certain proteins of bacterial cell walls and polyanionic structures such as the lipoteichoic acid on Gram-positive bacteria. A second is through binding to C-reactive protein, an acute-phase protein in human plasma that binds to phosphocholine residues in bacterial surface molecules such as pneumococcal C polysaccharide—hence the name C-reactive protein. We discuss the acute-phase proteins in detail in Chapter 3. However, a main function of C1q in an immune response is to bind to the constant, or Fc, regions of antibodies (see Section 1-9) that have bound pathogens via their antigen-binding sites. C1q thus links the effector functions of complement to recognition provided by adaptive immunity. This might seem to limit the usefulness of C1q in fighting the first stages of an infection, before the adaptive immune response has generated pathogen-specific antibodies. However, some antibodies, called natural antibodies, are produced by the immune system in the apparent absence of infection. These antibodies have a low affinity for many microbial pathogens and are highly cross-reactive, recognizing common membrane constituents such as phosphocholine and even recognizing some antigens of the body’s own cells (that is, self antigens). Natural antibodies may be produced in response to commensal microbiota or to self antigens, but do not seem to be the consequence of an adaptive immune response to infection by pathogens. Most natural antibody is of the isotype, or class, known as IgM (see Sections 1-9 and 1-20) and represents a considerable amount of the total IgM circulating in humans. IgM is the class of antibody most efficient at binding C1q, making natural antibodies an effective means of activating complement on microbial surfaces immediately after infection and leading to the clearance of bacteria such as Streptococcus pneumoniae (the pneumococcus) before they become dangerous.
2-8 Complement activation is largely confined to the surface on which it is initiated.
We have seen that both the lectin and the classical pathways of complement activation are initiated by proteins that bind to pathogen surfaces. During the triggered enzyme cascade that follows, it is important that activating events are confined to this same site, so that C3 activation also occurs on the surface of the
Fig. 2.23 The alternative pathway of complement activation can amplify the classical or the lectin pathway by forming an alternative C3 convertase and depositing more C3b molecules on the pathogen. C3b deposited by the classical or lectin pathway can bind factor B, making it susceptible to cleavage by factor D. The C3bBb complex is the C3 convertase of the alternative pathway of complement activation, and its action, like that of C4b2a, results in the deposition of many molecules of C3b on the pathogen surface.
pathogen and not in the plasma or on host-cell surfaces. This is achieved principally by the covalent binding of C4b to the pathogen surface. In innate immunity, C4 cleavage is catalyzed by a ficolin or MBL complex that is bound to the pathogen surface, and so the C4b cleavage product can bind adjacent proteins or carbohydrates on the pathogen surface. If C4b does not rapidly form this bond, the thioester bond is cleaved by reaction with water and C4b is irreversibly inactivated. This helps to prevent C4b from diffusing from its site of activation on the microbial surface and becoming attached to healthy host cells.