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FIGURE 12-11 C1 binding to the Fc portions of IgM and IgG. C1 must bind to two or more Fc portions to initiate the complement cascade. The Fc portions of soluble pentameric IgM are not accessible to C1 (A). After IgM binds to surface-bound antigens, it undergoes a shape change that permits C1 binding and activation (B). Soluble IgG molecules will also not activate C1 because each IgG has only one Fc region (C), but after binding to cell surface antigens, adjacent IgG Fc portions can bind and activate C1 (D).

FIGURE 12-11 C1 binding to the Fc portions of IgM and IgG. C1 must bind to two or more Fc portions to initiate the complement cascade. The Fc portions of soluble pentameric IgM are not accessible to C1 (A). After IgM binds to surface-bound antigens, it undergoes a shape change that permits C1 binding and activation (B). Soluble IgG molecules will also not activate C1 because each IgG has only one Fc region (C), but after binding to cell surface antigens, adjacent IgG Fc portions can bind and activate C1 (D).

is larger.) The resulting C4b2a complex is the classical pathway C3 convertase; it has the ability to bind to and proteolytically cleave C3. Binding of this enzyme complex to C3 is mediated by the C4b component, and proteolysis is catalyzed by the C2a component. Cleavage of C3 results in the removal of the small C3a fragment, and C3b can form covalent bonds with cell surfaces or with the antibody where complement activation was initiated. Once C3b is deposited, it can bind factor B and generate more C3 convertase by the alternative pathway, as discussed earlier. The net effect of the multiple enzymatic steps and amplification is that a single molecule of C3 convertase can lead to the deposition of hundreds or thousands of molecules of C3b on the cell surface where complement is activated. The key early steps of the alternative and classical pathways are analogous: C3 in the alternative pathway is homologous to C4 in the classical pathway, and factor B is homologous to C2.

Some of the C3b molecules generated by the classical pathway C3 convertase bind to the convertase (as in the alternative pathway) and form a C4b2a3b complex. This complex functions as the classical pathway C5 convertase; it cleaves C5 and initiates the late steps of complement activation.

An unusual antibody-independent variant form of the classical pathway, which is activated by carbohydrates binding to a cell surface lectin, occurs in pneumococcal infections. Splenic marginal zone macrophages express a cell surface C-type lectin called SIGN-R1 that can recognize the pneumococcal polysaccharide and can also bind C1q. Multivalent binding of whole bacteria or the polysaccharide to SIGN-R1 activates the classical pathway and permits the eventual coating of the pneumococcus with C3b. This is an example of a cell surface lectin that mediates activation of the classical pathway but without a requirement for antibody.

The Lectin Pathway

The lectin pathway of complement activation is triggered in the absence of antibody by the binding of micro-bial polysaccharides to circulating lectins, such as plasma mannose (or mannan)-binding lectin (MBL), or to fico-lins (Table 12-6). These soluble lectins are collagen-like proteins that structurally resemble C1q (see Fig. 4-10, Chapter 4). MBL, L-ficolin, and H-ficolin are plasma proteins; M-ficolin is mainly secreted by activated macrophages in tissues. MBL is a member of the collectin family and has an N-terminal collagen-like domain and a C-terminal carbohydrate recognition domain. The fico-lins have a similar structure with an N-terminal collagenlike domain and a C-terminal fibrinogen-like domain. The collagen-like domains help assemble basic triple-helical structures that can form higher order oligomers. MBL binds to mannose residues on polysaccharides; the ficolin fibrinogen-like domain binds N-acetylglucosamine-containing glycans. MBL and ficolins associate with MBL-associated serine proteases (MASPs) including MASP1, MASP2, and MASP3 (see Table 12-6). The MASP proteins are structurally homologous to the C1r and C1s proteases and serve a similar function, namely, the cleavage of C4 and C2 to activate the complement pathway. Higher order oligomers of MBL associate with MASP1 and MASP2, although MASP3/MASP2 complexes may also be found. MASP1 (or MASP3) can form a tetrameric complex with MASP2 similar to the one formed by C1r and C1s, and MASP2 is the protease that cleaves C4 and C2. Subsequent events in this pathway are identical to those that occur in the classical pathway.

Late Steps of Complement Activation

C5 convertases generated by the alternative, classical, or lectin pathway initiate activation of the late components of the complement system, which culminates in formation of the cytocidal membrane attack complex (MAC) (Table 12-7 and Fig. 12-12). C5 convertases cleave C5 into a small C5a fragment that is released and a two-chain C5b fragment that remains bound to the complement proteins deposited on the cell surface. C5a has potent biologic effects on several cells that are discussed later in this chapter. The remaining components of the complement

TABLE 12-6 Proteins of the Lectin Pathway of Complement

Protein

Structure

Serum Concentration

(|xg/mL)

Function

Mannose-binding lectin

Helical trimer of 32-kD chain and dimers to hexamers of this triple helix

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