Immunology. Richard Coico
4.6A). C3b and C4b are the major opsonins generated, but iC3b, a fragment of C3b that does not activate complement, also has opsonic activity. Bacteria coated by opsonins are rapidly taken up and destroyed by phagocytic cells such as macrophages and neutrophils. These cells express the receptors CR1, CR3, and CR4, which have broad specificities for complement pathway‐generated opsonins and for other complement components. Complement receptor of the immunoglobulin family (CRIg) is expressed on tissue‐resident macrophages, including those found in liver (Kupffer cells). It interacts with C3b and iC3b. CR1 is also a regulator of complement activation, as described earlier (see Figure 4.5).
Production of Anaphylatoxins
The second major function associated with complement activation is the action of anaphylatoxins (see Figure 4.6B). C5a is the most potent, followed by C3a; C4a is much less potent. The name “anaphylatoxin” derives from the earliest recognition of their function: the ability to induce the shock‐like characteristics of the systemic allergic or anaphylactic response (see Chapter 13). We now recognize that these small peptides play key roles in inducing inflammatory responses, which form part of the body’s defenses in removing an infectious agent that has penetrated the tissues.
The anaphylatoxins interact with receptors expressed on many different cell types (see Table 4.2 and Figure 4.6B). They activate vascular endothelial cells (lining the walls of blood vessels), increasing the vascular permeability and leading to local accumulation of fluid (edema) in the tissue. The influx into the tissue of fluid containing phagocytic cells (macrophages and neutrophils), antibodies, and complement components enhances the response to the pathogen. The anaphylatoxins are also chemotactic for neutrophils; that is, the cells migrate from an area of lesser concentration to an area of higher concentration. As a result, neutrophils circulating in the blood are activated, leave the circulation at the site of inflammation, and destroy the foreign material. The anaphylatoxins also induce smooth muscle contraction. Interaction of the anaphylatoxins with basophils or mast cells in tissues results in the release of many inflammatory mediators, including histamine. The effects of histamine (discussed in Chapter 13) and the anaphylatoxins on vascular permeability and smooth muscle contraction are similar.
Lysis
The third major function of complement is the lysis of pathogens (see Figure 4.6C). The terminal step in the three complement activation pathways is the formation of a MAC on the surface of a cell. This results in the lysis of the cell, particularly of microbial pathogens.
Other Important Complement Functions
Enhancing B‐Cell Responses to Antigens.
The binding of complement component C3d or the final breakdown product of C3, C3dg, to CR2 (CD21) enhances antibody responses in several ways (Figure 4.7Ai) and discussed in Chapter 9. First, C3dg binds to antigen that is also bound to B‐cell surface Ig (see Figure 4.7A). C3dg can bind simultaneously to CR2, which is part of the B‐cell co‐receptor (see Chapter 9). Signaling through both the surface Ig and the co‐receptor augments activation of the B cell. Thus, C3dg binding to antigen and the B‐cell surface lowers the threshold for B‐cell activation by as much as 1000‐fold compared to binding in the absence of C3dg.
Figure 4.6. Major functions of complement: (A) production of opsonins; (B) production of anaphylatoxins; and (C) pathogen lysis.
Second, follicular dendritic cells in the germinal center bind antigen–antibody complexes and present antigen to proliferating B cells. This interaction is critical for the eventual development of memory cells. Follicular dendritic cells express the complement receptors CR2, which binds C3dg, and CR1, which binds iC3b. Thus follicular dendritic cells can present antigen–antibody complexes bound to one of these complement components to germinal center B cells (see Figure 4.7Aii). In this way, complement components also play a role in the induction of B‐cell memory.
In addition, B‐cell processing of T‐dependent antigens is more rapid when the antigen is bound to C3dg than when it is not; presumably the binding of C3dg to CR2 on the B‐cell surface enhances uptake and processing of the antigen. This may be another way in which complement enhances B‐cell responses to T‐cell‐dependent antigens.
Controlling Formation and Clearance of Immune Complexes.
When antibodies bind to multivalent antigens, cross‐linking between the molecules tends to produce large antigen–antibody complexes that increase in size until they become insoluble. Although this precipitation of complexes has proved useful for identifying antigens and antibodies in vitro (see Chapter 6), the formation of large insoluble complexes in vivo can be detrimental to the host. As we describe in the final section of this chapter and in Chapter 16, individuals deficient in early components of the classical pathway components and in some autoimmune conditions such as systemic lupus erythematosus (SLE) may show large insoluble immune complexes in tissues such as the skin and kidneys, inducing inflammation and damaging surrounding cells (see also Figure 12.11 in Chapter 12).
Figure 4.7. Other key functions of complement: enhancement of B‐cell responses, removal of immune complexes, removal of necrotic cells and subcellular membranes, and responses to viruses.
TABLE 4.2. Complement Receptors
| Complement receptor | Cell distribution | Complement components bound | Receptor function |
|---|---|---|---|
| CR1 (CD35) | Erythrocytes, monocytes, macrophages, eosinophils, neutrophils, B cells, some T cells, follicular dendritic cells, mast cells | C3b, iC3b, C3c, C4b | Enhances phagocytosis; regulates complement activation pathways |
| CR2 (CD21) | Late precursor and mature B lymphocytes, some T cells (including thymocytes), follicular dendritic cells |
|