Читать книгу Immunology - Richard Coico - Страница 91

C3 cleavage is the first step that is common to all three complement pathways (Figure 4.3). In the classical and lectin pathways (Figure 4.3A), the C3 convertase C4b2a cleaves C3 into two fragments, C3a and C3b. In the alternative pathway (Figure 4.3B), the C3 convertase C3bBb cleaves C3 into the same two fragments. The smaller fragment, C3a, is released into the fluid phase, and the larger one, C3b, continues the complement activation cascade by binding covalently to the cell surface around the site of complement activation.

Note a unique feature of the alternative pathway shown in Figure 4.3B: binding of the serum protein properdin (also known as factor P) stabilizes C3bBb on the pathogen surface. As a result, C3bBb rapidly cleaves further C3 molecules, resulting in the huge build‐up of C3b on the surface of the pathogen. As we described above, the deposition of C3b on a cell surface is the initiating step in the activation of the alternative pathway. Thus, deposition on the cell surface of these rapidly produced and increased levels of C3b results in an almost explosive triggering of the alternative pathway. As we describe below, properdin’s ability to activate this amplification loop is balanced by negative or regulatory molecules. Consequently, under normal conditions, the alternative pathway is not continually activated.

Figure 4.3. Cleavage of C3 by C3 convertase and C5 by C5 convertase. (A) Classical and lectin pathways. (B) Alternative pathway. In all pathways, C3 is cleaved to C3b, which deposits on the cell surface, and C3a, which is released into the fluid phase. Similarly, C5 is cleaved into C5b, which deposits on the cell surface, and C5a, which is released into the fluid phase. In the alternative pathway, the stabilization of C3bBb by properdin increases C3b deposition on the cell surface and amplification of complement activation.

C3b binding to either the classical/lectin or alternative pathway C3 convertases allows the next component in the sequence, C5, to bind and be cleaved (middle section of Figure 4.3A,B). For this reason, the C3 convertases with bound C3b are referred to as C5 convertases—C4b2a3b in the classical/lectin pathways, C3bBb3b in the alternative pathway. The cleavage of C5 produces two fragments: C5a is released into the fluid phase and has potent anaphylatoxic properties, and C5b binds to the cell surface and forms the nucleus for the binding of the terminal complement components.