Distinct genes encode 6 human receptors for IgG (hFc␥Rs), 3 of which have 2 or 3 polymorphic variants. The specificity and affinity of individual hFc␥Rs for the 4 human IgG subclasses is unknown. This information is critical for antibodybased immunotherapy which has been increasingly used in the clinics. We investigated the binding of polyclonal and monoclonal IgG1, IgG2, IgG3, and IgG4 to Fc␥RI; Fc␥RIIA, IIB, and IIC; Fc␥RIIIA and IIIB; and all known polymorphic variants. Wild-type and low-fucosylated IgG1 anti-CD20 and anti-RhD mAbs were also examined. We found that (1) IgG1 and IgG3 bind to all hFc␥Rs; (2) IgG2 bind not only to Fc␥RIIA H131 , but also, with a lower affinity, to Fc␥RIIA R131 4 Other FcRs are inserted in the outer layer of the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor and contain no signaling motif. 5 FcRs have been associated with many antibodydependent diseases 6 and are key molecules in antibody-based immunotherapy. These include the treatment, for instance, of non-Hodgkin lymphomas by mouse/human chimeric IgG1 anti-CD20 antibodies 7 and the prevention of hemolytic disease of the newborn by a mixture of polyclonal IgG1 and IgG3 anti-RhD antibodies (eg, Rophylac). Therapeutic antibodies are, however, potentially harmful, as exemplified by a recent clinical trial using IgG4 anti-CD28 antibodies.Four human subclasses of IgG are produced in different amounts in response to various antigens. T-dependent protein antigens elicit primarily IgG1 and IgG3 antibodies, whereas T-independent carbohydrate antigens elicit primarily IgG2 antibodies. Chronic antigen stimulation, as in allergic desensitization, elicits IgG4 antibodies. The biological activities of each subclass of IgG are poorly known. IgG receptors (Fc␥Rs) are strikingly numerous in humans. They comprise high-affinity and low-affinity receptors. 8 Both high-affinity and low-affinity Fc␥Rs bind IgGimmune complexes with a high avidity, but only high-affinity Fc␥Rs bind monomeric IgG. There is one high-affinity IgG receptor in humans, hFc␥RI (CD64), and 2 families of low-affinity IgG receptors, hFc␥RIIA, IIB, and IIC (CD32), and hFc␥RIIIA and IIIB (CD16). hFc␥RI and hFc␥RIIIA are FcR␥-associated activating receptors, hFc␥RIIA and hFc␥RIIC are single-chain activating receptors, hFc␥RIIB are single-chain inhibitory receptors, and hFc␥RIIIB are GPI-anchored receptors whose function is uncertain. 1 The multiplicity of hFc␥Rs is further increased by a series of polymorphisms in their extracellular domains (reviewed in van Sorge et al 9 ). Two alleles of the gene encoding hFc␥RIIA generate 2 variants differing at position 131, named low-responder (H 131 ) and high-responder (R 131 ). 10 The H 131 and R 131 alleles are differentially distributed in whites, Japanese, and Chinese. 11 Two alleles of the gene-encoding hFc␥RIIIA generate 2 variants differing at 23 and hFc␥RIIIB NA2 to SLE in Japanese people. 24 The subclass specificity of hFc␥Rs has been investigated since the 1980s, that is, at a time when the complexity of hFc␥R...

This review deals with membrane Fc receptors (FcR) of the immunoglobulin superfamily. It is focused on the mechanisms by which FcR trigger and regulate biological responses of cells on which they are expressed. FcR deliver signals when they are aggregated at the cell surface. The aggregation of FcR having immunoreceptor tyrosine-based activation motifs (ITAMs) activates sequentially src family tyrosine kinases and syk family tyrosine kinases that connect transduced signals to common activation pathways shared with other receptors. FcR with ITAMs elicit cell activation, endocytosis, and phagocytosis. The nature of responses depends primarily on the cell type. The aggregation of FcR without ITAM does not trigger cell activation. Most of these FcR internalize their ligands, which can be endocytosed, phagocytosed, or transcytosed. The fate of internalized receptor-ligand complexes depends on defined sequences in the intracytoplasmic domain of the receptors. The coaggregation of different FcR results in positive or negative cooperation. Some FcR without ITAM use FcR with ITAM as signal transduction subunits. The coaggregation of antigen receptors or of FcR having ITAMs with FcR having immunoreceptor tyrosine-based inhibition motifs (ITIMs) negatively regulates cell activation. FcR therefore appear as the subunits of multichain receptors whose constitution is not predetermined and which deliver adaptative messages as a function of the environment.

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