Immunology. Richard Coico

Immunology - Richard Coico


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similar to MBL and also binds carbohydrates, such as N‐acetylglucosamine or N‐acetylgalactosamine, on microbial surfaces.

      Mannan‐binding lectin and ficolin are found in the circulation complexed with proteases, known as the mannose‐associated serine proteases (MASPs). Once bound to the bacterium, one of the proteases, MASP‐2, sequentially cleaves C4 and C2 to form C4b2a on the surface of the bacterium. As we discussed previously, C4b2a is also formed in the classical pathway; it is the C3 convertase that cleaves the next component in the pathway, C3. Thus, the lectin and classical pathways converge at this point.

      Alternative Pathway

       Activators.

       Early Steps in the Alternative Pathway That Lead to C3 Cleavage.

      The deposition of C3b on the cell surface initiates the alternative pathway (see Figure 4.2C). C3b is generated in the circulation in small amounts by the spontaneous cleavage of a reactive thiol group in C3; this “preformed” C3b can bind to proteins and carbohydrates expressed on cell surfaces, either of a pathogen or of a host (mammalian) cell. (If C3b does not bind to one of these surfaces, it is rapidly inactivated.)

      Thus, in a sense, the alternative pathway is always “on,” and continual activation could damage cells of the host. However, as we describe in more detail subsequently, mammalian cells regulate the progression of the alternative pathway. Microbial cells lack such regulators and cannot prevent the development of subsequent steps in the alternative pathway.

      Following the deposition of C3b, the serum protein factor B combines with C3b on the cell surface to form a complex, C3bB. Factor D then cleaves factor B in the cell surface‐associated C3bB complex, generating fragments Ba, which is released into the fluid phase, and Bb, which remains attached to C3b. C3bBb is the alternative pathway C3 convertase, which cleaves C3 into C3a and C3b.

      Steps Shared by All Pathways: Activation of C3 and C5

Schematic illustration of 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.

      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.

      Terminal Pathway

      The first step in MAC formation is C6 binding to C5b on the cell surface. C7 then binds to C5b and C6, with C7 inserting into the outer membrane of the cell. The subsequent binding of C8 to C5b67 results in the complex penetrating deeper into the cell’s membrane. C5b‐C8 on the cell membrane acts as a receptor for C9, a perforin‐like molecule that binds to C8. Additional C9 molecules interact with the C9 molecule in the complex to form polymerized C9 (poly‐C9). Poly‐C9 forms a transmembrane channel that disturbs the cell’s osmotic equilibrium: ions pass through the channel and water enters the cell. The cell swells and the membrane becomes permeable to macromolecules, which then escape from the cell. The result is cell lysis.

Schematic illustration of the formation of membrane attack complex. Late-stage complement components C5b–C9 bind sequentially to form a complex on the cell surface. Multiple C9 components bind to this complex and polymerize to form poly-C9, creating a channel that disrupts the cell membrane.

      Uncontrolled complement activation can rapidly deplete complement components, leaving the host unable to defend against subsequent invasion by infectious agents. In addition, the fragments generated by complement activation (especially the cleavage products of C3, C4, and C5) induce potent inflammatory responses, which may damage the host. Indeed, complement activation


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