The principal functions of the complement system in innate immunity and adaptive humoral immunity are to promote phagocytosis of microbes on which complement is activated, to stimulate inflammation, and to induce the lysis of these microbes. In addition, products of complement activation facilitate the activation of B lymphocytes and the production of antibodies. Phagocytosis, inflammation, and stimulation of humoral immunity are all mediated by the binding of proteolytic fragments of complement proteins to various cell surface receptors, whereas cell lysis is mediated by the MAC. In the following section, we will describe these functions of the complement system and their roles in host defense.
Opsonization and Phagocytosis
Microbes on which complement is activated become coated with C3b, iC3b, or C4b and are phagocytosed by the binding of these proteins to specific receptors on macrophages and neutrophils (Fig. 1A). As discussed previously, activation of complement leads to the generation of C3b and iC3b covalently bound to cell surfaces. Both C3b and iC3b act as opsonins by virtue of their ability to specifically bind to receptors on neutrophils and macrophages. C3b and C4b (the latter generated by the classical pathway only) bind to CR1, and iC3b binds to CR3 (MAC-1) and CR4. By itself, CR1 is inefficient at inducing the phagocytosis of C3b-coated microbes, but its ability to do so is enhanced if the microbes are coated with IgG antibodies that simultaneously bind to Fcγ receptors. Macrophage activation by the cytokine IFN-γ also enhances CR1-mediated phagocytosis. C3b- and iC3b-dependent phagocytosis of microorganisms is a major defense mechanism against infections in innate and adaptive immunity. One example of the importance of complement is host defense against bacteria with polysaccharide-rich capsules, such as pneumococci and meningococci, which is mediated primarily by humoral immunity. IgM antibodies against capsular poly saccharides bind to the bacteria, activate the classical pathway of complement, and cause phagocytic clearance of the bacteria in the spleen. This is why individuals lacking a spleen (e.g., as a result of surgical removal after traumatic rupture or in patients with autoimmune hemolytic anemia or thrombocytopenia, and in patients with sickle cell disease) are susceptible to disseminated pneumococcal and meningococcal septicemia.
Fig1. Functions of complement. The major functions of the complement system in host defense are shown. Cell-bound C3b is an opsonin that promotes phagocytosis of coated cells (A); the proteolytic products C5a, C3a, and (to a lesser extent) C4a stimulate leukocyte recruitment and inflammation (B); and the mem brane attack complex (MAC) lyses cells (C).
Stimulation of Inflammatory Responses
The proteolytic complement fragments C5a, C4a, and C3a induce acute inflammation by activating mast cells, neutrophils, and endothelial cells (see Fig. 1B). All three peptides bind to mast cells and induce degranulation, with the release of vasoactive mediators, such as histamine. These peptides are also called anaphylatoxins because the mast cell reactions they trigger are characteristic of anaphylaxis. In neutrophils, C5a stimulates motility, firm adhesion to endothelial cells, and, at high doses, stimulation of the respiratory burst and production of reactive oxygen species. In addition, C5a may act directly on vascular endothelial cells and induce increased vascular permeability and the expression of P-selectin, which promotes neutrophil binding. This combination of C5a actions on mast cells, neutrophils, and endothelial cells contributes to inflammation at sites of complement activation. C5a is the most potent mediator of mast cell degranulation, C3a is approximately 20-fold less potent, and C4a is approximately 2500-fold less.
Complement-Mediated Cytolysis
Complement-mediated lysis of microbes is mediated by the MAC (see Fig. 1C). Most pathogens have evolved thick cell walls or capsules that impede access of the MAC to their cell membranes. Complement-mediated lysis appears to be critical for defense against only a few pathogens that are unable to resist MAC insertion, such as bacteria of the genus Neisseria, which have thin cell walls.
Other Functions of the Complement System
By binding to antigen-antibody complexes, complement proteins promote the solubilization of these complexes and their clearance by phagocytes. Small numbers of immune complexes are frequently formed in the circulation when an individual mounts a vigorous antibody response to a circulating antigen. If the immune complexes accumulate in the blood, they may be deposited in vessel walls and lead to inflammatory reactions that damage the vessels and surrounding tissue. The formation of immune complexes may require not only the multivalent binding of Ig Fab regions to antigens but also noncovalent inter actions of Fc regions of juxtaposed Ig molecules. Complement activation on Ig molecules can sterically block these Fc-Fc interactions, thereby promoting dissolution of the immune complexes. In addition, as discussed earlier, immune complexes with attached C3b bind to CR1 on erythrocytes, and the complexes are cleared by phagocytes in the liver.
The C3d protein generated from C3 binds to CR2 on B cells and facilitates B-cell activation and the initiation of humoral immune responses. C3d is generated when complement is activated by an antigen, either directly (e.g., when the antigen is a microbial polysaccharide) or after the binding of an antibody. Complement activation results in the covalent attachment of C3b and its cleavage product C3d to the antigen. B lymphocytes can bind the antigen through their Ig receptors and simultaneously bind the attached C3d through CR2, the coreceptor on B cells, thus enhancing antigen-induced signaling in B lymphocytes. Opsonized antigens are also bound by FDCs in the germinal centers of lymphoid organs. FDCs display antigens to B cells in the germinal centers, and this process is important for the selection of high-affinity B cells. The importance of complement in humoral immune responses is illustrated by the severe impairment in antibody production and germinal center formation seen in knockout mice lacking C3 or C4 or the CR2 protein.
