Figure 2 - Activation, regulation and therapeutic modulation of the complement system.

(a) The complement cascade after activation by pathogens. In addition to a low level of constant activation by the alternative pathway (AP; tick-over via hydrolyzed C3 (C3w) results in the formation of the initial C3 convertase C3wBb), the complement cascade is usually activated by antibody complexes (classical pathway) or high-density mannose (lectin pathway) on the surface of pathogens. This activation leads to the formation of the C3 convertases C4bC2a and C3wBb, which cleave native C3 to C3b and C3a. Deposition of C3b on cell surfaces via its thioester group initiates the cleavage of more C3 (the amplification loop via the final AP C3 convertase C3bBb), opsonization and phagocytosis, as well as lysis as a result of the formation of the membrane attack complex (MAC). In addition, the anaphylatoxins C3a and C5a are released and trigger further immune reactions upon binding to their receptors (C3aR, C5aR, C5L2). These combined actions of complement lead to the elimination of pathogenic cells. Recently, studies have shown that some steps of the cascade can be directly initiated by certain proteolytic enzymes (the extrinsic protease pathway) or by MBL/MASP (the C2 bypass pathway). Furthermore, the regulatory protein properdin may propagate and stabilize the formation of C3 convertases on the surface of the cell. Protein conversions are shown as black arrows and enzymatic reactions as green arrows. (b) Regulation, deactivation and inhibition of the complement cascade on host cells by natural regulators and complement-specific therapeutics. Several pathogenic processes and diseases are the result of an erroneous activation or insufficient downregulation of the complement cascade. Under normal conditions, any host-associated C3 convertase (C3bBb) undergoes an accelerated decay mediated by complement receptor 1 (CR1), decay accelerating factor (DAF), C4b-binding protein (C4BP) or factor H (fH). C3b is degraded to inactive iC3b by factor I in a reaction that requires as cofactor CR1, fH, C4BP or membrane cofactor protein (MCP). In addition, CD59 prevents the formation of the MAC. Some of the therapeutic interventions focus on increasing this downregulation by using soluble forms of these regulators (that is, sCR1, sDAF, sMCP, sCD59). Other approaches involve the substitution of the natural C1 inhibitor (C1-INH), the inhibition of the central conversion of C3 to C3b and C3a (compstatin), blockage of C5 or C5a by antibodies, and the suppression of anaphylatoxic signaling by C5a receptor antagonists. For clarity, only the regulation of the alternative pathway, which may contribute up to 80% of all complement activity, is shown here. The C3 convertase of the classical pathway (C4bC2a), as well as the C5 convertases (C4bC2aC3b and C3bC3bBb), can be modulated by the same regulators and drug compounds. Therapeutic modulators in clinical trials or late preclinical development are indicated in red, with the circled letter referring to the corresponding drug class in Tables 1 and 2 and the main text.