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Fc Receptors Advanced article

Peter Boross, University Hospital Utrecht, Utrecht, The Netherlands Article Contents . Introduction Kees van de Poel, University Hospital Utrecht, Utrecht, The Netherlands . FcgR

Jan GJ Van de Winkel, University Hospital Utrecht, Utrecht, The Netherlands . FcaR Jeanette HW Leusen, University Hospital Utrecht, Utrecht, The Netherlands . FceR . FcmR and FcdR Receptors for the Fc region of immunoglobulins link humoral responses to cellular . FcamR activities within the . Leucocyte Fc receptors exist as hetero-oligomeric . Summary and Future Directions complexes with unique -binding a chains and promiscuous accessory subunits. Online posting date: 15th September 2008

Introduction transgenic for specific human FcR. See also: Activation Signals: Transduction Receptors for the Fc region of immunoglobulins (FcRs) link humoral responses to cellular activities within the im- mune system. Based on their function, two general groups c of FcR can be distinguished: those expressed predomi- Fc R nantly by leucocytes that trigger effector func- Leucocyte receptors for the Fc domain of IgG (FcgR) are tions and those that primarily mediate transport of members of the Ig supergene family and three classes have immunoglobulins across epithelial or endothelial surfaces been described in humans: FcgRI (CD64), FcgRII (CD32) (polyimmunoglobulin (poly-Ig) and FcRn, al- and FcgRIII (CD16) (Figure 1; Ravetch and Bolland, 2001). though the latter was shown recently to have a function in See also: Immunoglobulin Superfamily leucocytes as well) (Nimmerjahn and Ravetch, 2007). This review will focus on the general characteristics of the hu- FccRI man leucocyte FcRs for (IgG) (FcgR), IgA (FcaR), IgE (FceR), IgM (FcmR) and IgD (FcdR) Three have been characterized for the class I IgG (Figure 1). See also: ; Antibody Classes receptor – Fcg RIA, IB and IC. Only for FcgRIA functional Most leucocyte FcRs exist as hetero-oligomeric com- expression has been shown. The prototypic FcgRI, plexes with unique ligand-binding a chains and promiscu- has an extracellular region with three Ig-like domains, a ous accessory subunits (z, g or b chains). Within the transmembrane domain and a cytoplasmic tail. FcgRIa FcR family, the immunoreceptor -based activation represents the sole leucocyte FcgR capable of binding 8 9 21 motif (ITAM) plays an essential role in triggering bio- monomeric IgG with high affinity Ka=10 –10 L mol . logical functions. In addition, some FcRs contain inhibi- The receptor shows specificity for the subclasses IgG3, IgG1 tory motifs within their cytoplasmic regions known as and IgG4, in decreasing affinity (Table 1). immunoreceptor tyrosine-based inhibitory motif (ITIM). FcgRIa is constitutively expressed at high levels on In general, FcR crosslinking initiates a range of biological (progenitor) , and , and at low functions varying from activatory to inhibitory functions. levels on polymorphonuclear leucocytes (PMNs) and on The threshold for cell activation is set by the ratio of certain populations. Expression of FcgRIa is activating and inhibitory signalling when simultaneously enhanced by interferon g (IFNg), colony- triggered. A number of human Fc receptors have or- stimulating factor (G-CSF) and (IL-10), and thologues in the mouse. Although the murine FcR system is downregulated by IL-4 and IL-13 (Table 2). It exists as a differs from its human counterpart, our knowledge on FcR hetero-oligomeric receptor complex with a ligand-binding a biology greatly benefited from murine studies, especially chain, and an FcR g chain homodimer. with mice with targeted inactivation of individual FcRs or Although the FcR g chain is important during FcgRI signalling, several studies have suggested an additional role for the a chain. and presentation of endocytosed immunocomplexes is partly mediated by ELS subject area: Immunology the a chain cytoplasmic tail (FcgRI-CY) (van Vugt et al., 1999). Furthermore, deletion of FcgRI-CY abrogates the How to cite: production of IL-6 upon receptor crosslinking. Although Boross, Peter; van de Poel, Kees; Van de Winkel, Jan GJ; and, Leusen, downstream signalling events have not been elucidated Jeanette HW (September 2008) Fc Receptors. In: Encyclopedia of Life in detail, several have been shown to interact Sciences (ELS). John Wiley & Sons, Ltd: Chichester. with FcgRI-CY. The interacting proteins periplakin and DOI: 10.1002/9780470015902.a0000916.pub2 filamin A, play a role in modulation of ligand binding

ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net 1 Fc Receptors

FcγRI (CD64)

FcγRIIa (CD32) FcγRIIb (CD32) FcγRIIc (CD32) FcγRIlIa (CD16) FcγRIIIb (CD16)

s-s s-s

γγ γγ

plgR

FcRn

FcεRI FcεRII (CD23) FcαRI (CD89) FcαµR

s-s s-s

γγ β γγ

Figure 1 Schematic representation of human Fc receptors. The extracellular parts of most human Fc receptors are composed of varying amounts (1–5) of immunoglobulin domains. The two exceptions are the lectin family member FceRII and the major histocompatibility complex (MHC) class I protein family member FcRn. Based on their function FcR can mediate activating signals via ITAM (green box) which consist of YxxLxxxxxxxYxxL (Y 5 tyrosine, L 5 leucine, X 5 any ). The ITAM can either be located on the intracellular part of the receptors (FcgRIIa and FcgRIIc) or on the associated g chain (FcgRI, FcgRIIIa, FceRI, FcaRI). Next to its role in signalling, the g chain (in blue) is also essential for surface expression. The sole inhibiting FcR, FcgRIIb, bears an ITIM (red box) on its intracellular tail, which consists of Y/V/L/S/xYxxL/V (Y 5 tyrosine, V 5 valine, S 5 serine, L 5 leucine, X 5 any amino acid). FcgRIIIb is a glycosylphosphatidylinositol (GPI)-linked activating receptor that has no intracellular tail. and stabilization of the receptor at the plasma membrane, The FcR g chain molecules are critical for stabilization respectively (Beekman et al., 2004). The capacity to alter of FcgRI surface expression, for signalling, and for the affinity of the receptor for its ligand appears to be a ligand-binding affinity of the receptor. The FcR g feature shared among more Fc receptors, and is often chain contains a conserved ITAM signalling motif in referred to as ‘inside-out’ signalling. In general, this occurs its cytoplasmic region, consisting of two YxxL boxes when expressing cells are stimulated, for separated by seven amino acids. Upon FcgRIa cross- instance by , resulting in an activated cell with a linking this ITAM is phosphorylated on both higher capacity to bind immune complexes. A similar by Src and Syk protein tyrosine family kinases, initiating mechanism has been described for integrins. signalling events. See also: Cytokines; Interferons; Myeloid

2 ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net Table 1 General characteristics of human Fc receptors FcgRFceR FcgRI FcgRII FcgRIII FceRI FceRII FcaRI FcamRFcmRFcdR Poly-Ig FcRn CD CD64 CD32 CD16 CD23 CD89 Genomic 1q21.1 1q23-24 1q23-24 1q23 19q 19q13.4 1q32.3 1q31-41 19q13 location NYLPDAO IESCIENCES LIFE OF ENCYCLOPEDIA Molecular 72 kDa 40 kDa 50–80 kDa 45–65 kDa mFc eRII: 55– 70 kDa 58–60 kDa 46+14 kDa weight 45 kDasFc 100 kDa eRII: 25 kDa Genes 3 3 2 1 1 1 1 1 2 Isoforms Ia1 IIa, sIIa2 IIIa, IIIb Ia IIa, IIb Ia IIb1, IIb2, IIc Ligand IgG IgG IgG IgE CR2, IgE IgA, SIgA IgM and IgM IgD IgM and IgG concanavalin CR3 IgA IgA &

08 onWly&Sn,Ld www.els.net Ltd. Sons, & Wiley John 2008, A, Escherichia polymer polymer coli Affinity 108–109 5107 IIIa: 109–1010 106 5 Â 107 IgM: pH (L mol21 )  3 Â 107 3 Â 109 dependent IIIb: 5107 IgA: 3 Â 108 Isotype 341  4 IIa- 1–3a 1–2 specificity R131: 341 IIa- H131: 341–2 IIb1: 34144 Accessory ggNK cells: z/g Mast cells, g NK cells: b2m subunits : z/g b/g chains Other cells: g Monocytes/ M f: g chain Receptors Fc

