Pathways of Complement Activation

There are three major pathways of complement activation: the classical pathway, which is activated by certain isotypes of antibodies bound to antigens; the alternative pathway, which is activated on microbial cell surfaces in the absence of antibody; and the lectin pathway, which is activated by a plasma lectin that binds to mannose residues on microbes (Fig. 12-6). The names classical and alternative arose because the classical pathway was discovered and characterized first, but the alternative

Alternative Pathway

Binding of complement proteins to microbial cell surface or antibody

Formation of C3 convertase

Cleavage of C3

Formation of C5 convertase

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C5 convertase

C5 convertase

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Mannose binding lectin

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FIGURE 12-6 The early steps of complement activation by the alternative, classical, and lectin pathways. The alternative pathway is activated by C3b binding to various activating surfaces, such as microbial cell walls; the classical pathway is initiated by C1 binding to antigen-antibody complexes; and the lectin pathway is activated by binding of a plasma lectin to microbes. The C3b that is generated by the action of the C3 convertase binds to the microbial cell surface or the antibody and becomes a component of the enzyme that cleaves C5 (C5 convertase) and initiates the late steps of complement activation. The late steps of all three pathways are the same (not shown here), and complement activated by all three pathways serves the same functions.

pathway is phylogenetically older. Although the pathways of complement activation differ in how they are initiated, all of them result in the generation of enzyme complexes that are able to cleave the most abundant complement protein, C3. The alternative and lectin pathways are effector mechanisms of innate immunity, whereas the classical pathway is a major mechanism of adaptive humoral immunity.

The central event in complement activation is proteolysis of the complement protein C3 to generate biologically active products and the subsequent covalent attachment of a product of C3, called C3b, to microbial cell surfaces or to antibody bound to antigen (see Fig. 12-6). Complement activation depends on the generation of two proteolytic complexes: the C3 convertase, which cleaves C3 into two proteolytic fragments called C3a and C3b; and the C5 convertase, which cleaves C5 into C5a and C5b. By convention, the proteolytic products of each complement protein are identified by lowercase letter suffixes, a referring to the smaller product and b to the larger one. C3b becomes covalently attached to the microbial cell surface or to the antibody molecules at the site of complement activation. All the biologic functions of complement are dependent on the proteo-lytic cleavage of C3. For example, complement activation promotes phagocytosis because phagocytes (neutrophils and macrophages) express receptors for C3b. Peptides produced by proteolysis of C3 (and other complement proteins) stimulate inflammation. The C5 convertase assembles after the prior generation of C3b, and this convertase contributes both to inflammation (by the generation of the C5a fragment) and to the formation of pores in the membranes of microbial targets. The pathways of complement activation differ in how C3b is produced but follow a common sequence of reactions after the cleavage of C5.

With this background, we proceed to more detailed descriptions of the alternative, classical, and lectin pathways.

The Alternative Pathway

The alternative pathway of complement activation results in the proteolysis of C3 and the stable attachment of its breakdown product C3b to microbial surfaces, without a role for antibody (Fig. 12-7 and Table 12-4). The C3 protein contains a reactive thioester bond that is buried in a region of the protein known as the thioester domain. When C3 is cleaved, the C3b molecule undergoes a dramatic conformational change and the thioester domain flips out (a massive shift of about 85 A), exposing the previously hidden reactive thioester bond. Normally, C3 in plasma is being continuously cleaved at a low rate to generate C3b in a process that is called C3 tickover. A small amount of the C3b may become covalently attached to the surfaces of cells, including microbes, through the thioester domain, which reacts with the amino or hydroxyl groups of cell surface proteins or polysaccha-rides to form amide or ester bonds (Fig. 12-8). If these bonds are not formed, the C3b remains in the fluid phase, and the exposed and reactive thioester bond is quickly hydrolyzed, rendering the protein inactive. As a result, further complement activation cannot proceed.

When C3b undergoes its post-cleavage conformational change, a binding site for a plasma protein called factor B is also exposed. Factor B then binds to the C3b protein that is now covalently tethered to the surface of a micro-bial or host cell. Bound factor B is in turn cleaved by a plasma serine protease called factor D, releasing a small fragment called Ba and generating a larger fragment called Bb that remains attached to C3b. The C3bBb complex is the alternative pathway C3 convertase, and it functions to cleave more C3 molecules, thus setting up an amplification sequence. Even when C3b is generated by the classical or lectin pathways, it can form a complex with Bb, and this complex is able to cleave more C3. Thus, the alternative pathway C3 convertase functions to amplify complement activation when it is initiated by the alternative, classical, or lectin pathways. When C3 is broken down, C3b remains attached to cells and C3a is released. This soluble fragment has several biologic activities that are discussed later.

Alternative pathway activation readily occurs on microbial cell surfaces and not on mammalian cells. If the C3bBb complex is formed on mammalian cells, it is rapidly degraded and the reaction is terminated by the action of several regulatory proteins present on these cells (discussed later). Lack of the regulatory proteins on microbial cells allows binding and activation of the alternative pathway C3 convertase. In addition, another protein of the alternative pathway, called properdin, can bind to and stabilize the C3bBb complex, and the attachment of properdin is favored on microbial as opposed to normal host cells. Properdin is the only known positive regulator of complement.

Some of the C3b molecules generated by the alternative pathway C3 convertase bind to the convertase itself. This results in the formation of a complex containing one Bb moiety and two molecules of C3b, which functions as the alternative pathway C5 convertase, which will cleave C5 and initiate the late steps of complement activation.

The Classical Pathway

The classical pathway is initiated by binding of the complement protein C1 to the CH2 domains of IgG or the CH3 domains of IgM molecules that have bound antigen (Fig. 12-9 and Table 12-5). Among IgG antibodies, IgG3 and IgG1 (in humans) are more efficient activators of complement than are other subclasses. C1 is a large, multimeric protein complex composed of C1q, C1r, and C1s sub-units; C1q binds to the antibody, and C1r and C1s are proteases. The C1q subunit is made up of an umbrellalike radial array of six chains, each of which has a globular head connected by a collagen-like arm to a central stalk. This hexamer performs the recognition function of the molecule and binds specifically to the Fc regions of | and some y heavy chains (Fig. 12-10). Each Ig Fc region has a single C1q-binding site, and each C1q molecule must bind to at least two Ig heavy chains to be activated. This requirement explains why antibodies bound to antigens, and not free circulating antibodies, can initiate classical pathway activation (Fig. 12-11). Because each IgG molecule has only one Fc region, multiple IgG molecules must be brought close together before C1q can bind, and

Spontaneous cleavage of C3

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