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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 immune system. Leucocyte Fc receptors exist as hetero-oligomeric . Summary and Future Directions complexes with unique ligand-binding a chains and promiscuous accessory subunits. Online posting date: 15th September 2008 Introduction transgenic for specific human FcR. See also: Lymphocyte 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 antibody 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) receptor 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 immunoglobulin G (IgG) (FcgR), IgA (FcaR), IgE (FceR), IgM (FcmR) and IgD (FcdR) Three genes have been characterized for the class I IgG (Figure 1). See also: Antibodies; Antibody Classes receptor – Fcg RIA, IB and IC. Only for FcgRIA functional Most leucocyte FcRs exist as hetero-oligomeric com- protein 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 tyrosine-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) monocytes, and macrophages, 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 dendritic cell populations. Expression of FcgRIa is activating and inhibitory signalling when simultaneously enhanced by interferon g (IFNg), granulocyte colony- triggered. A number of human Fc receptors have or- stimulating factor (G-CSF) and interleukin 10 (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. Endocytosis and antigen 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 proteins 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 amino acid). 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 Fc receptor expressing cells are stimulated, for separated by seven amino acids. Upon FcgRIa cross- instance by cytokines, resulting in an activated cell with a linking this ITAM is phosphorylated on both tyrosines 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 ENCYCLOPEDIA OF LIFE SCIENCES 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 & 2008, John Wiley & Sons, Ltd. www.els.net 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 basophils: z/g b/g chains Other cells: g Monocytes/ M f: g chain Fc Receptors 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, eosinophils, (PMN: IFNg,G- Downregulation: IL-4, IL-13 generation, ADCC, phagocytosis, CSF). cytokine production FcgRII IIa: monocytes, macrophages, PMN, Downregulation: IL-4 IIa: internalization, ADCC, eosinophils, basophils, Langerhans phagocytosis, cytokine cells, platelets, placental endothelial production, respiratory burst 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, apoptosis IIIb: PMN Downregulation: IL-4 IIIb: superoxide generation, ADCC, degranulation FceRI Mast cells, basophils, Langerhans Upregulation: IgE Release inflammatory mediators, cells, eosinophils, platelets,
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