Notes: mFceRII, membrane-expressed FceRII; sFceRII, soluble FceRII and SIgA, secretory IgA. Polymorphisms of FcgRIII influence relative affinity for IgG subclasses. aFcgRIIIa-158Valine has higher affinity for IgG1 and 3 than FcgRIIIa-158Phenylalamine and binds IgG4. FcgRIIIb has higher affinity for IgG1 and IgG3 than FcgRIIIb-NA2. 3 Fc Receptors

Table 2 Cell distribution and function of human Fc receptors Expression Modulation Functions FcgRI Monocytes, macrophages, CD34+ Upregulation: G-CSF, IFNg, Internalization, antigen myeloid progenitor cells, dendritic IL-10 presentation, superoxide cells, , (PMN: IFNg,G- Downregulation: IL-4, IL-13 generation, ADCC, , CSF). production FcgRII IIa: monocytes, macrophages, PMN, Downregulation: IL-4 IIa: internalization, ADCC, eosinophils, basophils, Langerhans phagocytosis, cytokine cells, , placental endothelial production, cells, T cells, subpopulation IIb: B cells, basophils, macrophages, IIb1/IIb2: downmodulation eosinophils, dendritic cells, of B cells, mast cells, macrophages Langerhans cells IIb2: internalization IIc: NK cells FcgRIII IIIa: Macrophages, NK cells, Upregulation: TGFb IIIa: phagocytosis, ADCC, (monocytes, subpopulation: TGFb), superoxide generation, cytokine subpopulation of T cells, Langerhans production, induction of cells adhesion, IIIb: PMN Downregulation: IL-4 IIIb: superoxide generation, ADCC, FceRI Mast cells, basophils, Langerhans Upregulation: IgE Release inflammatory mediators, cells, eosinophils, platelets, anaphylaxis, fine-tuning of monocytes, dendritic cells specific immune responses FceRII IIa: B cells, follicular dendritic cells Upregulation: IL-4, IL-13; IIa: B-cell proliferation and IIb: CD5+ B cells, T cells, downregulation by IFNa/g; IIb: differentiation, regulation of IgE eosinophils, mast cells, platelets, upregulation by IFNa/g, TNFa production, , monocytes, Langerhans cells downregulates FceRII but cell adhesion upregulates sFceRII; IIb: expression depends on IL-4 FcaRI Macrophages, monocytes, PMN, Upregulation: TNFa, IL-8, Phagocytosis, ADCC, oxidative eosinophils IL-1b, GM-CSF, LPS burst, cytokine production, Downregulation: TGFb antigen presentation FcamR FDCs, B cells, macrophages Unknown FDC: trapping of IgA and IgM immune complexes B cells, macrophages: endocytosis of IgM immune complexes IIb: CD5+ B cells, T cells, Downregulation: IFNa/g eosinophils, mast cells, platelets, (FceRIIa), TNFa (mFceRII3) monocytes, Langerhans cells FcmR T cells, subpopulation, activated B Upregulation (B cells): IgM, PMA B-cell activation, downregulation cells, NK cells Downregulation (T cells): IgM of NK cell function FcdR T cells Upregulation: IgD, IL-2, IL-4, Helper function in antibody IFNg production Poly-Ig Epithelial cells Upregulation: IFNg, TNF, IL-1, Transcytosis of IgA and IgM to IL-4, diverse hormones, microbial mucosal surfaces factors FcRn Epithelial cells, placental IgG transport to , extending syncytiotrophoblasts, endothelial cells serum IgG half-life, phagocytosis

Cell Differentiation; ; Signal Transduction: Vugt et al., 1999). Furthermore, recent data suggests an Overview important role for human FcgRI in antibody-mediated Owing to its high affinity for IgG, FcgRIa may be ligand- malaria therapies (McIntosh et al., 2007). Expression saturated under serum conditions. A role of FcgRIa for of FcgRIa increases in a variety of inflammatory and pro- facilitation of antigen presentation has been proposed (Van inflammatory conditions; e.g. human immunodeficiency

