Fig. 2.15 Complement is a system of soluble pattern recognition receptors and effector molecules that detect and destroy microorganisms. The pathogen-recognition mechanisms of the three complement-activation pathways are shown in the top row, along with the complement components used in the proteolytic cascades leading to formation of a C3 convertase. This enzyme activity cleaves complement component C3 into the small soluble protein C3a and the larger component C3b, which becomes covalently bound to the pathogen surface (middle row). The components are listed by biochemical function in Fig, 2.14 and are described in detail in later figures. The lectin pathway of complement activation (top left) is triggered by the binding of mannose-binding lectin (MBL) or ficolins to carbohydrate residues in microbial cell walls and capsules. The classical pathway (top center) is triggered by binding of C1 either to the pathogen surface or to antibody bound to the pathogen. In the alternative pathway (top right), soluble C3 undergoes spontaneous hydrolysis in the fluid phase, generating C3(H2O), which is augmented by the action of factors B, D, and P (properdin). All pathways thus converge on the formation of C3b bound to a pathogen and lead to all of the effector activities of complement, which are shown in the bottom row. C3b bound to a pathogen acts as an opsonin, enabling phagocytes that express receptors for C3b to ingest the complement-coated microbe more easily (bottom center). C3b can also bind to C3 convertases to produce another activity, a C5 convertase (detail not shown here), which cleaves C5 to C5a and C5b. C5b triggers the late events of the complement pathway in which the terminal components of complement—C6 to C9—assemble into a membrane-attack complex (MAC) that can damage the membrane of certain pathogens (bottom right). C3a and C5a act as chemoattractants that recruit immune-system cells to the site of infection and cause inflammation (bottom left).
specific receptors and helps induce inflammation. Cleavage of C3 is the critical step in complement activation and leads directly or indirectly to all the effector activities of the complement system (see Fig. 2.15). C3b binds covalently to the microbial surface and acts as an opsonin, enabling phagocytes that carry receptors for complement to take up and destroy the C3b-coated microbe. Later in the chapter, we will describe the different complement receptors that bind C3b that are involved in this function of complement and how C3b is degraded by a serum protease into inactive smaller fragments called C3f and C3dg. C3b can also bind to the C3 convertases produced by the classical and lectin pathways and form another multisubunit enzyme, the C5 convertase. This cleaves C5, liberating the highly inflammatory peptide C5a and generating C5b. C5b initiates the ‘late’ events of complement activation, in which additional complement proteins interact with C5b to form a membraneattack complex (MAC) on the pathogen surface, creating a pore in the cell membrane that leads to cell lysis (see Fig. 2.15, bottom right).
The key feature of C3b is its ability to form a covalent bond with microbial surfaces, which allows the innate recognition of microbes to be translated into effector responses. Covalent bond formation is due to a highly reactive thioester bond that is hidden inside the folded C3 protein and cannot react until C3 is cleaved. When C3 convertase cleaves C3 and releases the C3a fragment, large conformational changes occur in C3b that allow the thioester bond to react with a hydroxyl or amino group on the nearby microbial surface (Fig. 2.16). If no bond is made, the thioester is rapidly hydrolyzed, inactivating C3b, which is one way the alternative pathway is inhibited in healthy individuals. As we will see below, some of the individual components of C3 and C5 convertases differ between the various complement pathways; the components that are different are listed in Fig. 2.17.