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ently mediate Ig uptake in the absence of associated molecules.

FcyRll (CD32) is a family of related 40 kDa glycoproteins identified by several mAbs, including IV.3, KB-61 and AT-10. Different FcyRII isoforms are-found on different hematopoietic cells, as well as on endothelium. All forms of FcyRII have low affinity for monovalent human IgG, and appear to bind only immune complexes and opsonized particles. The cytoplasmic domains of members of the CD32 family contain typical ITAMs (immunoreceptor tyrosine-based activation motifs) or ITIMs (immunoreceptor tyrosine-based inhibitor motifs) which enhance or inhibit effector functions, respectively.

FcyRIII (CD16) was originally identified as a 50-70 kDa glycoprotein which is recognized by various mAbs including 3G8, Gran 1 and B73.1. Two isoforms of FcyRIII exist. On neutrophils, the isoform designated FcyRIIIb has low affinity for IgG, lacks a cytoplasmic domain, and is bound to the membrane through a phosphatidylinositol glycan (PIG) linkage. On macrophages and LGI./NK cells, the isoform designated FcyRIIIa is a transmembrane molecule containing a typical cytoplasmic domain. The latter has an intermediate affinity for IgG (k'j - 3 > 10 7 m) and is expressed in association with sig naling molecules including £ and y chains.

Genes encoding the FC7R

Fight different genes coding for human FcyR. have been defined, and are transcribed into at least 12 different mRNAs. Along with the FceRIa gene, all art-localized to the long arm of chromosome I, band

Associated molecules

Monocytes, macrophages, dendritic cells, 7 chain neutrophils®

Monocytes, macrophages, granulocytes, 7 chain platelets, endothelial cells

B Cells, monocytes, macrophages None described

Monocytes, macrophages, granulocytes, None described platelets

Macrophages, LGL/NK 7 chain t chain

Neutrophils None described

Monocytes, macrophages, neutrophils, y chain eosinophils

Mast cells, basophils, dendritic cells, (3 chain eosinophils y chain

B Cells, T cells, eosinophils, platelets, None described monocytes, macrophages

ND, No CD assigned.

"Neutrophil CD64 is very low; increased by IFN-y and G-CSF. "Molecular weight varies due to differential glycosylation.

q23-24. Expressed proteins have been identified for six different FcyR isoforms (FcyRIa, Ila, Ilbl, IIb2, Ilia and Illb); it is unknown in which cells, if any, the remaining predicted mRNAs are expressed. Sequence homology indicates that all are members of the Ig gene superfamily. The FcyRII and III molecules have two extracellular Ig-like domains, while FcyRI has a third extracellular domain which imparts its higher affinity for IgG. Allelic variants of the FcyRIIa and FcyRIIIb genes have been described which result in polymorphisms in expression and function of these receptors, and have been associated with altered susceptibility to infectious and immune complex diseases.

Modulation of Fc-yR expression

Although strict measurement of the number of receptors per cell has not been made for many cell types, estimates based on quantitative flow cytometry have been obtained. FcyRI is almost exclusively restricted to monocytes (15 000^40 000 per cell), macrophages (>50 000 per cell) and dendritic cells (3000-20000 per cell). Less than 1000 FcyRI sites are found on freshly isolated granulocytes of healthy subjects, while there are 5000-20 000 receptors per cell when neutrophils are cultured with interferon y (IFNy) or are obtained from people who have bacterial infections. IFNy also causes a 5- to 10-fold increase in the number of FcyRI on monocytes, monocyte-derived macrophages, alveolar macrophages, peritoneal macrophages, dendritic cells and human myeloid cell lines. Granulocyte colony-stimulating factor (G-CSF) and interleukin 10 (IL-10) also induce increased FcyRI expression, but to a lesser extent than IFNy. Certain other cytokines, such as IL-4 and IL-13, decrease FcyRI expression.

Different FcyRII isoforms are expressed on the surface of virtually all hematopoietic cells except erythrocytes. FcyRIIa is found in similar numbers (20 000-40 000 sites per cell) on monocytes, macrophages and neutrophils. Its expression on myeloid cells is increased by granulocyte-macrophage colony-stimulating factor (GM-CSF) and inhibited by IL-4 and IL-13. FcyRIIa is probably the sole FcyR on human platelets, whereas FcyRIIb isoforms predominate on B lymphocytes.

FcyRIIIb is expressed at high levels (100 000-200000 sites per cell) only on human neutrophils, and is shed or internalized in response to neutrophil activation or exposure to tumor necrosis factor a (TNFa). The FcyRIIIa isoform is expressed by only a small subset of human monocytes, whereas macrophages and LGL/NK cells express high levels of this receptor. Culture of monocytes, particularly in the presence of exogenous transforming growth factor (3

(TGF3), increases expression of FcyRIIIa. Although its expression does not appear to be modulated by IL-2 and IFNy, these cytokines enhance macrophage cytotoxic activity triggered via FcyRIIIa.