4 ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net Fc Receptors (HIV) , sepsis and , studies this was not confirmed. See also: Systemic indicating a role for this molecule under such conditions. Erythematosus Analysis of FcgRI-deficient mice revealed a role for FcgRI The FcgRIIb1 and IIb2 isoforms are unique in that they in hypersensitivity responses, arthritis, protection against bear an ITIM within their cytoplasmic tails. An ITIM is a bacterial infection and tumour killing. highly conserved (13 amino acid) motif containing one Furthermore, because of both its unique - YxxL box, and FcgRIIb may inhibit cell activation trig- restricted expression pattern and its potent capacity to gered by receptors that signal via ITAM (B-cell receptor trigger immune functions, FcgRIa has been proposed as an (BCR), FceRI or FcgRIIa). Inhibition requires ITIM phos- attractive target for immunotherapy (Thepen et al., 2000). phorylation, and involves activation of the See also: AIDS: Clinical Manifestations; Human Immu- SHP-1 (B cells), SHIP (mast cells and B cells) and the CD19 nodeficiency (HIV); Rheumatoid Arthritis molecule on B cells. Furthermore, the FcgRIIb2 isoform proved effective in internalization of small immune com- FccRII plexes in contrast to FcgRIIb1 (Tarasenko et al., 2007). A polymorphism of FcgRIIb, FcgRIIbT232, encodes a Three genes have been identified for FcgRII (IIA, IIB and single amino acid substitution (from isoleucine to threo- IIC) (Figure 1). Six transcripts, resulting from alternative nine) at position 232 within the transmembrane domain. splicing, have been documented, all encoding true iso- This polymorphism leads to exclusion of FcgRIIb from forms. These molecules are conserved in their extracellular specialized membrane domains, called rafts, and is and transmembrane regions, but differ markedly in their thereby unable to inhibit activating FcRs. Its presence is cytoplasmic domains. strongly associated with SLE and with inflammatory dis- FcgRII molecules interact only with complexed or poly- eases, whereas it is more often found in regions where ma- meric IgG, and family members are expressed on most types laria is endemic and therefore increased effector responses of blood leucocytes (Table 2). FcgRIIa crosslinking triggers are favourable (Tarasenko et al., 2007). activation, whereas FcgRIIb initiates inhibitory signals. The third , FcgRIIc, probably results from an A genetic polymorphism in FcgRIIa at amino acid unequal crossover event between genes IIa and IIb, and position 131 within the extracellular region (either histidine encodes a protein which resembles FcgRIIa intracellularly or arginine), results in different affinities for IgG isotypes and FcgRIIb extracellularly. The majority of people (91%) (Table 1). do not express FcgRIIc due to a single nucleotide poly- FcgRIIa crosslinking triggers functions varying from morphism (SNP) in intron 3 that results in a stop codon. internalization, phagocytosis, cytokine production, anti- The remaining 9% have a functional receptor, bearing its gen presentation, superoxide generation, to antibody- own signalling motif that is able to mediate ADCC. The dependent cell-mediated (ADCC). FcgRIIa presence of a functional FcgRIIc variant is associated is unique among leucocyte FcRs in that it contains a with idiopathic thrombocytopenic purpura (ITP), due to noncanonical ITAM directly in its cytoplasmic region. disruption of balanced (Breunis et al., 2008). FcgRIIa can therefore transmit a phagocytic signal in the absence of other FcR subunits, and receptor crosslinking results in tyrosine of the a chain. FcgRIIa FccRIII can, in addition, associate with the FcR g chain on mon- ocytes and macrophages. Both the a chain and the g chain This receptor class is encoded by two genes FcgRIIIA and can activate signalling pathways, involving a variety of FcgRIIIB (Figure 1). FcgRIIIa has two extracellular Ig-like nonreceptor kinases (Table 2). Signalling via FcgRIIa has domains, and a 25-amino acid cytoplasmic tail, with me- 7 21 furthermore been shown to involve membrane molecules dium affinity for IgG (Ka=3 Â 10 L mol ). Expression such as CD45, CD148 and the integrin complement recep- and function of this receptor is dependent upon association tor 3 (CR3) (CD11b/CD18). In eosinophils, granulocyte– with the FcR g chain on monocytes and macrophages, or CSF (GM-CSF) stimulation leads to an with g or z chains on natural killer (NK) cells. activated FcgRII with increased binding affinity. See also: Expression of FcgRIIIA is upregulated by transforming Antibody-dependent Cell-mediated Cytotoxicity (ADCC); growth factor b (TGFb), and downregulated by IL-4. The Immune Response: Regulation ligand-binding chain of FcgRIIIA has recently been re- FcgRIIa-His131 represents the sole leucocyte FcR ported to be active in initiating calcium fluxes. Biological capable of interaction with IgG2. The capacity to interact function of this receptor, however, is critically dependent with this antibody subclass therefore depends on the on either the z and/or g accessory chains (Ravetch and individual’s FcgRIIa genotype, and polymorphisms of Bolland, 2001). See also: Transforming Growth Factor FcgRIIa are now considered to be heritable risk factors for beta (TGFb) both infectious diseases (such as meningitidis and period- FcgRIIIa has been shown to be polymorphic and two ontitis) and autoimmune diseases (such as systemic lupus allotypes have been defined that differ by a single amino erythrematosus, SLE) (Van de Velde et al., 2006). Certain acid at position 158 (either valine or phenylalanine). The studies have shown an association of polymorphisms allotypes exhibit different capacities to bind IgG1, IgG3 FcgRIIa-131-H with antibody therapy, whereas in other and IgG4, and preliminary evidence has been provided for

ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net 5 Fc Receptors skewing of the FcgRIIIa polymorphism in SLE patients binds both IgA1 and IgA2, and secretory IgA (SIgA), with 7 21 (Van Sorge et al., 2003). medium affinity (Ka=5 Â 10 L mol )(Table 1). Its ex- The FcgRIIIa-V158 variant of this polymorphism is as- pression can be upregulated by tumour necrosis factor a sociated with better outcome in (TNFa), IL-8, IL-1b and lipopolysaccharide (LPS), and treatment of non-Hodgkin lymphoma. Recently, copy downregulated by TGFb. Addition of GM-CSF, IL-3 or number variation (CNV) has been described in FcgRIIIA IL-5 can rapidly increase ligand-binding capacity without gene (Breunis et al., 2008). effects on receptor expression levels, known as inside-out The FcgRIIIb subclass exhibits low affinity for IgG, and regulation. (De)phosphorylation of the intracellular Serine is expressed exclusively on PMNs. Two allotypes and one 263 of the FcaRI a chain seems to be crucial in this process gene duplication exist that are designated FcgRIIIb-NA1, (Bracke et al., 2001). IIIb-NA2 and IIIb-SH, respectively. FcgRIIIb has two FcaRI exists as a hetero-oligomeric receptor complex extracellular Ig-like domains, and is uniquely anchored to containing the FcR g chain homodimer. The ligand- the outer leaflet of the lipid bilayer by a glycosylpho- binding chain of FcaRI is devoid of recognized signalling sphatidylinositol linkage. FcgRIIIb has been suggested to motifs, and requires the FcR g chain for signal transduct- interact with either FcgRIIa, the integrin CR3 (CD11b/ ion. A charge-based interaction underlies the assembly CD18), or accessory signalling molecules localized in lipid of the functional FcaRI/g chain complex. A positively rafts to confer signalling ability (Vidarsson and Van de charged arginine residue at position 209 in the transmem- Winkel, 1998). FcgRIIIb crosslinking can trigger a brane domain of FcaRI was shown to be essential for in- variety of activation events including superoxide genera- teraction with a negatively charged aspartic acid in the tion, degranulation and ADCC. FcgRIIIb can be released transmembrane region of the FcR g chain. In addition, the into serum upon cell activation or apoptosis induction orientation of FcaRI a chain to the g chain homodimer was through cleavage. The level of soluble also found to be important suggesting the involvement of FcgRIIIb in the circulation reflects the total body mass of additional amino acids in the interaction. neutrophils (Van der Pol and Van de Winkel, 1998). Triggering of FcaRI induces phosphorylation of cellular FcgRIIIb bears the antigen (NA) poly- proteins including Src and Syk family protein tyrosine morphism, which has been implicated in alloimmune and kinases, and increases in intracellular free Ca2+, resulting autoimmune neutropenias and blood transfusion reac- in phagocytosis, ADCC, superoxide generation, cytokine tions. The FcgRIIIb-NA1 exhibits higher affinity for production, antigen presentation and inflammatory medi- immune-complexed IgG1 and IgG3 than IIIb-NA2, and ator release (Tables 2). See also: Protein Kinases IgG1- and IgG3-opsonized particles are more efficiently Conversely, in the absence of sustained aggregation by phagocytosed via the IIIb-NA1 allotype. In addition, it has IgA-immune complexes FcaRI itself may act as an inhib- been shown that the FcgRIIIb allelic polymorphism is of itory modulator acting on Fcg and Fce receptor activation clinical importance for progression of periodontal disease or induce apoptosis. IgA Fc receptor I signals apoptosis (Van der Pol and Van de Winkel, 1998). Interestingly, low through the FcR g ITAM and affects tumour growth. copy numbers of FcgRIIIB has been found to associate Interestingly, FcaR is an effective cytotoxic trigger mol- with systemic – but not organ-specific – autoimmune dis- ecule, as shown by efficient ADCC of various tumour tar- eases in humans and rats, possibly owing to decreased gets. The FcaRI molecule is now considered an excellent clearance of apoptotic cells. See also: Blood Groups and target for immunotherapies of malignant and infectious Transfusion Science; Neutropenia diseases. Furthermore, FcaRI is thought to play an im- portant role in the removal of IgA immune complexes, and defective FcaRI-mediated endocytosis has been postulated FcaR to contribute to the pathogenesis of IgA nephropathy, al- coholic liver cirrhosis and the acquired immune deficiency Receptors for the Fc domain of IgA (FcaR) are members of syndrome (AIDS) (Monteiro and van de Winkel, 2003). the Ig supergene family. Genetic analyses suggest these See also: Tumours: Immunotherapy molecules to be more distantly related to FcgR and FceR. One class of IgA receptors has been characterized in humans and is designated FcaRI (CD89) (Monteiro and Fc«R van de Winkel, 2003). Two classes of receptors for the Fc domain of IgE (FceR) FcaRI have been described: FceRI and FceRII (CD23). FceRI belongs to the Ig supergene family, whereas FceRII is a Although multiple transcripts have been described, only member of the lectin family (Figure 1). one FcaRI transcript specifying two extracellular Ig-like domains, a transmembrane domain and a short cytoplas- Fc«RI mic tail, has been identified on myeloid cells (Figure 1). FcaRI is expressed on monocytes/macrophages, mesangial FceRI is expressed on mast cells, basophils, Langerhans cells, neutrophils and eosinophils (Table 2). The receptor cells, eosinophils, platelets, monocytes and dendritic

