Leukocytes express Fc receptors that bind to the constant regions of antibodies, and thereby promote the phagocytosis of Ig-coated particles and deliver signals that stimulate the microbicidal activities of the leukocytes and induce inflammation. Fc receptors for different Ig heavy chain isotypes are expressed on many leukocyte populations and serve diverse functions in immunity. Of these Fc receptors, the ones that are most important for phagocytosis of opsonized particles are receptors for the heavy chains of IgG antibodies, called Fcy receptors, and these are the receptors that will primarily be considered in this chapter. The Fc receptors that bind to IgE are discussed in Chapter 19. We have already considered the neonatal Fc receptor (FcRn), which is expressed in the placenta, on intestinal epithelial cells, and on vascular endothelium, in
Chapter 5. The poly-Ig receptor, which is involved in the transcytosis of IgA and IgM, is discussed in Chapter 13.
There are a number of different Fcy receptors that have different affinities for the heavy chains of different IgG subclasses and are expressed on different cell types. Most Fc receptors result in cellular activation when triggered except for FcyRII, which is an inhibitory receptor. All Fcy receptors contain a ligand-binding chain, called the a chain, that recognizes their IgG ligands. Differences in specificities or affinities of each FcyR for the various IgG isotypes are based on differences in the structure of these a chains. All Fc receptors are optimally activated by antibodies bound to their antigens and not by free, circulating antibodies. In all the FcRs except FcyRII, the a chain is associated with one or more additional polypeptide chains involved in signal transduction (Fig. 12-3). Signaling functions of FcyRII are mediated by the cytoplasmic tail of the a chain.
Fcy receptors have been classified into three groups based on their affinities for heavy chains of different IgG subclasses (Table 12-3). Some of these Fc receptors have multiple isoforms that may differ in structure and function.
• FcyRI (CD64) is the major phagocyte Fcy receptor. It is expressed on macrophages and neutrophils and is a high-affinity receptor that binds IgG1 and IgG3, with a Kd of 10-8 to 10-9 M. (In mice, FcyRI preferentially binds IgG2a and IgG2b antibodies.) The large extracellular amino-terminal region of the Fc-binding a chain folds into three tandem Ig-like domains. The a chain of FcyRI is associated with a disulfide-linked homodimer of a signaling protein called the FcR y chain. This y chain is also found in the signaling complexes associated with FcyRIII, FcaR, and FceRI. The y chain has
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