The Fc receptor y chain is essential for phagocytosis and ADCC triggered through FcyRI, and can also participate in signal transduction following engagement of FcyRII and FcyRIIIa. IFNy induces higher expression of y chain, and this may account for some of the enhanced functions of leukocytes following activation by IFNy.

Functional properties of FC7R

Mononuclear phagocytes FcyRI, FcyRII and FcyRIII all act as trigger molecules for phagocytosis and ADCC, the latter requiring engagement of adhesion molecules (e.g. LFA-1) for maximal efficiency. IFNy enhances monocyte-mediated killing through FcyRI, especially when limited antibody is available on the target. In contrast, IFNy does not enhance monocyte expression of FcyRII or FcyRIII. Although little FcyRIII is expressed on freshly isolated monocytes, this receptor is induced when monocytes mature into macrophages. Monocytes cultured for even short periods mediate lysis of tumor cells through FcyRIII. In addition, antigen-specific T cell activation is markedly enhanced when the antigen is targeted to cither FcyRI or FcyRII on monocytes or dendritic cells.

Neutrophils Freshly isolated neutrophils do not lyse nucleated targets through FcyR. However, when cultured with IFNy, they mediate killing through FcyRI and FcyRII. Killing through FcyRI correlates with the induction of this receptor on the neutrophil by IFNy, whereas, IFNy renders neutrophils capable of cytotoxicity via FcyRII by inducing changes which potentiate cytotoxic mechanisms, without increasing FcyRII expression. Neutrophil-mediated cytolysis of red blood cells occurs through FcyRII and FcyRIII, and incubation with IFNy enhances cytotoxicity through FcyRII but not FcyRIII. GM-CSF also significantly enhances killing by neutrophils through FcyRII, again without affecting expression of FcyRII. FcyRIII on neutrophils does not mediate cytotoxicity of tumor targets. These observations suggest that erythroid and tumor targets are killed through different pathways, and that triggering of FcyRI or FcyRII on neutrophils activates lytic mechanisms distinct from those initiated via FcyRIII.

Eosinophils Although freshly isolated eosinophils do not kill tumor targets, after activation with GM-CSF they mediate killing through FcyRII but not FcyRIII, even though both FcyRs are expressed on these cells. Thus, like neutrophils, eosinophils require lymphokine activation to perform ADCC of tumors through Fc-yRII. FC7RS have also been shown to mediate ADCC of parasites by eosinophils after activation by GM-CSF, TNF or IL-5.

Large granular lymphocytes and NK cells LGL/NK cells very efficiently mediate ADCC of tumor cells through Fc-yRIIIa. This contrasts with the inability of FcyRIIIb on neutrophils to mediate tumor cell killing, but is consistent with the cytolytic ability of macrophage Fc^yRIIIa. This difference correlates with the presence of transmembrane and cytoplasmic domains and/or association with 7 or t, chains, which occurs for Fc7RIIIa only, and appears to be required for signaling pathways resulting in lysis of tumor cells.

U937, HL-60 and THP-1 cells Myeloid cells representing various steps in monocyte differentiation have facilitated evaluation of the functional maturation of the different Fc-yRs. Although these cell lines express FC7RI and Fc-yRII, and are induced to express much larger numbers of FC7RI by IFN7, they do not lyse tumor targets through FC7RS, even after treatment with cytokines. They are, however, able to mediate ADCC of red cells through FC7RI and FC7RII after IFN7 or G-CSF treatment.

FcaRs in infectious disease

In addition to their role as cytotoxic trigger molecules which mediate killing of opsonized tumors and pathogens, FC7R have been shown, under certain conditions, to mediate enhanced infection by certain infectious agents. For example, FC7RS play a major role in dengue virus infection of human mononuclear phagocytes and the pathogenesis of the disease caused by this virus, as the rate of infection is markedly enhanced when these cells encounter antibody-coated virus. Human immunodeficiency virus type 1 (HIV-1) infection of monocytes and macrophages is also enhanced by opsonization of the virus with very small amounts of antibody. It would appear however, based on studies using bispecific antibodies, that FC7RS are not infectivity receptors for HIV, but rather increase cell contact with the virus, enhancing its ability to interact with CD4 on the cell and in this way contribute to enhanced infectivity. Such findings must obviously be taken into account in strategies for the development of vaccines for these and other intracellular pathogens.