6 ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net Fc Receptors

10 –1 cells and binds IgE with high affinity (Ka410 L mol ) B ; Follicular Dendritic Cells (B Lymphocyte (Table 1). Owing to the high ligand affinity, FceRI stably Stimulating) associates with monomeric IgE on the surface, Expression of FceRII and levels of secreted sFceRII are where it readily responds to foreign . The molecule under complex regulation of cytokines, mainly IL-4, IL-13, is composed of two extracellular Ig-like domains, a trans- IFNs and TNF a (Table 2). See also: Interleukins membrane domain and a cytoplasmic tail. On mast cells FceRII has been proposed to function in B-cell prolif- and basophils the ligand-binding a chain of FceRI is eration, differentiation, regulation of IgE production, associated with both the FcR b and g chains, whereas on antigen presentation and cell adhesion. On monocytes monocytes and macrophages an FceRI/g chain complex and macrophages, FceRII mediates phagocytosis and is expressed (Table 1). See also: Basophils; Macrophages; IgE-dependent cytotoxicity. Mast Cells Activation of FceRI on mast cells and basophils results in release of inflammatory mediators, including preformed FclRandFcdR granular mediators, lipid mediators and cytokines, and is considered important for host defence against invading Receptors for IgM (FcmR) and IgD (FcdR) have been iden- parasites (Table 2). Upon receptor engagement, phospho- tified, although structure–function analyses are still limited. rylation of the FcR b and g chains is essential for down- stream signalling. Phosphorylated ITAM tyrosine of the g chain specifically recruits Syk family protein tyrosine FcalR kinases, whereas the b subunit preferentially associates with Lyn. FceRI b subunit functions as a signalling FcamR is a functional Fc receptor that binds both IgM and amplifier via enhancing FcR g chain tyrosine phosphor- IgA polymers but not their monomeric forms. It is ex- ylation. Exposure of mast cells to IgE augments surface pressed as a 125-kDa homodimer and is structurally more expression of FceRI. Interestingly, already the binding of related to the polymeric Ig receptor (pIgR) than to other monoclonal IgE without ligand induces a variety of signals FcRs (Figure 1). The expression pattern of FcamRin such as survival, release and de novo synthesis of humans is more restricted than in mice that have no FcaR. inflammatory cytokines. FceRI signalling is under negative It is predominantly expressed on follicular dendritic regulation by CD31, CD81 and FcgRIIb. FcgRIIb-medi- cells (FDCs), suggesting a role in trapping of IgM and ated downregulation of FceRI requires coaggregation, and IgA immune complexes and in presenting intact to recruitment of the phosphatases SHIP, SHP-1 and SHP-2. B cells. That human mesangial cell lines express FcamR IgE- and antigen-specific mast cell activation and medi- transcripts together with the abundant expression of ator production is thought to be critical in allergic dis- FcamR messenger ribonucleic acid (mRNA) found in orders, associated with exaggerated production of IgE the kidney suggests that FcamR might be involved in IgA antibodies to environmental allergens. The importance of nephropathy (Shibuya and Honda, 2006). FceRI in and hypersensitivity is indicated by the protection from these diseases in mice lacking FceRI and the FclR enhanced reaction in mice deficient for negative regulatory Functional FcmRs that bind the IgM Fc fragment have molecules of FceRI, such as FcgRIIb or SHIP. The fact that been reported on subpopulations of B, T and NK cells. IgE upregulates FceRI expression may have potential for FcmR is expressed on activated B cells, as a glycosylpho- modulation of effector cell functions in IgE-dependent sphatidylinositol-linked receptor. FcmR represents an allergic reactions for immunological responses to parasites. activation antigen throughout pre-B and B-cell stages in differentiation, and expression is increased after exposure of B cells to IgM or the phorbolester phorbol myristate Fc«RII acetate (PMA). The precise role of FcmR on B cells is not known but a potential role in B-cell responses by its ability FceRII (CD23) is a low-affinity receptor for IgE 7 21 to bind both secreted IgM molecules and neighbouring (Ka510 L mol ). Besides binding IgE, FceRII also binds membrane-bound IgM molecules has been proposed. to CD21, CD11b/CD18 and CD11c/CD18 on monocytes. FceRII consists of a C-terminal extracellular domain, a FcdR transmembrane domain, and a cytoplasmic tail. Unlike the IgG, IgA and high-affinity IgE Fc receptors, FceRII has no Immunoglobulin receptors for IgD (FcdR) can bind IgD Ig-like domains and represents a member of the calcium- via both the Fd and Fc regions. Receptors for IgD have dependent animal lectin family. Two isoforms have been been documented on subpopulations of T cells, and their described, which differ in their 5’ untranslated region and in expression is under regulation by cytokines. FcdRs are not the first six amino acids of the cytoplasmic tail that have thoroughly investigated, but they may function as lectins different cellular distribution (Table 2). and seem to require calcium for binding IgD. FcdRs There is also a soluble FceRII described (sFceRII) are proposed to play a role in T-cell helper responses for that can be released from cells into serum. See also: antibody production. See also: Lectins

ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net 7 Fc Receptors

Polymeric Ig receptor capacity. Proceedings of the National Academy of Sciences of the USA 101(28): 10392–10397. The pIgR is expressed at the basolateral surface of secre- Bracke M, Lammers JW, Coffer PJ and Koenderman L (2001) tory epithelial cells and ensures efficient secretion of poly- Cytokine-induced inside-out activation of FcalphaR (CD89) is meric IgA (pIgA) and IgM (pIgM) at mucosal surfaces. mediated by a single serine residue (S263) in the intracellular After binding its ligand at the basolateral surface, pIgR domain of the receptor. Blood 97(11): 3478–3483. transcytoses to the apical surface, where its extracellular, Breunis WB, van Mirre E, Bruin M et al. (2008) Copy number ligand-binding domain is cleaved off and released as the variation of the activating FCGR2C gene predisposes to idio- secretory component (SC) bound to pIgA forming SIgA. pathic thrombocytopenic purpura. Blood 111(3): 1029–1038. The role of SC in SIgA is mainly stabilizing but free SC Kaetzel C (2005) The polymeric immunoglobulin receptor: bridg- released from unloaded pIgR has direct antimicrobial ing innate and adaptive immune responses at mucosal surfaces. function. Mice deficient for pIgR lack mucosal IgA and Immunological Reviews 206: 83–99. have reduced protection to influenza but not to McIntosh RS, Shi J, Jennings RM et al. (2007) The importance of bacterial infections (Kaetzel, 2005). human FcgammaRI in mediating protection to malaria. PLoS 3(5): e72. FcRn Monteiro RC and van de Winkel JG (2003) IgA Fc receptors. Annual Review of Immunology 21: 177–204. The for IgG (FcRn) transfers anti- Nimmerjahn F and Ravetch JV (2007) Fc-receptors as regulators bodies from mother to her fetus. FcRn uniquely binds IgG of immunity. Advances in Immunology 96: 179–204. in a pH-dependent manner, not on physiological pH (7.4) Ravetch JV and Bolland S (2001) IgG Fc receptors. Annual but only in acidic environment of endocytic vacuoles. It is Reviews in Immunology 19: 275–290. classically expressed on epithelial cells, placental syncy- Roopenian DC and Akilesh S (2007) FcRn: the neonatal Fc re- tiotrophoblasts and endothelial cells, but recently expres- ceptor comes of age. Nature Reviews. Immunology 7(9): 715–725. sion was shown in leucocytes as well. Upon internalization Shibuya A and Honda S (2006) Molecular and functional char- of IgG into endosomes, these vesicles are gradually acid- acteristics of the Fcalpha/muR, a novel Fc receptor for IgM and ified thereby allowing IgG to bind to FcRn present in this IgA. Springer Seminars in Immunopathology 28(4): 377–382. compartment. Subsequent fusion of the vesicle with mem- Tarasenko T, Dean JA and Bolland S (2007) FcgammaRIIB as a modulator of autoimmune disease susceptibility. Autoimmuni- branes