Overview of complement activation and regulation

Abstract

Complement is an important component of the innate immune system that is crucial for defense from microbial infections and for clearance of immune complexes and injured cells. In normal conditions complement is tightly controlled by a number of fluid-phase and cell surface proteins to avoid injury to autologous tissues. When complement is hyperactivated, as occurs in autoimmune diseases or in subjects with dysfunctional regulatory proteins, it drives a severe inflammatory response in numerous organs. The kidney appears to be particularly vulnerable to complement-mediated inflammatory injury. Injury may derive from deposition of circulating active complement fragments in glomeruli, but complement locally produced and activated in the kidney also may have a role. Many kidney disorders have been linked to abnormal complement activation, including immune-complex-mediated glomerulonephritis and rare genetic kidney diseases, but also tubulointerstitial injury associated with progressive proteinuric diseases or ischemia-reperfusion.

Keywords: Complement; adaptive immunity; complement regulators; innate immunity; kidney; kidney diseases.

Figure 1

Schematic overview of the complement cascade illustrating the three activation pathways (classical, lectin, and alternative) and the MAC.

Figure 2

The alternative pathway of complement activation. The AP is activated continuously in plasma by low-grade hydrolysis of C3. The latter binds factor B to form a C3(H₂O)B complex. CFD cleaves factor B to form the AP initiation C3 convertase that cleaves C3 to C3b. The activation then is amplified by the covalent binding of a small amount of C3b to hydroxyl groups on cell-surface carbohydrates and proteins of target cells such as bacterial cells. This C3b binds factor B, to form the amplification loop C3 convertase C3bBb. The binding of properdin (P) stabilizes this enzyme. C3 convertase enzymes cleave many molecules of C3, resulting in a positive feedback amplification loop. C3b also binds to the C3 convertase, forming the C5 convertase enzyme C3b₂Bb. The AP is highly regulated to prevent nonspecific damage to host cells and limit the deposition of complement to the surface of pathogens. This fine regulation occurs through a number of membrane-anchored and fluid phase regulators. CFI (degrades C3b and C4b); CFH and CR1 both act as cofactors for factor I for C3b cleavage and favor the decay of the C3 convertase of the AP; C4BP: C4b binding protein (beside inhibiting the classic and the lectin pathways of complement, it also controls the alternative pathway by acting as a cofactor for factor I in the cleavage of C3b); MCP binds C3b and C4b and has cofactor activity for both the classic and the alternative pathways.

Figure 3

Mechanisms of complement regulation. (A) DAF (or CFH, CR1) destabilizes C3 convertases and accelerates the dissociation of C3bBb (depicted) and C4bC2a. (B) Cofactor activity: MCP (or CFH, CR1) binds to C3b and serves as a cofactor for CFI-mediated cleavage and inactivation of C3b (or C4b). (C) C1 complex inactivation. C1INH binds to C1r and C1s to inactivate the C1 enzyme complex. (D) MAC inhibition: CD59 inhibits C9 association with C5b-8 and prevents MAC (C5b-9) formation.