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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	C3b, iC3b, C3d/C3dg	Part of B‐cell co‐receptor: lowers threshold for B‐cell activation by antigen
CR3 (CD11b/CD18, also known as Mac‐1)	Monocytes, macrophages, NK cells, granulocytes	iC3b (and many noncomplement components, including bacterial lipopolysaccharide and other surface molecules, and fibrinogen)	Enhances phagocytosis
CR4 (CD11c/CD18)	Myeloid cells, dendritic cells, activated B cells, NK cells, some cytotoxic lymphocytes, platelets	iC3b (and many noncomplement ligands, similar to those interacting with CR3)	Enhances phagocytosis
CRIg	Macrophages	C3b, iC3b	Enhances phagocytosis
C3a receptor	Smooth muscle cells, endothelial cells, epithelial cells, platelets, mast cells, macrophages, neutrophils, basophils, eosinophils	C3a	Mediates anaphylatoxic response
C5a receptor (CD88)	Smooth muscle cells, endothelial cells, epithelial cells, platelets, mast cells, macrophages, neutrophils, basophils, eosinophils	C5a	Mediates anaphylatoxic response

Complement plays a role in clearing these complexes (see Figure 4.7B). Deposition of C3b on a large antigen–antibody complex interferes with the bonds that keep the complex together. As a result, it breaks up into smaller pieces that can be cleared by macrophages. Deposition of C3b on the antigen–antibody complex also allows binding to erythrocytes, which express the receptor CR1 on their surface. Erythrocytes clear the complexes from the circulation by transporting them to the liver and spleen. In these organs, the complexes are transferred from the erythrocyte CR1 to macrophage CR3 and Fc receptors. Macrophages phagocytose the complexes and destroy them.