at the fetal side of the syncytiotrophoblasts, ty. 40(6): 409–417. results in dissociation of IgG at local physiological pH Thepen T, van Vuuren AJ, Kiekens RC et al. (2000) Resolution of (Roopenian and Akilesh, 2007). FcRn plays a crucial role cutaneous inflammation after local elimination of macro- in prolonging the half-life of serum IgG antibodies by re- phages. Nature Biotechnology 18(1): 48–51. cycling. In addition, recent data show an additional role for Van de Velde NC, Mottram PL and Hogarth PM (2006) FcRn in enhancing phagocytosis (Vidarsson et al., 2006). FcgammaRII and multi-system autoimmune disease. Springer Seminars in Immunopathology 28(4): 329–338. Van der Pol W-L and Van de Winkel JGJ (1998) IgG receptor poly- Summary and Future Directions morphisms: risk factors for disease. Immunogenetics 48: 222–232. Van Sorge NM, van der Poll WL and van de Winkel JG (2003) Over the last decade, knowledge about FcR structure and Fcgamma polymorphisms: implications for function, disease function has increased dramatically. The function of each susceptibility and therapy. Tissue Antigens 61(3): 189–202. FcR is now known to be determined by the specificity of its Vidarsson G, Stemerding AM, Stapleton NM et al. (2006) FcRn: ligand-binding a chain, a family of accessory subunits and an IgG receptor on with a novel role in phago- several key intracellular signalling molecules. The cell type, cytosis. Blood 108(10): 3573–3579. cytokine milieu and communication with other FcRs or Vidarsson G and Van de Winkel JGJ (1998) Fc receptor and other membrane molecules have decisive effects on Fc re- complement receptor mediated phagocytosis in host defence. ceptor-mediated responses. Since Fc receptors are crucial Current Opinion in Infectious Diseases 11: 271–278. in the mechanism of action of therapeutic antibodies, cur- van Vugt MJ, Kleijmeer MJ, Keler T et al. (1999) The Fcgamm- rent efforts are aimed at modulating antibody interaction aRIa (CD64) ligand binding chain triggers major histocompat- with activating or inhibiting FcgRs or with FcRn to change ibility complex class II antigen presentation independently of its Blood its serum half-life. In the future, replacing the mouse FcRs associated FcR gamma-chain. 94(2): 808–817. with its human counterpart will provide a valuable plat- form for in vivo testing of therapeutic antibodies. Further Reading References van Egmond M (2007) FcaRI: a case of multiple personality Beekman JM, Bakema JE, van de Winkel JG and Leusen JH disorder? Blood 109: 1–2. (2004) Direct interaction between FcgammaRI (CD64) and Honda Z (2006) Fcepsilon- and Fcgamma-receptor signalling in periplakin controls receptor endocytosis and ligand binding disease. Springer Seminars in Immunopathology 28(4): 365–375.

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