The complement system was originally known only from vertebrates, but homologs of C3 and factor B and a prototypical ‘alternative pathway’ have been discovered in nonchordate invertebrates. This is not altogether surprising since C3, which is cleaved and activated by serine proteases, is evolutionarily related to the serine protease inhibitor α2-macroglobulin, whose first appearance likely was in an ancestor to all modern vertebrates. The amplification loop of the alternative pathway also has an ancestral origin, as it is present in echinoderms (which include sea urchins and sea stars) and is based on a C3 convertase formed by the echinoderm homologs of C3 and factor B. These factors are expressed by phagocytic cells called amoeboid coelomocytes present in the coelomic fluid. Expression of C3 by these cells increases when bacteria are present. This simple system seems to function to opsonize bacterial cells and other foreign particles and facilitate their uptake by coelomocytes. C3 homologs in invertebrates are clearly related to each other. They all contain the distinctive thioester linkage and form a family of proteins, the thioester proteins, or TEPs. In the mosquito Anopheles, the production of protein TEP1 is induced in response to infection, and the protein may directly bind to bacterial surfaces to mediate phagocytosis of Gram-negative bacteria. Some form of C3 activity may even predate the evolution of the Bilateria—animals with bilateral symmetry, flatworms being
Fig. 2.28 There is a close evolutionary relationship among the factors of the alternative, lectin, and classical pathways of complement activation.
Most of the factors are either identical or the homologous products of genes that have duplicated and then diverged in sequence. The proteins C4 and C3 are homologous and contain the unstable thioester bond by which their large fragments, C4b and C3b, bind covalently to membranes. The genes encoding proteins C2 and factor B are adjacent in the MHC region of the genome and arose by gene duplication. The regulatory proteins factor H, CR1, and C4BP share a repeat sequence common to many complement-regulatory proteins. The greatest divergence between the pathways is in their initiation: in the classical pathway the C1 complex binds either to certain pathogens or to bound antibody, and in the latter circumstance it serves to convert antibody binding into enzyme activity on a specific surface; in the lectin pathway, mannose-binding lectin (MBL) associates with a serine protease, activating MBL-associated serine protease (MASP), to serve the same function as C1r:C1s; in the alternative pathway this enzyme activity is provided by factor D.
Fig. 2.29 Complement component C5 is cleaved when captured by a C3b molecule that is part of a C5 convertase complex. As shown in the top panel, C5 convertases are formed when C3b binds either the classical or lectin pathway C3 convertase C4b2a to form C4b2a3b, or the alternative pathway C3 convertase C3bBb to form C3b2Bb. C5 binds to C3b in these complexes (center panel). The bottom panel shows that C5 is cleaved by the active enzyme C2a or Bb to form C5b and the inflammatory mediator C5a. Unlike C3b and C4b, C5b is not covalently bound to the cell surface. The production of C5b initiates the assembly of the terminal complement components.
the most primitive modern representatives—because genomic evidence of C3, factor B, and some later-acting complement components has been found in the Anthozoa (corals and sea anemones).