See also complement inhibitor targetting under “Pharmacology” and “Drug delivery” See also Human Complement Regulatory Proteins (CRegs) 

See also disease mechanisms of viruses and bacteria for how pathogens use complement regulatory proteins to evade the immune system

Mechanisms of Complement Regulation

The complement system is regulated via a number of interrelated mechanisms. There are two broad mechanisms for inhibition of the complement system; inhibitors of the complement activation pathway (inibitors of C3 convertase formation) and inhibitors of the terminal complement pathway (inhibit MAC formation).

(1) Inactivation of Complement Enzymes: In the first mechanism, CRegs function by inactivating enzymes, such as the C3 and C5 convertases, which are formed during C activation and which are responsible for cleavage of C3 and C5. The first mechanism is generally reversible, facilitating the dissociation of the C3 convertases (i.e., C3b from Bb and C4b from C2a). The dissociation may also involve reversible binding of the antagonist proteins to C3b or C4b components, thus preventing their reassociation.

(2) Interference with MAC: In the second mechanism, CRegs function by interfering with MAC formation. This second mechanism, which is an irreversible inactivation process, results from proteolytic cleavage of the C3 convertase components C3b or C4b by the serine protease factor I. 

Both general regulatory mechanisms, the facilitation of dissociation of C3b and C4b and the inactivation of C3b and C4b through cleavage by factor I, also apply to the inhibition of the alternative pathway C5 convertase (C3bBbC3b) and the classical pathway C5 convertase (C4bC2aC3b).

The proteins encoded by a region of the genome which designated the regulators of complement activation (RCA) gene cluster are involved in both mechanisms.