Receptors for Complement Proteins

Many of the biologic activities of the complement system are mediated by the binding of complement fragments to membrane receptors expressed on various cell types. The best characterized of these receptors are specific for fragments of C3 and are described here (Table 12-8). Other receptors include those for C3a, C4a, and C5a, which stimulate inflammation, and some that regulate complement activation.

• 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 in the follicles of peripheral 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 Fcy receptor is simultaneously engaged by antibody-coated particles. CR1 on erythrocytes binds circulating immune complexes with attached C3b and C4b and transports the complexes to the liver and spleen. Here, the immune complexes are removed from the erythrocyte surface by phagocytes, and the erythrocytes continue to circulate. CR1 is also a regulator of complement activation (see next section).

• The type 2 complement receptor (CR2, or CD21) functions to stimulate humoral immune responses by enhancing B cell activation by antigen and by promoting the trapping of antigen-antibody complexes in germinal centers. CR2 is present on B lymphocytes, follicular dendritic cells, and some epithelial cells. It specifically 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 nonco-valently attached proteins called CD19 and target of antiproliferative antibody 1 (TAPA-1, or CD81). This complex delivers signals to B cells that enhance the responses of B cells to antigen (see Fig. 7-20, Chapter

TABLE 12-8 Receptors for Fragments of C3

Receptor

Structure

Ligands

Cell Distribution

Function

Type 1 complement receptor (CR1, CD35)

160-250 kD; multiple CCPRs

C3b > C4b > iC3b

Mononuclear phagocytes, neutrophils, B and T cells, erythrocytes, eosinophils, FDCs

Phagocytosis

Clearance of immune complexes Promotes dissociation of C3 convertases by acting as cofactor for cleavage of C3b, C4b

Type 2 complement receptor (CR2, CD21)

145 kD; multiple CCPRs

C3d, C3dg > iC3b

B lymphocytes, FDCs, nasopharyngeal epithelium

Coreceptor for B cell activation Trapping of antigens in germinal centers Receptor for EBV

Type 3 complement receptor (CR3, Mac-1, CD11bCD18)

Integrin, with 165-kD a chain and 95-kD p2 chain

iC3b, ICAM-1; also binds microbes

Mononuclear phagocytes, neutrophils, NK cells

Phagocytosis

Leukocyte adhesion to endothelium (via ICAM-1)

Type 4 complement receptor (CR4, p150,95, CD11cCD18)

Integrin, with 150-kD a chain and 95-kD p2 chain

iC3b

Mononuclear phagocytes, neutrophils, NK cells

Phagocytosis, cell adhesion?

CCPRs, complement control protein repeats; EBV, Epstein-Barr virus; FDCs, follicular dendritic cells; ICAM-1, intercellular adhesion molecule 1.

7). On follicular dendritic cells, CR2 serves to trap iC3b- and C3dg-coated antigen-antibody complexes in germinal centers. The functions of complement in B cell activation are described later.

In humans, CR2 is the cell surface receptor for Epstein-Barr virus, a herpesvirus that causes infectious mononucleosis and is also linked to several malignant tumors. Epstein-Barr virus infects B cells and can remain latent in these cells for life.

• 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. It is a member of the integrin family of cell surface receptors (see Chapter 3) and consists of an a chain (CD11b) noncovalently linked to a P chain (CD18) that is identical to the P chains of two closely related integrin molecules, leukocyte function-associated antigen 1 (LFA-1) and p150,95. Mac-1 on neutrophils and monocytes promotes phagocytosis of microbes opso-nized with iC3b. In addition, Mac-1 may directly recognize bacteria for phagocytosis by binding to some unknown microbial molecules (see Chapter 4). It also binds to intercellular adhesion molecule 1 (ICAM-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 (see Chapter 3).

• The type 4 complement receptor (CR4, p150,95, CD11c/ CD18) is another integrin with a different a chain (CD11c) and the same P chain as Mac-1. It also binds iC3b, and the function of this receptor is probably similar to that of Mac-1. CD11c is also 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.

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