The Complement System cHAPTER 13 305 Initiators of the alternative pathway ment binds to mannose residues, some authors designate this TABLE 13-1 of complement activation the MBLectin pathway or mannan-binding lectin pathway. The lectin pathway, like the alternative pathway, does not de- PATHOGENS AND PARTICLES OF MICROBIAL ORIGIN pend on antibody for its activation. However, the mechanism is more like that of the classical pathway, because after initia Many strains of gram-negative bacteria tion, it proceeds, through the action of C4 and C2, to pro- Lipopolysaccharides from gram-negative bacteria duce a C5 convertase(see Figure 13-2) Many strains of gram-positive bacteria The lectin pathway is activated by the binding of man- nose-binding lectin (MBL) to mannose residues on glyce proteins or carbohydrates on the surface of microorganisms Fungal and yeast cell walls(zymosa including certain Salmonella, Listeria, and Neisseria strains, Some viruses and virus-infected cells ell as Cryptococcus neoformans and Candida albicans. Some tumor cells(Raji) MBL is an acute phase protein produced in inflammatory Its function in the way is sin Parasites(trypanosomes to that of C1q, which it resembles in structure. After MBL NONPATHOGENS binds to the surface of a cell or pathogen, MBL-associated serine proteases, MASP-1 and MASP-2, bind to MBL. The ac Human igG, IgA and ige in complexes tive complex formed by this association causes cleavage and Rabbit and guinea pig IgG in complexes activation of C4 and C2. The MASP-1 and-2 proteins have Cobra venom factor structural similarity to CIr and Cls and mimic their activi- ties. This means of activating the C2-C4 components to Heterologous erythrocytes(rabbit, mouse, chicken) form a C5 convertase without need for specific antibody Anionic polymers(dextran sulfate) binding represents an important innate defense mechanism Pure carbohydrates(agarose, inulin) able to the alternative pathway but utilizing the ele- ments of the classical pathway except for the Cl proteins SOURCE: Adapted from M.K. Pangburn, 1986, in Immunobiology of the Complement System, Academic Press The Three Complement Pathways Converge at the Membrane-Attack Complex The terminal sequence of complement activation involves strate for an enzymatically active serum protein called factor C5b, C6, C7, C8, and C9, which interact sequentially to form D Factor d cleaves the C3b-bound factor B, releasing a small a macromolecular structure called the membrane-attack fragment(Ba)that diffuses away and generating C3bBb. The complex (MAC). This complex forms a large channel C3bBb complex has C3 convertase activity and thus is analo- through the membrane of the target cell, enabling ions and gous to the C4b2a complex in the classical pathway. The C3 small molecules to diffuse freely across the membrane convertase activity of C3b Bb has a half-life of only 5 minutes The end result of activating the classical, alternative, or unless the serum protein properdin binds to it, stabilizing lectin pathways is production of an active C5 convertase it and extending the half-life of this convertase activity to his enzyme cleaves C5, which contains two protein chains, 30 minutes a and B After binding of C5 to the nonenzymatic C3b com The C3bBb generated in the alternative pathway can acti- ponent of the convertase, the amino terminus of the a chain te unhydrolyzed C3 to generate more C3b autocatalytically. is cleaved. This generates the small C5a fragment, which dif- As a result, the initial steps are repeated and amplified, so fuses away, and the large C5b fragment, which binds to the that more than 2 x 106 molecules of C3b can be deposited surface of the target cell and provides a binding site for the on an antigenic surface in less than 5 minutes. The C3 con- subsequent components of the membrane-attack complex vertase activity of c3bbb generates the C3bBb36 complex, see Figure 13-5, step 5). The C5b component is extremely la which exhibits C5 convertase activity, analogous to the bile and becomes inactive within 2 minutes unless c6 binds C4b2a3b col to it and stabilizes its activity matic C3b component binds C5, and the Bb component Up to this point, all the complement reactions take place C5b(see Figure 13-7); the latter binds to the antigenic surface. complexes in the fluid phase. As C5b6 binds to C7, the result ing complex undergoes a hydrophilic-amphiphilic structural The Lectin Pathway Originates With Host transition that exposes hydrophobic regions, which serve as Proteins Binding Microbial Surfaces binding sites for membrane phospholipids. If the occurs on a target-cell membrane, the hydrophobic Lectins are proteins that recognize and bind to specific car- sites enable the C5b67 complex to insert into the phospho- bohydrate targets. (Because the lectin that activates comple- lipid bilayer. If, however, the reaction occurs on an immunestrate for an enzymatically active serum protein called factor D. Factor D cleaves the C3b-bound factor B, releasing a small fragment (Ba) that diffuses away and generating C3bBb . The C3bBb complex has C3 convertase activity and thus is analo￾gous to the C4b2a complex in the classical pathway. The C3 convertase activity of C3bBb has a half-life of only 5 minutes unless the serum protein properdin binds to it, stabilizing it and extending the half-life of this convertase activity to 30 minutes. The C3bBb generated in the alternative pathway can acti￾vate unhydrolyzed C3 to generate more C3b autocatalytically. As a result, the initial steps are repeated and amplified, so that more than 2  106 molecules of C3b can be deposited on an antigenic surface in less than 5 minutes. The C3 con￾vertase activity of C3bBb generates the C3b Bb3b complex, which exhibits C5 convertase activity, analogous to the C4b2a 3b complex in the classical pathway. The nonenzy￾matic C3b component binds C5, and the Bb component subsequently hydrolyzes the bound C5 to generate C5a and C5b (see Figure 13-7); the latter binds to the antigenic surface. The Lectin Pathway Originates With Host Proteins Binding Microbial Surfaces Lectins are proteins that recognize and bind to specific car￾bohydrate targets. (Because the lectin that activates comple￾ment binds to mannose residues, some authors designate this the MBLectin pathway or mannan-binding lectin pathway.) The lectin pathway, like the alternative pathway, does not de￾pend on antibody for its activation. However, the mechanism is more like that of the classical pathway, because after initia￾tion, it proceeds, through the action of C4 and C2, to pro￾duce a C5 convertase (see Figure 13-2). The lectin pathway is activated by the binding of man￾nose-binding lectin (MBL) to mannose residues on glyco￾proteins or carbohydrates on the surface of microorganisms including certain Salmonella, Listeria, and Neisseria strains, as well as Cryptococcus neoformans and Candida albicans. MBL is an acute phase protein produced in inflammatory responses. Its function in the complement pathway is similar to that of C1q, which it resembles in structure. After MBL binds to the surface of a cell or pathogen, MBL-associated serine proteases, MASP-1 and MASP-2, bind to MBL. The ac￾tive complex formed by this association causes cleavage and activation of C4 and C2. The MASP-1 and -2 proteins have structural similarity to C1r and C1s and mimic their activi￾ties. This means of activating the C2–C4 components to form a C5 convertase without need for specific antibody binding represents an important innate defense mechanism comparable to the alternative pathway, but utilizing the ele￾ments of the classical pathway except for the C1 proteins. The Three Complement Pathways Converge at the Membrane-Attack Complex The terminal sequence of complement activation involves C5b, C6, C7, C8, and C9, which interact sequentially to form a macromolecular structure called the membrane-attack complex (MAC). This complex forms a large channel through the membrane of the target cell, enabling ions and small molecules to diffuse freely across the membrane. The end result of activating the classical, alternative, or lectin pathways is production of an active C5 convertase. This enzyme cleaves C5, which contains two protein chains, and . After binding of C5 to the nonenzymatic C3b com￾ponent of the convertase, the amino terminus of the chain is cleaved. This generates the small C5a fragment, which dif￾fuses away, and the large C5b fragment, which binds to the surface of the target cell and provides a binding site for the subsequent components of the membrane-attack complex (see Figure 13-5, step 5). The C5b component is extremely la￾bile and becomes inactive within 2 minutes unless C6 binds to it and stabilizes its activity. Up to this point, all the complement reactions take place on the hydrophilic surface of membranes or on immune complexes in the fluid phase. As C5b6 binds to C7, the result￾ing complex undergoes a hydrophilic-amphiphilic structural transition that exposes hydrophobic regions, which serve as binding sites for membrane phospholipids. If the reaction occurs on a target-cell membrane, the hydrophobic binding sites enable the C5b67 complex to insert into the phospho￾lipid bilayer. If, however, the reaction occurs on an immune The Complement System CHAPTER 13 305 TABLE 13-1 Initiators of the alternative pathway of complement activation PATHOGENS AND PARTICLES OF MICROBIAL ORIGIN Many strains of gram-negative bacteria Lipopolysaccharides from gram-negative bacteria Many strains of gram-positive bacteria Teichoic acid from gram-positive cell walls Fungal and yeast cell walls (zymosan) Some viruses and virus-infected cells Some tumor cells (Raji) Parasites (trypanosomes) NONPATHOGENS Human IgG, IgA, and IgE in complexes Rabbit and guinea pig IgG in complexes Cobra venom factor Heterologous erythrocytes (rabbit, mouse, chicken) Anionic polymers (dextran sulfate) Pure carbohydrates (agarose, inulin) SOURCE: Adapted from M. K. Pangburn, 1986, in Immunobiology of the Complement System, Academic Press.