Chapter 2 introduced the complement system as an essential component of innate immunity. Complement activation can proceed in the absence of antibody via the lectin pathway through the actions of mannose-binding lectin (MBL) and ficolins. But complement is also an important effector of antibody responses via the classical pathway. The different pathways of complement activation converge to coat pathogen surfaces or antigen:antibody complexes with covalently attached complement fragment C3b, which acts as an opsonin to promote uptake and removal by phagocytes. In addition, the terminal complement components can form a membrane-attack complex that damages some bacteria.
In the classical pathway, complement activation is triggered by C1, a complex of C1q and the serine proteases C1r and C1s (see Section 2-7). Complement activation is initiated when antibodies that are attached to the surface of a pathogen then bind to C1 via C1q (Fig. 10.35). C1q can be bound by either
Fig. 10.34 Antibodies can prevent the attachment of bacteria to cell surfaces. Many bacterial infections require an interaction between the bacterium and a cell-surface receptor. This is particularly true for infections of mucosal surfaces. The attachment process involves very specific molecular interactions between bacterial adhesins and their receptors on host cells; antibodies against bacterial adhesins can block such infections.
Fig. 10.35 The classical pathway of complement activation is initiated by the binding of C1q to antibody on a pathogen surface. When a molecule of IgM binds several identical epitopes on a pathogen surface, it is bent into the ‘staple’ conformation, which allows the globular heads of C1q to bind to the Fc regions of IgM (left panels). Multiple molecules of IgG bound on the surface of a pathogen allow the binding of a single molecule of C1q to two or more Fc regions (right panels). In both cases, the binding of C1q to the Fc regions induces a conformational change that activates the associated C1r, which becomes an active enzyme that cleaves the pro-enzyme C1s, generating a serine protease that initiates the classical complement cascade (see Chapter 2).
Fig. 10.36 The two conformations of IgM. The left panel shows the planar conformation of soluble IgM; the right panel shows the ‘staple’ conformation of IgM bound to a bacterial flagellum. Photographs (×760,000) courtesy of K.H. Roux.
IgM or IgG antibodies, but, because of the structural requirements of binding to C1q, neither of these antibody classes can activate complement in solution; the complement reactions are initiated only when the antibodies are already bound to multiple sites on a cell surface, normally that of a pathogen.
Each globular head of a C1q molecule can bind to one Fc region, and binding of two or more heads activates the C1 complex. In plasma, the pentameric IgM molecule has a planar conformation that does not bind C1q (Fig. 10.36, left panel); however, binding to the surface of a pathogen deforms the IgM pen-tamer so that it looks like a staple (see Fig. 10.36, right panel), and this distortion exposes binding sites for the C1q heads. As mentioned in Section 10-15, IgM hexamers can also form but comprise less than 5% of total serum IgM. Hexameric IgM activates complement about 20 times more efficiently than its pentameric form, possibly because C1q is also a hexamer. The in vivo role of IgM hexamers in protecting against infections has not been fully established, and it has even been suggested that IgM hexamers are too reactive and may be harmful.