After its initial appearance, the complement system seems to have evolved by the acquisition of new activation pathways that allow specific targeting of microbial surfaces. The first to evolve was likely the ficolin pathway, which is present both in vertebrates and in some closely related invertebrates, such as the urochordates. Evolutionarily, the ficolins may predate the collectins, which are also first seen in the urochordates. Homologs of MBL and of the classical pathway complement component C1q, both collectins, have been identified in the genome of the ascidian urochordate Ciona (sea squirt). Two invertebrate homologs of mammalian MASPs also have been identified in Ciona, and it seems likely that they may be able to cleave and activate C3. Thus, the minimal complement system of the echinoderms appears to have been expanded in the urochordates by the recruitment of a specific activation system that may target C3 deposition onto microbial surfaces. This also suggests that when adaptive immunity evolved, much later, the ancestral antibody molecule used an already diversified C1q-like collectin member to activate the complement pathway, and that the complement activation system evolved further by use of this collectin and its associated MASPs to become the initiating components of the classical complement pathway, namely, C1q, C1r, and C1s.
2-12 Surface-bound C3 convertase deposits large numbers of convertase activity.
We now return to the present-day complement system. The formation of C3 convertases is the point at which the three pathways of complement activation converge. The convertase of the lectin and classical pathways, C4b2a, and the convertase of the alternative pathway, C3bBb, initiate the same subsequent events—they cleave C3 to C3b and C3a. C3b binds covalently through its thioester bond to adjacent molecules on the pathogen surface; otherwise it is inactivated by hydrolysis. C3 is the most abundant complement protein in plasma, occurring at a concentration of 1.2 mg/ml, and up to 1000 molecules of C3b can bind in the vicinity of a single active C3 convertase (see Fig. 2.23). Thus, the main effect of complement activation is to deposit large quantities of C3b on the surface of the infecting pathogen, where the C3b forms a covalently bonded coat that can signal the ultimate destruction of the pathogen by phagocytes.
The next step in the complement cascade is the generation of the C5 convertases. C5 is a member of the same family of proteins as C3, C4, α2-macroglobulin, and the thioester-containing proteins (TEPs) of invertebrates. C5 does not form an active thioester bond during its synthesis but, like C3 and C4, it is cleaved by a specific protease into C5a and C5b fragments, each of which exerts specific downstream actions that are important in propagating the complement cascade. In the classical and the lectin pathways, a C5 convertase is formed by the binding of C3b to C4b2a to yield C4b2a3b. The C5 convertase of the alternative pathway is formed by the binding of C3b to the C3bBb convertase to form C3b2Bb. A C5 is captured by these C5 convertase complexes through binding to an acceptor site on C3b, and is thus rendered susceptible to cleavage by the serine protease activity of C2a or Bb. This reaction, which generates C5b and C5a, is much more limited than cleavage of C3, because C5 can be cleaved only when it binds to C3b that is in turn bound to C4b2a or C3bBb to form the active C5 convertase complex. Thus, complement activated by all three pathways leads to the binding of large numbers of C3b molecules on the surface of the pathogen, the generation of a more limited number of C5b molecules, and the release of C3a and a smaller amount of C5a (Fig. 2.29).
The complement system and innate immunity.