Fc receptors for IgE (FceR)

IgE-binding proteins subserve a variety of functions. The type 1 FceR, a multimeric complex once thought to be exclusively expressed by mast cells and basophils, has more recently been identified on eosinophils, monocytes, Langerhans cells and blood dendritic cells. Thus, in addition to playing a central role in the release of inflammatory mediators in atopic disease, it may also facilitate antigen uptake by anti-gen-presenting cells. The low-affinity type II FceR (CD23), which bears no homology to FceRl, is found on B cells, eosinophils, monocytes, Langerhans cells, platelets and probably T cells. FceRII is a B cell differentiation antigen and also a trigger moiecule for IgE-mediated lysis of parasites by myeloid cells. Soluble FceRII is found in the blood, and appears to influence B cell differentiation and monocyte migration.

Distribution and properties of FceR

FceRI is highly expressed (>100 000 sites per cell) on mast cells and basophils, where it consists of a heterotetrameric complex containing one <*, one 3 and two 7 polypeptide chains (Figure 1). It appears at lower levels on a variety of other cells (Table 1), where its association with accessory molecules may be different. It binds the Ce2 and Ce3 domains of the Fc region of IgE with high affinity (Kd =10 10 m) via the glycosylated a chain of the receptor. The 7 chains are essential for efficient and stable expression of the receptor on the cell surface, and are also required for signal transduction.

FceRII is a single-chain glycoprotein (Figure 1) which exists in two forms (FceRIIa and FceRIlb) that differ only in their cytoplasmic tails. FceRIIa appears to be restricted to B lymphocytes, while FceRIlb has been found on B cells, T cells, eosinophils, platelets, monocytes, macrophages, Langerhans cells and human myeloid cell lines such as U-937. The Ce3 domain of IgE is involved in binding to this receptor. A soluble form of FceRII, termed IgE-binding factor (IgE-BF) or soluble FceRII/CD23 (sCD23), appears to be released from CD23 cells by an autocatalytic mechanism, although alternative transcripts encoding for a soluble CD23 have been defined.

Genes encoding FceR

The cDNA for the a subunit of FceRI encodes a polypeptide with structural similarity to the FC7 receptors. There are two immunoglobulin-related extracellular domains, a transmembrane domain containing eight residues that are identical to those of Fc7RIIIa, and a relatively unique cytoplasmic domain consisting of 31 amino acids. The cDNA for the (3 subunit predicts four transmembrane domains and no homology to the immunoglobulin gene super-family. The cDNA for the y subunit indicates homology with the £ chain which is expressed both in association with FcyRIIIa on large granular lymphocytes and with the T cell receptor (TCR) complex on T cells. The y chain consists of five extracellular amino acids, a single transmembrane domain and a 42 residue cytoplasmic tail.

The two forms of FceRII (FceRIIa and lib) arise from alternative splicing of a single gene. Both molecules consist of 321 amino acids with the C-terminus on the outside of the plasma membrane, no leader sequence, and a single transmembrane domain. The Ila and lib forms differ only at seven residues in the N-terminus, and share apparently identical extracellular C-terminal domains.

Modulation of FceR

FceRI is uniformly distributed throughout the plasma membrane, but is rapidly aggregated and internalized upon cross-linking of receptor-bound IgE. The expression of FceRII is increased by elevated IgE levels, apparently by protection from degradation to the soluble form. IL-4 and IFNy upregulate CD23 expression by increasing FceRII synthesis, while IFNa suppresses FceRII expression.

Functional properties of FceR

FceRIs expressed on antigen-presenting cells, such as monocytes and Langerhans cells, are able to enhance antigen presentation to T cells. The cross-linking of FceRI on mast cells and basophils, in contrast, triggers phosphoinositide hydrolysis, mobilization of cytoplasmic calcium, influx of extracellular calcium, explosive release of granular components such as histamine, and synthesis of potent inflammatory mediators, such as leukotrienes and platelet-activat-ing factor. A large number of cytokines are also released in response to FceRI triggering, including IL-1, IL-3, IL-4, IL-5, IL-6, TNFa, IFNy, GM-CSF, macrophage inflammatory protein la (MlPla) and MIP1 p. These may contribute markedly to the inflammatory reaction associated with mast cell degranulation.

FceRII on macrophages, eosinophils and platelets can mediate cytotoxicity and/or phagocytosis of IgE-coated particles. In addition, aggregated IgE triggers release of reactive oxygen metabolites and other inflammatory mediators from FceRII-bearing cells. Thus, on some cell populations this receptor may be involved in inflammation and/or removal of IgE-coated agents. On other cells (e.g. B cells, Langerhans cells), FceRII may be involved in modulation of the isotype of humoral immune responses and enhancement of antigen presentation. Moreover, soluble FceRII appears to play a role in B cell growth and differentiation, and in association with IL-4, enhances IgE synthesis.

