300 paRt I Immune Effector Mechanisms LYSIS OPSONIZATION ACTIVATION OF INFLAMMATORY LEARANCE OF RESPONSE IMMUNE COMPLEXES Bacteria Complement complex Extravasation Blood Target cell P FIGURE 13-1 The multiple activities of the complement system. phagocytes: activation of inflammatory responses; and clearance of Serum complement proteins and membrane-bound complement circulating immune complexes by cells in the liver and spleen receptors partake in a number of immune activities: lysis of foreign Soluble complement proteins are schematically indicated by a trian- cells by antibody-dependent or antibody-independent pathways: gle and receptors by a semi-circle; no attempt is made to differenti opsonization or uptake of particulate antigens, including bacteria, by ate among individual components of the complement system here C5b, can occur by the classical pathway, the alternative The Complement Components pathway, or the lectin pathway. The final steps that lead to a membrane attack are the same in all pathways The proteins and glycoproteins that compose the complement system are synthesized mainly by liver hepatocytes, although signilicant amounts are also produced by blood monocytes, tis. The Classical Pathway Begins with sue macrophages, and epithelial clls of the gastrointestinal and Antigen-Antibody Binding weight) of the serum globulin fraction. Most circulate in the Complement activation by the classical pathway commonly serum in functionally inactive forms as proenzymes, or zymo- begins with the formation of soluble antigen-antibody com gens, which are inactive until proteolytic cleavage, which re- plexes(immune complexes)or with the binding of antibody moves an inhibitory fragment and exposes the active site. The to antigen on a suitable target, such as a bacterial cell IgM and complement-reaction sequence starts with an enzyme cascade. certain subclasses of IgG(human IgG1, IgG2, and igG3)can Complement components are designated by numerals activate the classical complement pathway. The initial stage of (C1-C9), by letter symbols (e.g, factor D), or by trivial activation involves C1, C2, C3, and CA, which are present in names(e.g, homologous restriction factor). Peptide frag- plasma in functionally inactive forms. Because the compo- ments formed by activation of a component are denoted by nents were named in order of their discovery and before their small letters. In most cases, the smaller fragment resulting functional roles had been determined, the numbers in their from cleavage of a component is designated"a"and the larger names do not always reflect the order in which they react. fragment designated"b"(e. g, C3a, C3b: note that C2 is an The formation of an antigen-antibody complex induces exception: C2a is the larger cleavage fragment). The larger conformational changes in the Fc portion of the igM mole fragments bind to the target near the site of activation, and cule that expose a binding site for the cl component of the the smaller fragments diffuse from the site and can initiate complement system. Cl in serum is a macromolecular com localized inflammatory responses by binding to specific re- plex consisting of Clq and two molecules each of Cir and ceptors. The complement fragments interact with one an- Cls, held together in a complex(C1qr2S2)stabilized by Ca other to form functional complexes. Those complexes that ions. The Clq molecule is composed of 18 polypeptide nated by a bar over the num- chains that associate to form six collagen-like triple helical ber or symbol (e.g, C4b2a, arms, the tips of which bind to exposed Clq- binding sites in the Ch2 domain of the antibody molecule(Figure 13-3, page 302). Each Clr and Cls monomer contains a catalytic Complement Activation domain and an interaction domain the latter facilitates in- teraction with Clq or with each other. Figure 13-2 on page 301 outlines the pathways of com Each C1 molecule must bind by its C1q globular heads to ment activation. The early steps, culminating in formation at least two Fc sites for a stable Cl-antibody interaction toThe Complement Components The proteins and glycoproteins that compose the complement system are synthesized mainly by liver hepatocytes, although significant amounts are also produced by blood monocytes, tis￾sue macrophages, and epithelial cells of the gastrointestinal and genitourinary tracts. These components constitute 5% (by weight) of the serum globulin fraction. Most circulate in the serum in functionally inactive forms as proenzymes, or zymo￾gens, which are inactive until proteolytic cleavage, which re￾moves an inhibitory fragment and exposes the active site. The complement-reaction sequence starts with an enzyme cascade. Complement components are designated by numerals (C1–C9), by letter symbols (e.g., factor D), or by trivial names (e.g., homologous restriction factor). Peptide frag￾ments formed by activation of a component are denoted by small letters. In most cases, the smaller fragment resulting from cleavage of a component is designated “a” and the larger fragment designated “b” (e.g., C3a, C3b; note that C2 is an exception: C2a is the larger cleavage fragment). The larger fragments bind to the target near the site of activation, and the smaller fragments diffuse from the site and can initiate localized inflammatory responses by binding to specific re￾ceptors. The complement fragments interact with one an￾other to form functional complexes. Those complexes that have enzymatic activity are designated by a bar over the num￾ber or symbol (e.g., C4b2a, C3bBb). Complement Activation Figure 13-2 on page 301 outlines the pathways of comple￾ment activation. The early steps, culminating in formation of 300 PART III Immune Effector Mechanisms C5b, can occur by the classical pathway, the alternative pathway, or the lectin pathway. The final steps that lead to a membrane attack are the same in all pathways. The Classical Pathway Begins with Antigen-Antibody Binding Complement activation by the classical pathway commonly begins with the formation of soluble antigen-antibody com￾plexes (immune complexes) or with the binding of antibody to antigen on a suitable target, such as a bacterial cell. IgM and certain subclasses of IgG (human IgG1, IgG2, and IgG3) can activate the classical complement pathway. The initial stage of activation involves C1, C2, C3, and C4, which are present in plasma in functionally inactive forms. Because the compo￾nents were named in order of their discovery and before their functional roles had been determined, the numbers in their names do not always reflect the order in which they react. The formation of an antigen-antibody complex induces conformational changes in the Fc portion of the IgM mole￾cule that expose a binding site for the C1 component of the complement system. C1 in serum is a macromolecular com￾plex consisting of C1q and two molecules each of C1r and C1s, held together in a complex (C1qr2s2) stabilized by Ca2 ions. The C1q molecule is composed of 18 polypeptide chains that associate to form six collagen-like triple helical arms, the tips of which bind to exposed C1q-binding sites in the CH2 domain of the antibody molecule (Figure 13-3, on page 302). Each C1r and C1s monomer contains a catalytic domain and an interaction domain; the latter facilitates in￾teraction with C1q or with each other. Each C1 molecule must bind by its C1q globular heads to at least two Fc sites for a stable C1-antibody interaction to FIGURE 13-1 The multiple activities of the complement system. Serum complement proteins and membrane-bound complement receptors partake in a number of immune activities: lysis of foreign cells by antibody-dependent or antibody-independent pathways; opsonization or uptake of particulate antigens, including bacteria, by phagocytes; activation of inflammatory responses; and clearance of circulating immune complexes by cells in the liver and spleen. Soluble complement proteins are schematically indicated by a trian￾gle and receptors by a semi-circle; no attempt is made to differenti￾ate among individual components of the complement system here. Complement receptor Blood Tissue Phagocyte Phagocyte Degranulation Target cell Ag-Ab complex Complement Extravasation Bacteria LYSIS OPSONIZATION ACTIVATION OF INFLAMMATORY RESPONSE CLEARANCE OF IMMUNE COMPLEXES