Many of the biologic activities of the complement system are mediated by the binding of complement fragments to mem brane receptors expressed on various cell types. The best characterized of these receptors are specific for fragments of C3 and are described here (Table 1).
• The type 1 complement receptor (CR1, or CD35) functions mainly to promote phagocytosis of C3b- and C4b-coated particles and clearance of immune complexes from the circulation. CR1 is a high-affinity receptor for C3b and C4b. It is expressed mainly on bone marrow–derived cells, including erythrocytes, neutrophils, monocytes, macrophages, eosinophils, and T and B lymphocytes; it is also found on follicular dendritic cells (FDCs) in the follicles of secondary lymphoid organs. Phagocytes use this receptor to bind and internalize particles opsonized with C3b or C4b. The binding of C3b- or C4b-coated particles to CR1 also transduces signals that activate the microbicidal mechanisms of the phagocytes, especially when the Fcγ receptor is simultaneously engaged by antibody-coated particles. CR1 on erythrocytes binds circulating immune complexes with attached C3b and C4b and these complexes are transported to the liver and spleen. Here, phagocytes remove the immune complexes from the erythrocyte surface, and the erythrocytes continue to circulate. CR1 is also a regulator of complement activation (discussed in the next section).
• The type 2 complement receptor (CR2, or CD21) functions to stimulate humoral immune responses by enhancing B-cell activation by antigens and by promoting the trapping of antigen-antibody complexes in germinal centers. CR2 is present on B lymphocytes, FDCs, and some epithelial cells. It binds the cleavage products of C3b, called C3d, C3dg, and iC3b (i referring to inactive), which are generated by Factor I–mediated proteolysis (discussed later). On B cells, CR2 is expressed as part of a trimolecular complex that includes two other noncovalently attached proteins called CD19 and CD81 (or TAPA1, target of antiproliferative antibody-1). This complex delivers signals to B cells that enhance their responses to antigens. On FDCs, CR2 serves to trap iC3b-, C3d-, and C3dg-coated antigen-antibody complexes in germinal centers. The functions of complement in B-cell activation are described later.
• The type 3 complement receptor, also called MAC-1 (CR3, CD11bCD18), is an integrin that functions as a receptor for the iC3b fragment generated by proteolysis of C3b. MAC-1 is expressed on neutrophils, mononuclear phagocytes, mast cells, and NK cells. This member of the integrin family consists of an α chain (CD11b) noncovalently linked to a β chain (CD18) that is identical to the β chains of two closely related integrin molecules, leukocyte function–associated antigen 1 (LFA-1) and p150,95 (CR4). MAC-1 on neutrophils and monocytes promotes phagocytosis of microbes opsonized with iC3b. In addition, MAC-1 may directly recognize bacteria for phagocytosis by binding to some unknown microbial molecules. MAC-1 also binds to ICAM-1 (intercellular adhesion molecule 1) on endothelial cells and promotes stable attachment of the leukocytes to endothelium, even without complement activation. This binding leads to the recruitment of leukocytes to sites of infection and tissue injury.
• The type 4 complement receptor (CR4, p150,95, CD11c/ CD18) is another integrin with a different α chain (CD11c) and the same β chain as MAC-1. It also binds iC3b, and the function of this receptor is probably similar to that of MAC-1. CD11c is abundantly expressed on dendritic cells and is used as a marker for this cell type.
• The complement receptor of the immunoglobulin family (CRIg) is expressed on the surface of macrophages in the liver known as Kupffer cells. CRIg is an integral membrane protein with an extracellular region made up of Ig domains. It binds the complement fragments C3b and iC3b and is involved in the clearance of opsonized bacteria and other blood-borne pathogens.
Table1. Receptors for Fragments of C3
Other receptors include those for C3a, C4a, and C5a, which stimulate inflammation, and for C1q. The proinflammatory effects of C3a, C4a, and C5a are mediated by binding of these fragments to specific receptors on various cell types. The C5a receptor, C5aR1, is the most thoroughly characterized. It is a member of the G protein–coupled receptor family expressed on many cell types, including neutrophils, eosinophils, basophils, monocytes, macrophages, mast cells, endothelial cells, smooth muscle cells, epithelial cells, and astrocytes. The C3a receptor is also a member of the G protein–coupled receptor family. These receptors collaborate with TLRs in the activation of sentinel cells and phagocytes. The C1q receptor is expressed on phagocytes and may assist in the clearance of apoptotic bodies and protein fibers such as amyloid fibrils, both of which bind C1q.