Fc receptors for IgA (FcaR)

IgA fulfills a critical protective role against the constant environmental insults encountered at mucosal surfaces. Although the mechanism of protection is not well understood, the IgA-mediated mucosal immune response may be at least partially manifest through binding of IgA-coated targets to Fc receptors for IgA on effector cells. Monocytes, macrophages, neutrophils, eosinophils and myeloid cell lines express cell surface IgA Fc receptors (FcaR; CI)89) consisting of a 50-70 kDa molecule which, like FcyRI, FcyRIIIa and FceRI, associates with the signal-transducing y chain. The IgA-binding chain contains a 206 amino acid extracellular domain including six potential sites for N-linked glycosyl-ation, a feature that, along with O-glycosylation, accounts for the significantly higher molecular weight observed for native FcaR. The extracellular region is followed by a 19 residue transmembrane region and an intracytoplasmic region of 41 amino acids. Sequence analysis indicates that FcaR is a member of the immunoglobulin superfamily and is homologous to other known Fc receptors (Figure li. Binding of monomeric IgA probably occurs under physiological conditions, but binding per se does not trigger function. Rather, cell signaling for phagocytosis, ADCC, degranulation, and/or inflammatory mediator release requires receptor cross-linking.

Various cytokines play a role in regulating FcaR expression and function by monocytes, macrophages and neutrophils. LPS, in addition to TNFa and IL-1, which are produced in response to LPS, strongly upregulate monocyte FcaR expression, as does GM-CSF. Increases in EcaR-specific mRNA are also detectable following monocyte stimulation with either TNFa, IL-1, GM-CSF or LPS. IFNy, in contrast, downmodulates both surface expression of FcaR and intracellular FcaR-specific mRNA levels. These results indicate that FcaR on monocytes are modulated by endotoxin and an array of cytokines distinct from those that regulate expression of FcRs for IgG.

Summary

The distinct human FcR classes perform discrete tasks, with their function largely dictated by the receptor isoform and the cell type on which they are displayed. Receptor signaling is mediated both through phosphorylation domains in the cytoplasmic tail of the ligand-binding a chain (e.g. FcyRII), and via associated molecules such as 7- or ^-chains (e.g. Fc-yRI, FcyRII, FcyRIIIa, FceRI and FcaR). FcRs have in common the requirement for receptor cross-linking to trigger most cell functions, with the probable exception of endocytosis. Cytokines modulate both FcR expression and function, but sometimes in opposite directions. In some cases, FcR function is enhanced without any overt change in receptor expression (e.g. in response to G-CSF or GM-CSF). It seems likely that the specific tissue microenvironment which dictates the overall molecular interactions of the FcR-bearing cell plays a crucial role in the ultimate level of function that is triggered by engagement of FcR.

See also: Antibody-dependent cellular cytotoxicity; Basophils; Mast cells; Cytokines; Degranulation; Eosinophils; IgA; IgE; IgG; Immune complexes; Mononuclear phagocyte system; Natural killer (NK) cells; Neutrophils; Phagocytosis.

Further reading

Anderson CL, Shen L, Eicher DM, Wewers MD and Gill JK (1990) Phagocytosis mediated by three distinct Fc gamma receptor classes on human leukocytes. Journal of Experimental Medicine 171: 1333-1345. Capron M and Capron A (1994) Immunoglobulin E and effector cells in schistosomiasis. Science 264: 1876-1877.

Dacron M (1997) Fc receptor biology. Annual Review of Immunology 15: 203-234.

Deo YM, Graziano RF, Repp R et al (1997) Clinical significance of IgG Fc receptors and Fc gamma R-directed immunotherapies. Immunology Today 18: 127-135.

Fridman WH, Teillaud J-L, Bouchard C et al (1993) Soluble Fc receptors, journal of Leukocyte Biology 54: 504-512.

Hulett MD and Hogarth PM (1994) Molecular hasis of Fc receptor function. Advances in Immunology 57: I -12".

Jouvin MH, Numerof RP and Kinet JP (1995) Signal transduction through the conserved motifs of the high affinity IgE receptor Fc epsilon RI. Seminars in immunology 7:' 29-35.

Kimberly RP, Salmon JE and Edberg JC (1995) Receptors for immunoglobulin G. Molecular diversity and implications for disease. Arthritis and Rheumatism 38: 306-314.

Morton C, van Egmond M and van de Winkel JGJ (1996) Structure and function of human IgA Fc receptors (FcaR). Critical Reviews in Immunology 16: 423—440.

Ravetch JV and Clynes RA (1998) Divergent roles of Fc receptors and complement in vivo. Annual Review of Immunology 16: 421-432.

Unkeless JC, Shen Z, Lin CW and DeBcus E (1995) Function of human Fc gamma R1IA and Fc gamma R1I1B. Seminars in Immunology 7: 37-44.

van de Winkel JGJ and Capel PJA (eds) (1996) Human IgG Fc Receptors. Austin, TX: RG Landes.

Wallace PK, Howell AL and Fanger MW (1994) Role of Fc gamma receptors in cancer and infectious disease. Journal of Leukocyte Biology 55: 816-826.

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