Several mechanisms ensure that complement activation will proceed only on the surface of a pathogen or on damaged host cells, and not on normal host cells and tissues. After initial complement activation by any pathway, the extent of amplification via the alternative pathway is critically dependent on the stability of the C3 convertase C3bBb. This stability is controlled by both positive and negative regulatory proteins. We have already described how properdin acts as a positive regulatory protein on foreign surfaces, such as those of bacteria or damaged host cells, by stabilizing C3bBb.
Several negative regulatory proteins, present in plasma and in host-cell membranes, protect healthy host cells from the injurious effects of inappropriate complement activation on their surfaces. These complement-regulatory proteins interact with C3b and either prevent the convertase from forming or promote its rapid dissociation (Fig. 2.27). For example, a membrane-attached protein known as decay-accelerating factor (DAF or CD55) competes with factor B for binding to C3b on the cell surface and can displace Bb from a convertase that has already formed. Convertase formation can also be prevented by cleaving C3b to an inactive derivative, iC3b. This is achieved by a plasma protease, factor I, in conjunction with C3b-binding proteins that act as cofactors, such as membrane cofactor of proteolysis (MCP or CD46), another host-cell membrane protein (see Fig. 2.27). Cell-surface complement receptor type 1 (CR1, also known as CD35) behaves similarly to DAF and MCP in that it inhibits C3 convertase formation and promotes the catabolism of C3b to inactive products, but it has a more limited tissue distribution. Factor H is another complement-regulatory protein in plasma that binds C3b, and like CR1, it is able to compete with factor B to displace Bb from the convertase; in addition, it acts as a cofactor for factor I. Factor H binds preferentially to C3b bound to vertebrate cells because it has an affinity for the sialic acid residues present on their cell surfaces (see Fig. 2.18). Thus, the amplification loop of the alternative pathway is allowed to proceed on the surface of a pathogen or on damaged host cells, but not on normal host cells or on tissues that express these negative regulatory proteins.
The C3 convertase of the classical and lectin pathways (C4b2a) is molecularly distinct from that of the alternative pathway (C3bBb). However, understanding of the complement system is simplified somewhat by recognition of the close evolutionary relationships between the different complement proteins (Fig. 2.28). Thus the complement zymogens, factor B and C2, are closely related proteins encoded by homologous genes located in tandem within the major
The complement system and innate immunity.
histocompatibility complex (MHC) on human chromosome 6. Furthermore, their respective binding partners, C3 and C4, both contain thioester bonds that provide the means of covalently attaching the C3 convertases to a pathogen surface.
Only one component of the alternative pathway seems entirely unrelated to its functional equivalents in the classical and lectin pathways: the initiating serine protease, factor D. Factor D can also be singled out as the only activating protease of the complement system to circulate as an active enzyme rather than a zymogen. This is both necessary for the initiation of the alternative pathway (through the cleavage of factor B bound to spontaneously activated C3) and safe for the host, because factor D has no other substrate than factor B bound to C3b. This means that factor D finds its substrate only at pathogen surfaces and at a very low level in plasma, where the alternative pathway of complement activation can be allowed to proceed.
2-11 Complement developed early in the evolution of multicellular organisms.