Functions of Complement

The principal effector functions of the complement system in innate immunity and specific 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 describe each of these functions of the complement system and their role in host defense.

Opsonization and Phagocytosis

Microbes on which complement is activated by the alternative or classical pathway become coated with C3b, iC3b, or C4b and are phagocytosed by the binding of these proteins to specific receptors on macrophages and neutrophils (Fig. 12-17A). 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 the fact that they 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

Activation of late components of complements É Jc7|c3

Poly-C9

CD59 inhibits poly-C9 assembly

S protein inhibits membrane insertion of C5b-C7

Poly-C9

FIGURE 12-16 Regulation of formation of the MAC. The MAC is formed on cell surfaces as an end result of complement activation. The membrane protein CD59 and S protein in the plasma inhibit formation of the MAC.

of C3b-coated microbes, but its ability to do so is enhanced if the microbes are coated with IgG antibodies that simultaneously bind to Fcy receptors. Macrophage activation by the cytokine IFN-y 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 pneu-mococci and meningococci, which is mediated primarily by humoral immunity. IgM antibodies against capsular polysaccharides bind to the bacteria, activate the classical pathway of complement, and cause phagocytic clearance of the bacteria in the spleen. In addition, SIGN-R1-ex-pressing marginal zone macrophages may also bind to capsular polysaccharides and activate the classical pathway in the absence of antibody. This is why individuals lacking the spleen (e.g., as a result of surgical removal after traumatic rupture or in patients with autoimmune hemolytic anemia or thrombocytopenia) are susceptible to disseminated pneumococcal and meningococcal septicemia. C3-deficient humans and mice are extremely susceptible to lethal bacterial infections.

Stimulation of Inflammatory Responses

The proteolytic complement fragments C5a, C4a, and C3a induce acute inflammation by activating mast cells and neutrophils (Fig. 12-17B). All three peptides bind to mast cells and induce degranulation, with the release of vaso-active mediators such as histamine. These peptides are also called anaphylatoxins because the mast cell reactions they trigger are characteristic of anaphylaxis (see Chapter 19). 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 about 20-fold less potent, and C4a is about 2500-fold less. The proinflammatory effects of C5a, C4a, and C3a are mediated by binding of the peptides to specific receptors on various cell types. The C5a receptor is the most thoroughly characterized. It is a

Opsonization and phagocytosis

C3b]

Binding of C3b (or C4b) to microbe (opsonization)

Microbe

Microbe

Recognition of bound C3b by phagocyte C3b receptor

Phagocytosis of microbe

Stimulation of inflammatory reactions tí

Binding of C3b to microbe, release of C3a; proteolysis of C5, releasing C5a

Binding of C3b to microbe, release of C3a; proteolysis of C5, releasing C5a

Complement-mediated cytolysis

Binding of C3b to bacteria, activation of late components of complement

Binding of C3b to bacteria, activation of late components of complement

FIGURE 12-17 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 MAC lyses cells (C).

Formation of the membrane attack complex (MAC)

FIGURE 12-17 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 MAC lyses cells (C).

member of the seven-a-helical transmembrane G protein-coupled receptor family. The C5a receptor is expressed on many cell types, including neutrophils, eosinophils, basophils, monocytes, macrophages, mast cells, endothelial cells, smooth muscle cells, epithelial cells, and astrocytes. The C3a receptor is also a member of the G protein-coupled receptor family.

Complement-Mediated Cytolysis

Complement-mediated lysis of foreign organisms is mediated by the MAC (Fig. 12-17C). 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 infections by bacteria of the genus Neisseria that have very 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 interactions 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 are bound 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 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 for the B cell antigen receptor, thus enhancing antigen-induced signaling in B cells (see Chapter 7). Opsonized antigens are also bound by follicular dendritic cells in the germinal centers of lymphoid organs. Follicu-lar dendritic cells display antigens to B cells in the germinal centers, and this process is important for the selection of high-affinity B cells (see Chapter 11, Fig. 11-13). 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.

Although our discussion has emphasized the physiologic functions of complement as an effector mechanism of host defense, the complement system is also involved in several pathologic conditions. Some autoimmune diseases are associated with the production of autoantibodies specific for self proteins expressed on cell surfaces (see Chapter 18). Binding of these antibodies results in complement-dependent lysis and phagocytosis of the cells. In other diseases, immune complexes deposit in tissues and induce inflammation by complement-mediated recruitment and activation of leukocytes.

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