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 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 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/.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 –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 .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 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 , pattern of linkage dis- FcgRI has been found on the surface of , equilibrium and common (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 . 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 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 gene encodes an extracellular Figure 1) that is also shared with FceRI and FcaRI.19 On domain that is highly homologous to FcgRIIB and an natural killer (NK) cells, FcgRIIIa associates with a intracellular cytoplasmic domain that is nearly identical homodimer of the T-cell receptor z-chain. The ligand- to the cytoplasmic domain of FCGR2A. Characterization binding a-chain of most FcgRs consists of two or three of the FCGR2C locus has suggested that the FCGR2C Ig-like domains in the extracellular region, a transmem- gene is the result of an unequal crossover event between brane domain and an intracellular cytoplasmic domain. FCGR2A and FCGR2B.

NA1/NA2/SH 13STP/Q Extracellular Domains 131H/R γ 158V/F γ -chain -chain GPI 187I/T ITAM ITAM ITIM ITAM ITAM Intracellular Cytoplasmic FcγRI FcγRIIA FcγRIIB FcγRIIC FcγRIIIA FcγRIIIB Domains Figure 1 Structure of human classical Fcg receptors and location of functionally characterized SNP variants. SNP, single-nucleotide polymorphism.

Genes and Immunity FccR and SLE XLiet al 382 FcgRIII phosphorylation of the ITAM itself, with recruitment of Two genes, FCGR3A and FCGR3B, encode the two various downstream targets, including other kinases, receptors of the FcgRIII family (FcgRIIIa and FcgRIIIb). adaptor molecules and other signaling intermediates (see FcgRIII is also considered as of low affinity; however, Bezman and Koretzky32 for a review). In many cell types, FcgRIIIA can bind monomeric IgG with an intermediate activation of phosphoinositide-3 kinase results in the affinity and both FcgRIIIA and FcgRIIIB bind multimeric recruitment of phospholipase Cg, which in turn induces IgG and IC efficiently. FcgRIIIa ligand binding is further a phospholipase Cg-mediated calcium influx triggering influenced by receptor glycosylation. Different glyco- different effector functions.33,34 In antigen-presenting forms of FcgRIIIa are expressed on human NK cells and cells, such as macrophages and DCs, activating FcgRs monocytes/macrophages and these glycoforms have mediate cell functions such as phagocytosis, respiratory different abilities to bind IgG ligand. burst and cytokine production (-a The FcgRIIIa protein is expressed as a transmembrane and interleukin-6); in neutrophils and NK cells, they protein on monocytes, tissue-specific macrophages, DCs, trigger antibody-dependent cellular cytotoxicity and d/gT cells and NK cells.19 On these cells, g-chain (or the degranulation; and in mast cells, they induce degranula- T-cell receptor z-chain on NK cells) is necessary for both tion.35,36 It is a noteworthy finding that these so-called stable expression of the protein on the cell surface and activating receptors are not merely overlapping in for signal transduction through the FcgRIIIa receptor functional properties but in fact have specialized func- complex. Interestingly, in mast cells, the FcgRIIIa tions that are due in part to the differences in the receptor complex can also incorporate the b-chain from cytoplasmic domains of the ligand-binding a-chains. For the IgE receptor, resulting in an a/b/g-g complex on the example, a recent study has shown the unique ability of cell surface. FcgRIa to facilitate antigen presentation.37 Even more The FcgRIIIB gene is unique among the FcgR genes in surprising is our recent finding that FcgRIa is unique that it encodes a glycosylphosphatidylinositol-anchored among FcgR, and among other g-chain-associated Fc (GPI) receptor, FcgRIIIb. This receptor is expressed on the receptors, in its ability to regulate the cell surface surface of neutrophils and .28 It is worth noting expression of TNFSF13b (also called BLyS or BAFF) that on the surface of neutrophils, FcgRIIIb is highly upon cross-linking with either IgG ligand or with the expressed, with 150 000–200 000 receptors expressed per innate immune opsonin, CRP.38 Other differences in cell. Biochemical studies have suggested that when receptor function are the result of differences in cell FcgRIIIb is expressed on the surface of neutrophils, it surface expression. FcgRIIa is unique in its expression on interacts with the b2-integrin, CD11b/CD18. This is of platelets, and cross-linking of FcgRIIa can directly interest given the recent demonstration of the strong activate platelets resulting in platelet aggregation. genetic association between a variant in the CD11b/ Although all of these functions are dependent on the ITGAM locus and SLE. ITAM, it is likely that the sequences in the associated As mentioned above, each FcgR protein has differen- a-chains are also contributing to net receptor function. tial ligand-binding preferences with respect to IgG Indeed, we have shown that the cytoplasmic domain of subclasses and differing affinities for IgG subclasses. FcRIa, devoid of any known signaling motifs, modifies These preferences are summarized in Table 1 and have g-chain-based signaling and other recent studies have been recently reviewed in great detail.29 It is worth shown that these cytoplasmic domains can recruit noting that the binding of IgG2 is generally limited to the different molecules to the receptor complex. Future work R131 allele of FcgRIIa, whereas the binding of IgG4 is will be required to fully delineate the signaling elements limited to the 159V allele of FcgRIIIa (see below). engaged by the ITAM-expressing FcgR, and this work promises to provide additional insights into the func- FcgR function tions of each of these different FcgRs. Regulation of cell signaling. Upon cross-linking by IC, A key function of these activating FcgRs is the removal activating FcgRs (FcgR associated with the common FcR or clearance of ICs. As noted above, this function is g-chain or the T-cell receptor z-chain or FcgRIIa/c) known to be altered in patients with SLE. Of all FcgRs, initiate a signaling cascade through the ITAM, which FcgRIIIa is thought to play an important role in IC normally starts with sequential activation of protein clearance. The intermediate affinity of this receptor on tyrosine kinases of the Src family followed by activation macrophages (fixed tissue macrophages) makes it ideally of the Syk tyrosine kinase.30,31 This results in the tyrosine suited as a capture receptor to facilitate clearance. Of

