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There are three pathways of complement activation: the classical, lectin, and alternative pathways. The key features of each are shown in Figure 4.1. Each pathway is initiated when a serum protein binds to the surface of a pathogen. The classical pathway is activated when complement component C1 binds to an antigen–antibody complex (most often, antibody bound to the surface of a pathogen such as a bacterium). The lectin pathway is activated when mannan‐binding lectin (MBL) binds to terminal polysaccharide residues on the surface of many types of microbes (Gram‐positive and Gram‐negative bacteria, fungi, or yeast); the lectin pathway can also be activated by another serum protein, ficolin, which binds to acetylated molecules on microbial surfaces. The alternative pathway is activated when complement component C3b deposits on the surface of a pathogen.

TABLE 4.1. Complement protein synthesis/secretion by various immune cells

Cell	Complement proteins
B cell	C5
T cell	C3, C5, factor B, factor D, factor P
Polymorphonuclear leukocyte	C3, C6, C7, ficolin‐1, factor B, factor P
Mast cell	C3, C5, C1q
Monocyte	C1q, C1r, C3, C5, C6, C7, C8, factor B, factor D
Macrophage	C1q, C1r, C3, C5, factor B, factor D
Dendritic cell	C1q, C1r, C3, C5, C7, C8, CD9, factor B, factor D

Although the three pathways are initiated by different activators, the early steps in each have a common general mechanism: complement components are sequentially activated on the surface of the pathogen. That is, activation of the component induces enzymatic function that acts on the next component in the cascade, splitting it into biologically active fragments, and so on. In addition, several activated complement components build up on the surface of the pathogen.

Figure 4.1. Summary of classical, lectin, and alternative complement activation pathways: key activators, initiating complement components, components common to all pathways, and major activities generated.

After the early steps, the pathways converge at the cleavage of complement component C3. Cleavage of C3 forms C3b and a small fragment, C3a. C3b covalently binds to the surface of the pathogen. C3b is an opsonin, which means that its deposition on the pathogen surface enhances pathogen uptake by phagocytic cells (see also Chapter 6). Thus opsonization of pathogens is one of the key functions of the complement activation pathways. C3a, released into the fluid phase, is an anaphylatoxin, a molecule that induces potent inflammatory responses by activating multiple cells. Thus, induction of inflammatory responses is a second key function resulting from complement activation.

As we describe in more detail below, in the alternative pathway the generation of C3b from C3 sets up an amplification loop that results in further triggering of the pathway.

After C3b has bound to the pathogen surface, the next component in the sequence, C5, is cleaved to produce C5b and C5a. C5b deposits on the surface of the pathogen, allowing the binding of components C6 through C9. These terminal components, C5b to C9, form a complex known as the membrane attack complex (MAC) on the surface of the pathogen that leads to the killing (lysis) of the pathogen. Thus, killing of pathogens is the third major function of complement activation. C5a, like C3a, is a small fluid‐phase anaphylatoxin.

Thus, all three pathways of complement activation result in three major biological activities: the production of opsonins on the pathogen surface, the synthesis of fluid‐phase anaphylatoxins that enhance inflammatory responses, and direct killing of the pathogen. All these activities lead to either rapid removal or direct destruction of the pathogen. We now describe each of the pathways and biological activities in more detail.