PART III Immune Effector mechanisms damage and restore its osmotic stability. An unfortunate con- C3a, C5a, and C5b67 can each induce monocytes and sequence of this effect is that complement-mediated lysis by neutrophils to adhere to vascular endothelial cells, ex- antibodies specific for tumor-cell antigens, which offers a po- travasate through the endothelial lining of the capillary, and tential weapon against cancer, may be rendered ineffective by migrate toward the site of complement activation in the tis- endocytosis of the MAc (see Chapter 22) sues. C5a is most potent in mediating these processes, effec- tive in picomolar quantities. The role of complement in Cleavage Products of Complement leukocyte chemotaxis is discussed more fully in Chapter 15 Components Mediate Inflammation The complement cascade is often viewed in terms of the fi- C3b and C4b Binding Facilitates nal outcome of cell lysis, but various peptides generated Opsonization during formation of the mac play a decisive role in the de- C3b is the major opsonin of the complement system, al- velopment of an effective inflammatory response(see Table though C4b and iC3b also have opsonizing activity. The am- 13-3). The smaller fragments resulting from complement plification that occurs with C3 activation results in a coating cleavage, C3a, C4a, and C5a, called anaphylatoxins, bind to of C3b on immune complexes and particulate antigens. receptors on mast cells and blood basophils and induce de- Phagocytic cells, as well as some other cells, express comple granulation, with release of histamine and other pharmaco- ment receptors(CRl, CR3, and Cr4)that bind C3b, C4b, or logically active mediators. The anaphylatoxins also induce iC3b(see Table 13-4) Antigen coated with C3b binds to cells smooth-muscle contraction and increased vascular perme- bearing CRl. If the cell is a phagocyte (e. g, a neutrophil, ability. Activation of the complement system thus results in monocyte, or macrophage), phagocytosis will be enhanced influxes of fluid that carries antibody and phagocytic cells (Figure 13-12). Activation of phagocytic cells by various to the site of antigen entry. The activities of these highly re- agents, including C5a anaphylatoxin, has been shown to in tive anaphylatoxins are regulated by a serum protease crease the number of CRls from 5000 on resting phagocytes called carboxypeptidase N, which cleaves an Arg residue to 50,000 on activated cells, greatly facilitating their phagocy from the C terminus of the molecules, yielding so-called tosis of C3b-coated antigen. Recent studies indicate that des-Arg forms. The des-Arg forms of C3a and C4a are com- complement fragment C3b acts as an adjuvant when coupled pletely inactive while that of C5a retains about 10% of its with protein antigens. C3b targets the antigen directly to the chemotactic activity and 1%of its ability to cause smooth phagocyte, enhancing the initiation of antigen processing muscle contraction and accelerating specific antibody production Coated rticle Bacterium Complement activation o Fc receptor C3b Nucleus FIGURE 13-12(a)Schematic representation of the roles of C3b C3b receptor(CR1)on a B lymphocyte /Part(b)from NR.Cooper and antibody in opsonization. (b)Electron micrograph of Epstein- and G. R. Nemerow, 1986, in Immunobiology of the Complement Barr virus coated with antibody and C3b and bound to the Fc and System, Academic Press. jdamage and restore its osmotic stability. An unfortunate con￾sequence of this effect is that complement-mediated lysis by antibodies specific for tumor-cell antigens, which offers a po￾tential weapon against cancer, may be rendered ineffective by endocytosis of the MAC (see Chapter 22). Cleavage Products of Complement Components Mediate Inflammation The complement cascade is often viewed in terms of the fi￾nal outcome of cell lysis, but various peptides generated during formation of the MAC play a decisive role in the de￾velopment of an effective inflammatory response (see Table 13-3). The smaller fragments resulting from complement cleavage, C3a, C4a, and C5a, called anaphylatoxins, bind to receptors on mast cells and blood basophils and induce de￾granulation, with release of histamine and other pharmaco￾logically active mediators. The anaphylatoxins also induce smooth-muscle contraction and increased vascular perme￾ability. Activation of the complement system thus results in influxes of fluid that carries antibody and phagocytic cells to the site of antigen entry. The activities of these highly re￾active anaphylatoxins are regulated by a serum protease called carboxypeptidase N, which cleaves an Arg residue from the C terminus of the molecules, yielding so-called des-Arg forms. The des-Arg forms of C3a and C4a are com￾pletely inactive while that of C5a retains about 10% of its chemotactic activity and 1% of its ability to cause smooth muscle contraction. C3a, C5a, and C5b67 can each induce monocytes and neutrophils to adhere to vascular endothelial cells, ex￾travasate through the endothelial lining of the capillary, and migrate toward the site of complement activation in the tis￾sues. C5a is most potent in mediating these processes, effec￾tive in picomolar quantities. The role of complement in leukocyte chemotaxis is discussed more fully in Chapter 15. C3b and C4b Binding Facilitates Opsonization C3b is the major opsonin of the complement system, al￾though C4b and iC3b also have opsonizing activity. The am￾plification that occurs with C3 activation results in a coating of C3b on immune complexes and particulate antigens. Phagocytic cells, as well as some other cells, express comple￾ment receptors (CR1, CR3, and CR4) that bind C3b, C4b, or iC3b (see Table 13-4). Antigen coated with C3b binds to cells bearing CR1. If the cell is a phagocyte (e.g., a neutrophil, monocyte, or macrophage), phagocytosis will be enhanced (Figure 13-12). Activation of phagocytic cells by various agents, including C5a anaphylatoxin, has been shown to in￾crease the number of CR1s from 5000 on resting phagocytes to 50,000 on activated cells, greatly facilitating their phagocy￾tosis of C3b-coated antigen. Recent studies indicate that complement fragment C3b acts as an adjuvant when coupled with protein antigens. C3b targets the antigen directly to the phagocyte, enhancing the initiation of antigen processing and accelerating specific antibody production. 314 PART III Immune Effector Mechanisms FIGURE 13-12 (a) Schematic representation of the roles of C3b and antibody in opsonization. (b) Electron micrograph of Epstein￾Barr virus coated with antibody and C3b and bound to the Fc and C3b receptor (CR1) on a B lymphocyte. [Part (b) from N. R. Cooper and G. R. Nemerow, 1986, in Immunobiology of the Complement System, Academic Press.] Bacterium Complement activation Fc receptor CR1 C3b Phagocytosis Nucleus IgG (a) Phagocyte (b) Coated virus particle