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FcΓ Receptors: Structure, Function and Role As Genes and Immunity (2009) 10, 380–389 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene REVIEW Fcg receptors: structure, function and role as genetic risk factors in SLE XLi1,2, TS Ptacek1,3, EE Brown1,4 and JC Edberg1 1Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA; 3Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA and 4Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA Over 30 years ago, receptors for the Fc region of IgG (FcgR) were implicated in the pathogenesis of systemic lupus erythematosus (SLE). Since those pioneering studies, our knowledge of the structure and function of these FcgRs has increased dramatically. We now know that FcgR contributes to the regulation of acquired immunity and to the regulation of innate immune responses where FcgRs act as specific receptors for innate opsonins (CRP and SAP). Our understanding of the genomic architecture of the genes encoding the FcgR has also witnessed remarkable advances. Numerous functionally relevant single-nucleotide polymorphism (SNP) variants and copy number (CN) variants have been characterized in the FcgR genes. Many of these variants have also been shown to associate with risk to development of SLE and some have been associated with disease progression. This review will provide an overview of the FcgR in relation to SLE, including consideration of the role of genetic variants in FcgR in SLE pathogenesis. The difficulties in assessing genetic variation in these genes will be discussed. To enhance our understanding of the functional roles of these receptors in SLE, future research will need to integrate our knowledge of SNP variants, CN variants and the functional diversity of these receptors. Genes and Immunity (2009) 10, 380–389; doi:10.1038/gene.2009.35; published online 7 May 2009 Keywords: Fc receptors; SLE; genetics Introduction production of autoantibodies, resulting in IC formation. Altered or delayed clearance of these autoantibody- Systemic lupus erythematosus (SLE) is a prototypic containing ICs results in the deposition of these ICs in autoimmune disease characterized by the presence of various tissues, eliciting inflammation and damage by autoreactive B cells and the formation and deposition of engaging FcgRs and complement. Even from decades antibody–antigen immune complexes (IC) consistent ago it was well known that FcgR expression levels and with the diathesis, which involves multiple organ function were altered in SLE. The classic antibody systems. Evidences from familial aggregation studies,1–5 opsonized erythrocyte (EA) clearance studies16,17 showed together with a high concordance among monozygotic delayed in vivo FcgR-mediated clearance in patients with twins,6–8 suggest a genetic contribution. However, a SLE and ex vivo studies showed altered FcgR functions single gene with a clearly causal Mendelian effect has such as phagocytosis.18 These alterations in FcgR func- not been identified, underscoring a multigenic mode tion correlate with disease activity, suggesting that of inheritance. Among the quantitative trait loci identi- disease activity may alter receptor function. However, fied from candidate gene-association studies of murine extensive studies of FcgRs in both animal models and lupus models and diverse human populations, human population studies have since been per- consistent linkage at chromosome 1q21.1–24, a region formed,19,20 and several functional genetic polymorph- that includes a functionally and structurally diverse isms have been identified and associated with SLE in group of receptors that recognize the constant (Fc) several ethnic populations. Thus, FcgR function in portion of specific immunoglobulin (Ig) isotypes, has patients with SLE is influenced by both inherited genetic been shown9–15. variation and by acquired differences in function Consistent with a role for receptors for the Fc region of attributable to disease activity. IgG (FcgR), the pathogenesis of SLE involves the Fc receptors are a heterogeneous group of hemato- poietic cell surface glycoproteins that facilitate the efficiency of antibody–antigen interactions with effector Correspondence: Dr JC Edberg, Division of Clinical Immunology cells of the immune system. These receptors regulate a and Rheumatology, Department of Medicine, University of Alaba- variety of humoral and cellular immune responses, ma at Birmingham, 1825 University Blvd, Room 207 Shelby, including phagocytosis, degranulation, antibody-depen- Birmingham, AL 35294-2182, USA. E-mail: [email protected] dent cellular cytotoxicity, transcriptional regulation of Received 26 March 2009; accepted 30 March 2009; published