What is the complement System?

A key step in the activation of complement is the formation of a complement C3 convertase, which is responsible for the limited proteolytic degradation of complement factor C3 to its subunits C3a and C3b. There is one alternative C3 convertase initiated through the alternative pathway, and one classical C3 convertase initiated through either the classical-, or the MBL pathway. The alternative pathway is continuously activated by low-level spontaneous hydrolysis of C3 to C3b, followed by the attachment of C3b to cell/pathogen surfaces. A similar, spontaneous, and low-level activation of the classical pathway has recently been described. The subsequent association of the covalently attached C3b with complement factor B (fB) and factor D (fD) leads to the generation of the alternative C3 convertase C3bBb.

The classical C3 convertase is initiated either through the classical pathway, following the interaction of C1q with immunoglobulin (Ig) in immune complexes, or through the soluble MBL pathway. Both lead to the cleavage of C4 to C4a and C4b, followed by that of C2 to C2a and C2b. The deposition of C4b on an activating surface and binding of the subunit C2a culminates in the formation of the classical C3 convertase (C4bC2a).

Progression of the classical, MBL, or the alternative pathways leads to the formation of the classical (C4b3b2a) or alternative ((C3b)2BbP) C5 convertases that are equally potent in the activation of C5 and the production of C5b, which upon binding C6, C7, C8 and C9, leads to the formation of the effector MAC. This is a pore-forming complex that results in irreversible damage to both the host and bacterial cell membranes and eventually cell lysis.