the fragments generated by complement activation (especially the cleavage products of C3, C4, and C5) induce potent inflammatory responses, which may damage the host. Indeed, complement activation is believed to play an adverse role in autoinflammatory conditions such as rheumatoid arthritis and in myocardial infarctions (heart attacks) in which complement is activated by necrotic tissue (discussed later in the chapter). In addition, dysregulation of complement function in the eye has been suggested as playing a major role in age‐related macular degeneration, the leading cause of visual impairment and blindness in the USA among individuals over 60 years of age.
Normally, inappropriate activation of complement does not occur, because many steps in the complement pathways are negatively regulated by specific inhibitors. Some of these negative regulators are specific for one complement activation pathway, but many inhibit all the pathways. The importance of these complement regulators is underscored by the clinical conditions that arise when regulatory molecules are lacking: The individual may either be damaged by inflammatory responses or become susceptible to infectious diseases. Some of these conditions are described later in the chapter.
Many of the molecules that regulate complement activation are expressed on the surface of mammalian cells but not microbial cells. Consequently, damage to the host by complement activation is generally limited compared to damage to the pathogen. In the paragraphs below and Figure 4.5, we describe the major regulators of complement activation.
C1 esterase inhibitor (C1INH) is a serum protein that inhibits the first step in the activation of the classical complement pathway. C1INH binds to C1r and C1s, causing them to dissociate from C1q and preventing complement activation. In addition, C1INH regulates the alternative pathway by inhibiting the function of C3bBb, and recent evidence indicates that it controls the lectin pathway by inhibiting MASP1 and MASP2. As described in the final section of the chapter, C1INH also inhibits the function of enzymes in other serum cascades, particularly those involved in clotting and in the formation of kinins, potent mediators of vascular effects.
C4b‐binding protein (C4BP) is found in serum and decay‐accelerating factor (DAF, CD55), complement receptor (CR) 1 (CD35), and membrane cofactor protein (MCP, CD46) are widely distributed cell surface molecules that regulate the classical and lectin pathway C3 convertase, C4b2a. Figure 4.5A shows that all these proteins can bind individually to C4b and displace the activated enzyme component, C2a.
Factor I, another serum protein, cleaves C4b on the cell surface after C2a has been displaced (see Figure 4.5A). Because factor I cleavage of C4b requires the presence of one or more of C4BP, MCP, and CR1, these molecules are referred to as co‐factors for factor I‐mediated cleavage. Note that DAF dissociates the C4b2a complex but does not act as a co‐factor for factor I. Factor I cleaves C4b into two fragments: C4c, released into the fluid phase, and C4d, which remains attached to the cell surface. C4c and C4d do not continue the complement cascade and have no known biological activity. C4BP regulates the classical (and lectin) pathways, which use C4bC2a as the C3 convertase. CR1, MCP, and DAF regulate the classical, lectin, and alternative pathways (described below and shown in Figure 4.5B).
Factor H, a serum protein, has two important regulatory functions in the alternative pathway. First, it competes with the previously described factor B for binding to C3b on a cell surface (see Figure 4.2, bottom line). Factor B binding to C3b continues the alternative pathway, but if factor H binds to C3b, the pathway stops. The nature of the surface to which the C3b is bound is important in determining which factor binds to C3b. The sialic acid coating of mammalian cells favors the binding of factor H, but bacterial cells lack sialic acid, so they favor the binding of factor B to C3b. As a result, mammalian cells are protected by the regulatory function of factor H, but bacterial cells are targeted for further activation of the complement pathway.
Factor H has a second function: it binds to C3 convertase C3bBb in the alternative pathway and displaces Bb, preventing further activation of the complement cascade (see Figure 4.5B). Once factor H has bound to C3b, factor I cleaves C3b; thus, factor H is a co‐factor for factor I‐mediated cleavage of C3b in the alternative pathway. C3b is cleaved stepwise, first to iC3b (indicating an inactive C3b) and then to two additional fragments: C3c, which is released into the fluid phase and lacks biological function, and C3d, which remains attached to the cell surface. The breakdown products iC3b, C3c, and C3d do not continue the complement cascade, but iC3b and C3d have important biological functions that we describe in the next section.
The same cell surface molecules that inhibit the function of classical pathway C3 convertase C4b2a (DAF, MCP, and CR1) regulate the alternative pathway convertase, C3bBb (see Figure 4.5B). As we mentioned above, factor I regulates both the classical and alternative pathways by cleaving C4b in the former and C3b in the latter.
Figure 4.5. Regulators of C3 convertases in (A) classical pathway and (B) alternative pathway. Regulators may dissociate the convertase, cleave the complement component remaining on the cell surface, or act as a co‐factor for this cleavage. C4 binding protein exclusively regulates the classical pathway and factor H regulates the alternative pathway. Factor I, DAF, CR1, and MCP regulate both pathways.
The terminal pathway of complement activation and the formation of the MAC are also strictly regulated. Because the association of C5b with cell membranes is relatively nonspecific, the association of terminal pathway components C6–C9 with C5b on cell surfaces can form a MAC that damages or lyses “innocent bystander” cells of the host. Both membrane‐associated proteins and fluid‐phase proteins prevent this from occurring. CD59, a widely distributed membrane protein, prevents lysis by binding to the C5b–C8 complex on the cell surface and preventing C9 polymerization. S‐protein (vitronectin) and SP‐40,40 (clusterin) are fluid‐phase proteins that bind to C5b6, C5b67, C5b678, and C5b6789, and prevent their interaction with membranes.
BIOLOGICAL ACTIVITIES OF COMPLEMENT
The major functions of the complement system are summarized below and shown in Figures 4.6 and 4.7. Complement components interact with a wide range of cells that express specific receptors. The receptors fall into two broad categories: receptors that bind to C3b or C4b and their breakdown products; and receptors for the anaphylatoxins C3a and C5a (Table 4.2). (Distribution of the C4a receptor is not shown; it overlaps with the cellular distribution of the C3a receptor.) The receptors and cells that bind C3b, C4b, and their breakdown products are involved in responses that enhance phagocytosis of pathogens, and the receptors and cells that bind the anaphylatoxins are involved in inflammatory responses.
The three main functions of complement are shown in Figure
