C2 becomes susceptible to cleavage by C1s only when it is bound by C4b, and the active C2a serine protease is thereby also confined to the pathogen surface, where it remains associated with C4b, forming the C3 convertase C4b2a. Cleavage of C3 to C3a and C3b is thus also confined to the surface of the pathogen. Like C4b, C3b is inactivated by hydrolysis unless its exposed thioester rapidly makes a covalent bond (see Fig. 2.16), and it therefore opsonizes only the surface on which complement activation has taken place. Opsonization by C3b is more effective when antibodies are also bound to the pathogen surface, as phagocytes have receptors for both complement and Fc receptors that bind the Fc region of antibody (see Sections 1-20 and 10-20). Because the reactive forms of C3b and C4b are able to form a covalent bond with any adjacent protein or carbohydrate, when complement is activated by bound antibody, a proportion of the reactive C3b or C4b will become linked to the antibody molecules themselves. Antibody that is chemically cross-linked to complement is likely the most efficient trigger for phagocytosis.
2-9 The alternative pathway is an amplification loop for C3b formation that is accelerated by properdin in the presence of pathogens.
Although probably the most ancient of the complement pathways, the alternative pathway is so named because it was discovered as a second, or ‘alternative,’ pathway for complement activation after the classical pathway had been defined. Its key feature is its ability to be spontaneously activated. It has a unique C3 convertase, the alternative pathway C3 convertase, that differs from the C4b2a convertase of the lectin or classical pathways (see Fig. 2.17). The alternative pathway C3 convertase is composed of C3b itself bound to Bb, which is a cleavage fragment of the plasma protein factor B. This C3 convertase, designated C3bBb, has a special place in complement activation because, by producing C3b, it can generate more of itself. This means that once some C3b has been formed, by whichever pathway, the alternative pathway can act as an amplification loop to increase C3b production rapidly.
The alternative pathway can be activated in two different ways. The first is by the action of the lectin or classical pathway. C3b generated by either of these pathways and covalently linked to a microbial surface can bind factor B (Fig. 2.23). This alters the conformation of factor B, enabling a plasma protease
The complement system and innate immunity.
The C3(H2O)Bb complex is a C3 convertase, cleaving more C3 into C3a and C3b. C3b is rapidly inactivated unless it binds to a cell surface
Complement component C3 hydrolyzes spontaneously in plasma to give C3(H2O), which binds factor B and enables the bound factor B to be cleaved by factor D (first panel). The resulting ‘soluble C3 convertase’ cleaves C3 to give C3a and C3b, which can attach to host cells or pathogen surfaces (second panel). Covalently bound to the cell surface, C3b binds factor B; in turn, factor B is rapidly cleaved by factor D to Bb, which remains bound to C3b to form a C3 convertase (C3bBb), and Ba, which is released (third panel). This convertase functions in the alternative pathway as the C4b2a C3 convertase does in the lectin and classical pathways (see Fig. 2.17).