Table 1 General features of human Fcg receptors

Name Chromosome location Isoforms IgG subclass specificity Distribution

FcgRI(CD64) 1q21 G1 ¼ G34G4bG2 Mon/Mac/PMN/DC FcgRII(CD32) 1q23 G3XG1bG44G2 FcgRIIA Mon/Mac/DC/PMN/platelet FcgRIIB B/Mon/Mac/DC FcgRIIC NK FcgRIII(CD16) 1q23 G1 ¼ G3bG24G4 FcgRIIIA Mon/Mac/NK/dgT FcgRIIIB PMN

Abbreviations: DC, dendritic cell; Mac, macrophage; Mon, ; NK, natural killer cell; PMN, neutrophil.

Genes and Immunity FccR and SLE XLiet al 383 course, this does not preclude a role for other FcgRinIC More recent data from a number of different receptor handling, and it is likely that IC clearance represents the systems have challenged the conventional ITAM/ITIM integrated function of multiple FcgR working in concert concept.42,43 Extensive cross-talk, or co-modulation, with complement receptors. between receptor systems has now been described and As the sole Fcg receptor bearing an ITIM, FcgRIIb acts is likely to be pervasive across many different receptor as a suppresser of IC-mediated cell activation and when systems. For example, the IgA Fc receptor, FcaRI, can not co-cross-linked with surface Ig FcgRIIb functions as a only activate cells but also cross-inhibit other receptors, suppressor of B-cell activation. When FcgRIIb is cross- including the classical FcgR. Similarly, engagement of linked with other activating receptors, the ITIM is receptors containing ITIMs can result in the induction of phosphorylated by an Src family kinase such as Lyn, functional responses such as antigen presentation which leads to the recruitment of Src homology 2 through FcgRIIb on DCs. The regulation and determina- domain-containing protein tyrosine phosphatase (SHP-1), tion of the activating and inhibitory potential of FcgR are SHP-2 and/or SH2-domain-containing inositol polypho- likely influenced through the complex interplay of the sphate 50 phosphatase (SHIP). In B cells, SHIP can inhibit degree of receptor cross-linking, the nature of interaction activation pathways mediated by pleckstrin homology- between receptor subunits and the interactions with domain-containing kinases, such as phospholipase Cg other cell surface receptors (such as CD11b/CD18). and Bruton’s tyrosine kinase, therefore suppressing downstream events such as the Ig-induced calcium flux and diminish multiple cellular functions induced by FccR polymorphisms and association ITAM-containing receptors as mentioned above.39 A key role for FcgRIIb in regulating autoimmunity has been with SLE shown in both murine models and in patients with SLE. Sequencing of the genes in the Fcg receptor cluster has Certain mouse strains that are deficient in FcgRIIb resulted in the identification of numerous genetic develop a spontaneous lupus-like disease, resulting in variants, including functionally relevant variants. The glomerulonephritis and premature mortality.40 Conver- importance of FcgR variants as SLE susceptibility factors sely, increases in FcgRIIb expression in these mice can and as factors influencing disease outcomes is high- restore tolerance and ameliorate the spontaneous auto- lighted by the consistent association of many of these immune phenotype.41 In patients with SLE, alterations in genetic variants with disease. Table 2 highlights some of FcgRIIb expression have also been noted. However, the consistent associations observed between FcgR disease is associated with increased expression of the variants and SLE. However, limiting the ability to FcgRIIb protein on the surface of B cells. Clearly, examine the role of genetic variants in these genes is additional work is needed to more fully understand the the high degree of sequence homology between genes critical role of this receptor in the regulation of immune (Figure 2). Indeed, this sequence homology precludes the tolerance and autoimmunity. assessment of most single-nucleotide polymorphisms

