Complement regulators: balancing the complement system with new antibody tools

What are complement regulators?

Complement activation occurs through three main pathways: the classical, lectin and alternative pathways. Although these pathways are activated in different ways, they ultimately converge on the activation of C3 and C5 and, eventually, formation of the membrane attack complex (MAC).

To prevent excessive activation, the complement system is tightly regulated by a network of regulatory proteins. These regulators can inhibit complement activation, accelerate the decay of complement convertases, or promote the inactivation of complement components.

Meet the complement regulators

C1 inhibitor: regulating the classical and lectin pathways

C1 inhibitor (C1-INH) is an important soluble regulator of the classical and lectin pathways. It inhibits the proteases C1r and C1s, thereby limiting activation of the classical pathway. C1-INH also regulates MASP-1 and MASP-2 in the lectin pathway.

Because of its role in controlling early complement activation, C1-INH is an important regulator of complement-mediated inflammation.

Factor H: regulating the alternative pathway

Factor H is one of the most important soluble regulators of the alternative pathway. It binds to C3b and helps control the formation and stability of the alternative pathway C3 convertase. Factor H also acts as a cofactor for Factor I-mediated inactivation of C3b.

Because of its central role in alternative pathway regulation, Factor H has become an important focus of complement research.

Factor I: inactivating C3b and C4b

Factor I is a soluble serine protease that regulates complement by cleaving and inactivating C3b and C4b. Its activity depends on cofactors, including Factor H, CD46 and CR1.

Together, Factor I and its cofactors provide an important mechanism for preventing prolonged complement activation.

C4b-binding protein: regulating the classical and lectin pathways

C4b-binding protein (C4BP) is a soluble complement regulator that primarily controls the classical and lectin pathways. It binds to C4b and promotes the dissociation of the C3 convertase. C4BP also acts as a cofactor for Factor I-mediated cleavage of C4b.

Through these activities, C4BP helps limit complement activation and protect host tissues from excessive complement-mediated damage.

Clusterin: regulating terminal complement complex formation

Clusterin is a soluble complement regulator that acts primarily at the terminal stage of complement activation. It binds to components of the terminal complement pathway and inhibits the assembly and insertion of the membrane attack complex (MAC), also known as the terminal complement complex (TCC).

By interfering with MAC formation, clusterin helps protect host cell membranes from complement-mediated damage.

Vitronectin: regulating terminal pathway activity

Vitronectin is a soluble complement regulator that acts mainly on the terminal pathway. It binds to the soluble terminal complement complex and prevents its insertion into cell membranes, thereby limiting formation of the membrane attack complex (MAC).

Together with clusterin, vitronectin helps protect host cells from complement-mediated membrane damage.

CD46: protecting cells through cofactor activity

CD46, also known as membrane cofactor protein (MCP), is a membrane-bound complement regulator found on most nucleated cells.

CD46 acts as a cofactor for Factor I, helping to inactivate C3b and C4b deposited on the cell surface. In this way, CD46 contributes to the protection of host cells from complement-mediated damage.

CD55: accelerating complement convertase decay

CD55, also known as decay-accelerating factor (DAF), provides another important layer of protection at the cell surface.

Rather than directly inactivating C3b or C4b, CD55 accelerates the decay of C3 and C5 convertases. By reducing the lifetime of these convertases, CD55 helps limit amplification of complement activation.

CD59: blocking the final step

Complement regulation does not stop at C3 and C5. At the terminal stage of the cascade, CD59 helps protect host cells by inhibiting formation of the membrane attack complex (MAC).

This makes CD59 an important final line of defense against complement-mediated cell damage.