Fig. 1. The main proteins involved in the complement activation cascades.
The complement pathway begins with the enzyme cascade, which involves de novo assembly of enzyme complexes known as convertases. The enzyme cascade can proceed via three different activation pathways: the classical pathway (CP), the lectin pathway (LP) and the alternative pathway (AP). The classical pathway begins with antibody-mediated activation of C1, which leads to formation of the C4bC2a complex, which is the C3 convertase. This C3 convertase cleaves C3 to produce C3b, which forms a complex with C4b and C2a. This complex is the C5 convertase, which cleaves C5 to produce C5a and C5b. The lectin pathway begins with signal recognition by oligomeric structures of mannose-binding lectin (MBL), ficolins and collectins, which activate mannan-binding lectin serine protease 1 (MASP1) and MASP2, which in turn mediate production of C4b. From this point, the lectin pathway follows the same steps as the classical pathway. In the alternative pathway, C3 interacts with factor B and factor D, leading to cleavage of further C3, and this process is perpetuated through an amplification loop. In the final step of this pathway, an additional C3b binds to the C3 convertase and forms a C5 convertase, which cleaves C5. All three pathways generate C5b, which initiates the second part of the system — the lytic pathway and membrane attack complex (MAC) formation. C5b associated with the surface-bound convertases sequentially accepts C6 and C7. For successful continuation of MAC formation, the C5b–7 complex must translocate to the outer part of the lipid bilayer. The translocation results in conformational changes and the complex becomes transmembrane, exposing lipophilic structures that enable association with C8 and C9. Further binding with up to another 17 C9 molecules widens the inner pore size, resulting in the osmolytic MAC. Molecules and processes that represent therapeutic targets are shown on the right along with drugs that are available or are in development. The complement protein nomenclature used is in accordance with Kemper et al.10. IVIg, intravenous immunoglobulin.