Since their initial discovery over 30 years ago, cellular receptors for the Fc domain of immunoglobulins (FcRs) have posed something of an enigma for immunologists. These surface glycoproteins were known to be widely distributed on cells of the immune system, had specificity for different isotypes of immunoglobulin, and could mediate a variety of effector responses when cross-linked in vitro (Ravetch and Kinet, 1991). Molecular analysis of the genes and protein complexes that constitute these receptors had yielded a rich diversity of structures, revealing subunits, protein motifs, and signal transduction pathways shared with the more familiar immune receptors such as the antigen receptors on T cells and B cells (Keegan and Paul, 1992; Weiss and Littman, 1994). Yet, despite their ability to mediate a wide range of biological activities on isolated cells, ranging from antibody-dependent cellular cytoxicity to phagocytosis and mediator release from effector cells, the role of many of these receptors in vivo had remained obscure until relatively recently. The basic problem in determining their function in vivo was the redundancy of effector pathways triggered by immune complexes. Defined mutations were lacking in specific FcRs that would facilitate clarifying their contribution, as compared with other immunoglobulin-binding proteins like the complements, to the effector arm of an immune response. Several reports in the last 6 months, utilizing targeted gene disruption of many of the FcRs (Takai et al., 1994; Dombrowicz et al., 1993) have defined a critical and unexpected role for these receptors in the antibody-mediated inflammatory response. These studies demonstrated that F&s have a central role in initiating immunocomplex-triggered inflammation and are likely to be major contributors to the process of lymphocyte regulation of antibody production.

Structural Diversity of FcRs Several different classes of receptors have the ability to interact with the Fc domain of immunoglobulins. These include the immunoglobulin transporters, exemplified by the polyimmunoglobulin receptor for immunoglobulin M (IgM) and IgA and the IgG transporter of neonatal gut (Mostov, 1994) and the lectin-like molecules that bind to IgE (Conrad, 1990). The largest and best-characterized group, however, are the immunoglobulin FcRs, which belong to the immunoglobulin supergene family. This group includes the high affinity receptor for IgE on mast cells and basophils, the high and low affinity receptors for IgG, and the high affinity receptor for IgA. It is this class of receptors that is commonly meant when the term FcRs is used and the one that will be the focus of this review. The general structural features of the IgG and IgE FcRs are summarized in Figure 1. All are membrane glycoproteins composed of a ligand-binding a subunit that consists