (1999). Biology of the complement system. Inflammation: Basic principles and clinical correlates, 281.