The Alternative Pathway Is Antibody Independent

The alternative pathway generates bound C5b, the same product that the classical pathway generates, but it does so without the need for antigen-antibody complexes for initiation. Because no antibody is required, the alternative pathway is a component of the innate immune system. This major pathway of complement activation involves four serum proteins: C3, factor B, factor D, and properdin. The alternative pathway is initiated in most cases by cell-surface constituents that are foreign to the host (Table 13-1). For example, both gram-negative and gram-positive bacteria have cell-wall constituents that can activate the alternative pathway. The intermediates in the alternative pathway for generating C5b are shown schematically in Figure 13-7 (page 306).

In the classical pathway, C3 is rapidly cleaved to C3a and C3b by the enzymatic activity of the C3 convertase. In the alternative pathway, serum C3, which contains an unstable thioester bond, is subject to slow spontaneous hydrolysis to yield C3a and C3b. The C3b component can bind to foreign surface antigens (such as those on bacterial cells or viral particles) or even to the host's own cells (see Figure 13-6c). The membranes of most mammalian cells have high levels of sialic acid, which contributes to the rapid inactivation of bound C3b molecules on host cells; consequently this binding rarely leads to further reactions on the host cell membrane. Because many foreign antigenic surfaces (e.g., bacterial cell walls, yeast cell walls, and certain viral envelopes) have only low levels of sialic acid, C3b bound to these surfaces remains active for a longer time. The C3b present on the surface of the foreign cells can bind another serum protein called factor B to form a complex stabilized by Mg2 + . Binding to C3b exposes a site on factor B that serves as the sub-

C4b2a

Activated C3b

Cell membrane

Bound C3b

FIGURE 13-6

Hydrolysis of C3 by C3 convertase C4b2a (a) Native C3. (b) Activated C3 showing site of cleavage by C4b2a resulting in production of the C3a and C3b fragments. (c) A labile internal thioester bond in C3 is activated as C3b is formed, allowing the C3b fragment to bind to free hydroxyl or amino groups (R) on a cell membrane. Bound C3b exhibits various biological activities, including binding of C5 and binding to C3b receptors on phagocytic cells.

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.

strate 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 analogous to the C4b4a 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 activate unhydrolyzed C3 to generate more C3b autocatalytically. As a result, the initial steps are repeated and amplified, so that more than 2 X 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 CBBBb3b complex, which exhibits C5 convertase activity, analogous to the C4b2a3b 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.

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