online cytokine and chemokine expression, B-cell activation and 7 May 2009 IC clearance. The cellular distribution and Ig isotype FccR and SLE XLiet al 381 (IgA, IgD, IgE, IgG and IgM) specificity influence the FcgRI regulatory roles of Fc receptors. In addition, common Located in chromosome 1q21, FcgRI is the only high- variation in the genes that encode Fc receptors, capable affinity Fcg receptor that can strongly bind monomeric of altering the efficiency of the mononuclear phagocyte IgG. This receptor is also unique from other FcgRs in system to clear Ig ICs, provides a mechanism for the having three extracellular Ig-like domains (see Figure 1). heritable differences observed in the susceptibility to SLE The FcgRI family has three genes (FCGRIA, FCGRIB and and subsequent IC-mediated tissue injury.21,22 FCGRIC) but only the FcgRIa product of FCGRIA has The Fc receptor complex is noteworthy for its high been identified as a full-length cell surface receptor.23 degree of sequence homology, pattern of linkage dis- FcgRI has been found on the surface of monocytes, equilibrium and common copy number variation (CNV). dendritic cells (DCs), macrophages and also activated This group of structurally and functionally diverse neutrophils.24 Stable expression of FcgRIa requires the receptor genes are co-localized to a region on chromo- presence of the common FcR g-chain homodimer, some 1q21.1–24 that includes the classical Fc receptors resulting in the expression of a complex of FcgRIa (the for IgG (Fcg) and non-classical Fc-like receptors (FCR1- a-chain)/g-g on the cell surface. FcgRIa can be expressed FCRL6L), Fc receptors for IgE (FceRI) and IgA/IgM in the absence of this g-chain homodimer, but its (Fca/mR). The consistency of genotype–phenotype find- expression is transient. ings coupled with the topology of the Fcg receptor gene cluster underscores the importance of this locus as FcgRII containing susceptibility alleles with potentially deleter- The FcgRII subclass of receptors on human chromosome ious functional consequences. 1q23 is composed of three genes (FCGR2A, FCGR2B and FCGR2C) that encode the FcgRIIa, FcgRIIb and FcgRIIc proteins. Expressed on monocytes, certain DCs, neutro- Human Fcc receptor structure and phils, B cells, platelets and NK cells, FcgRII (CD32) is the function most widely distributed FcgR, with low binding affinity for IgG.25 With two extracellular Ig-like domains, FcgRII FcgRs bind to the Fc portion of IgG and serve as a crucial has a low binding affinity for monomeric IgG, but binds link between humoral and cell-mediated immune IgG aggregates and ICs readily. As mentioned earlier, responses. In addition, more recent data showed that unlike other FcgRs, the FcgRII proteins bear signaling FcgRs also function as receptors for innate immune motifs directly in their intracellular cytoplasmic domains opsonins (CRP and SAP) and provide a link between and do not require the common FcR g-chain for stable innate and acquired immunity. In human, the classical expression or function. Although the FcgRIIa and FcgRIIc FcgR family is divided into three receptor families (FcgRI proteins contain the ITAM, the FcgRIIb protein is the (CD64), FcgRII (CD32) and FcgRIII (CD16)) based on only inhibitory Fcg receptor containing an ITIM in its structural homology, difference in affinity and differ- cytoplasmic domain. An additional level of complexity ences in specificity for IgG subclasses. These FcgRs are in the FCGR2B locus is that three alternatively spliced also defined as either activating receptors (FcgRI, transcripts can be expressed: b1 and b2 differ by an insert FcgRIIA/C and FcgRIII) or as inhibitory receptor of 19 amino acids in the FcgRIIb cytoplasmic domain, (FcgRIIB) as they elicit or inhibit immune functions such whereas the b3 form lacks part of the signal sequence. as phagocytosis, cytotoxicity, degranulation, antigen pre- FcgRIIb1 is expressed on B cells as the only currently sentation and cytokine production through immune recognized Fcg receptor on B cells, whereas FcgRIIb2 is tyrosine activating or inhibitory motifs (immunoreceptor found on myeloid cells together with FcgRIIa. The tyrosine activation motif (ITAM) or immunoreceptor FCGR2C gene has a stop codon (STP)/glutamine (Q) tyrosine inhibitory motif (ITIM)). These signaling motifs polymorphism at amino-acid position 13 in the first are either on the same ligand-binding a-chain as for FcgRII extracellular domain and has been described as an or on the associated homodimer accessory chains such as expressed protein on NK cells only when the 13Q allele the common Fc receptor g-chain (for FcgRI and FcgRIII, is present.26,27 The FCGR2C
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