Complement cascade and its inhibitors

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The complement system is a heat-labile component of blood that confers bactericidal properties. The functions of complement include the attraction of inflammatory cells, opsonization to promote phagocytosis, immune complex clearance and direct microbial killing through the formation of the membrane attack complex (MAC). Three pathways lead to complement activation; the classical pathway initiated by antibodies bound to the surface of foreign bodies and the alternative and lectin pathways that provide an antibody-independent mechanism for complement activation, induced by the presence of bacteria and other micro-organisms.​

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The classical pathway

C1 is the first molecule in the classical complement cascade and comprises C1q and two molecules of C1r and C1s respectively. C1q attaches to antibodies bound on the pathogen surface, leading to the activation of C1s. C1s cleaves C4 present in the plasma releasing C4a and C4b. C4b binds C2, which is subsequently cleaved by C1s. This results in the release of C2b and C2a. C2a remains associated with C4b to form the classical pathway C3 convertase (C4b2a). C2a in the convertase complex cleaves C3 releasing C3a and C3b. The latter binds to the C3 convertase complex to form C4b2a3b, the classical pathway C5 convertase. This complex cleaves C5 leading to the release of C5a and C5b. C5b sequentially associates with C6, C7 and C8 to form a complex which attaches on the outer surface of the pathogen’s plasma membrane. This assembly acts as a receptor for C9 and also promotes the latter’s oligomerization into a pore (MAC) that allows the free exchange of ions and fluid between the extracellular and intracellular spaces, leading to osmotic cell lysis.

Mannan-binding lectin (MBL) and MBL-associated serine proteases (MASPs) are involved in the initial step of the lectin pathway of complement activation. The binding of MBL to mannose and N-acetyl glucosamine in micro-organisms leads to the activation of MASPs, which subsequently cleave C4 and C2. Following these cleavage events, complement pathway activation continues as in the classical pathway.

The alternative pathway

The alternative pathway of complement activation is in a constant state of low-level activation (known as tickover). C3 is hydrolysed in the plasma to C3i, which has many of the properties of C3b. C3i then binds the plasma protein, Factor B. Bound Factor B is cleaved by Factor D to produce Ba and Bb. Ba is released and the remaining complex comprised of C3iBb forms the alternative pathway C3 convertase. Most of the C3b generated by the convertase is hydrolysed. However, if C3b comes into contact with an invading micro-organism it binds and amplification of the alternative pathway is promoted by the binding of C3b to Factor B. The plasma protein, properdin stabilizes the C3 convertase to prolong activity. C3b produced in this pathway also yields the C5 convertase, C3bBb3b, which leads to the production of C5a and C5b. Note, C3b generated in the classical pathway feeds into the alternative pathway to amplify the activation of complement.

Inhibitors of the complement syste

The complement cascade is tightly controlled to protect host cells from indiscriminate attack. Complement inhibitors include the plasma serine proteinase inhibitor serpin (C1 inactivator). The plasma proteins, Factor I and C4 binding protein (C4-bp), inhibit the activity of the classical C3 convertase. Classical pathway activation is also inhibited by the surface bound proteins, CD55 (also known as decay accelerating factor or DAF), CD35 (also known as complement receptor 1 or CR1) and CD46(also known as membrane co-factor protein or MCP). The alternative pathway is regulated by Factor H, CD55 and CD35, which inhibit the C3 convertase of the alternative pathway. Factor I promotes the catabolism of C3i and C3b (Factor H and CD46 act as co-factors).