We learned in Section 2-4 that proteolysis can be used as a means of activating antimicrobial proteins. In the complement system, activation by proteolysis is inherent, with many of the complement proteins being proteases that successively cleave and activate one another. The proteases of the complement system are synthesized as inactive pro-enzymes, or zymogens, which become enzymatically active only after proteolytic cleavage, usually by another complement protein. The complement pathways are triggered by proteins that act as pattern recognition receptors to detect the presence of pathogens. This detection activates an initial zymogen, triggering a cascade of proteolysis in which complement zymogens are activated sequentially, each becoming an active protease that cleaves and activates many molecules of the next zymogen in the pathway, amplifying the signal as the cascade proceeds. This results in activation of three distinct effector pathways—inflammation, phagocytosis, and membrane attack—that help eliminate the pathogen. In this way, the detection of even a small number of pathogens produces a rapid response that is greatly amplified at each step. This overall scheme for complement is shown in Fig. 2.13.
Fig. 2.13 The complement system proceeds in distinct phases in the elimination of microbes. Proteins that can distinguish self from microbial surfaces (yellow box) activate a proteolytic amplification cascade that ends in the formation of the critical enzymatic activity (green box) of C3 convertase, a family of proteases. This activity is the gateway to three effector arms of complement that produce inflammation (purple), enhance phagocytosis of the microbe (blue), and lyse microbial membranes (pink). We will use this color scheme in the figures throughout this chapter to illustrate which activity each complement protein serves.
MOVIE 2.1
Nomenclature for complement proteins can seem confusing, so we will start by explaining their names. The first proteins discovered belong to the classical pathway, and they are designated by the letter C followed by a number. The native complement proteins—such as the inactive zymogens—have a simple number designation, for example, C1 and C2. Unfortunately, they were named in the order of their discovery rather than the sequence of reactions. The reaction sequence in the classical pathway, for example, is C1, C4, C2, C3, C5, C6, C7, C8, and C9 (note that not all of these are proteases). Products of cleavage reactions are designated by adding a lowercase letter as a suffix. For example, cleavage of C3 produces a small protein fragment called C3a and the remaining larger fragment, C3b. By convention, the larger fragment for other factors is designated by the suffix b, with one exception. For C2, the larger fragment was named C2a by its discoverers, and this system has been maintained in the literature, so we preserve it here. Another exception is the naming of C1q, C1r, and C1s: these are not cleavage products of C1 but are distinct proteins that together comprise C1. The proteins of the alternative pathway were discovered later and are designated by different capital letters, for example, factor B and factor D. Their cleavage products are also designated by the addition of lowercase a and b: thus, the large fragment of B is called Bb and the small fragment Ba. Activated complement components are sometimes designated by a horizontal line, for example, C2a; however, we will not use this convention. All the components of the complement system are listed in Fig. 2.14.
Besides acting in innate immunity, complement also influences adaptive immunity. Opsonization of pathogens by complement facilitates their uptake by phagocytic antigen-presenting cells that express complement receptors; this enhances the presentation of pathogen antigens to T cells, which we discuss in more detail in Chapter 6. B cells express receptors for complement proteins that enhance their responses to complement-coated antigens, as we describe later in Chapter 10. In addition, several of the complement fragments can act to influence cytokine production by antigen-presenting cells, thereby influencing the direction and extent of the subsequent adaptive immune response, as we describe in Chapter 11.
2-5 The complement system recognizes features of microbial with C3b.