FCGR2A HSPA6FCGR3A FCGR2C FCGR3B FCGR2B

14.1kb 2.6kb 8.8kb 18.9kb 8.1kb 15.0kb

Known CNV Interval

Annotated Segmental Duplications

50kb Figure 2 Schematic genomic structure of the classical low-affinity Fcg receptor cluster on human chromosome 1q23. Identical colors represent regions of high sequence homology between genes.

Table 2 Functional polymorphisms of classical Fcg receptors and association with SLE

Name Alleles Association with SLE Mechanism

FcgRII (CD32) FcgRIIA H/R131 (rs1801274) R131(multiple ethnic populations) Altering ligand binding (R: lower affinity, no binding to G2) FcgRIIB I/T187a (rs1050501) T187 (Asian) Altering signaling 2B.1/2B.4a 2B.4 (Caucasian) Altering transcription factor binding FcgRIIC STP/Q13 Unknown

FcgRIII (CD16) FcgRIIA V/F158 (rs396991 ) F158 (multiple ethnic populations) Altering ligand binding (F: lower affinity) FcgRIIB NA1/NA2 NA2 (Japanese) Altering ligand binding (NA2: lower affinity) CNV Low CN (Caucasian) Altering protein expression level

Abbreviations: CNV, copy number variant; SLE, systemic lupus erythematosus. aPromoter haplotype. 2B.1: À120G-386T; 2B.4: À120C-386A.

Genes and Immunity FccR and SLE XLiet al 384 (SNPs) in these genes on the currently available genome- promoter haplotype was associated with SLE in a wide SNP arrays. In the first two published genome- Caucasian population with an odds ratio of 1.6.65 wide association studies (GWAS),44,45 the arrays con- Confirmation of this association has been published tained only 11 and 19 SNPs across the entire low-affinity and has shown that the same À386G/C SNP associates FcgR cluster, precluding a detailed analysis of association with SLE susceptibility.67 The analysis of these promoter between these genes and SLE. We will summarize the variants in FCGR2B is hampered by complete sequence current knowledge regarding associations between identity with the proximal promoter of FCGR2C.65 genetic variants in each of the low-affinity classical FcgR Studies examining these SNPs need to take care to and SLE. ensure gene specificity in any analysis of this genomic region. FCGR2A A non-synonymous G-to-A variant in the FCGR2A gene FCGR3A (rs1801274) results in a single amino-acid difference at As noted above, FcgRIIIa is thought to play a critical role position 131 (R131 and H131) in the second extracellular in IC clearance. In addition, this receptor is an important Ig-like domain of the FcgRIIa protein. This allelic mediator of antibody-dependent cell-mediated cytotoxi- difference alters recognition of ligand. The FcgRIIA- city functions on NK cells.68 A non-synonymous SNP H131 (histidine residue at position 131) allele is able to (rs396991) that encodes a T-to-G change at nt559 results bind IgG2 effectively, whereas the R131 (arginine residue in a phenylalanine (F) to valine (V) amino-acid change at at position 131) allele does not bind IgG2.21,46 This position 159 in the second extracellular domain of the affinity variation leads to functional difference: phago- FcgRIIIa protein. These alleles of FcgRIIIA have differing cytes from homozygous H131 individuals are much binding affinities for IgG. The FcgRIIIA-158V allele (also more effective than those from homozygous R131 donors known as 176V/F when the leader sequence is included) in terms of phagocytosis of IgG2-opsonized particles.47 binds IgG1, IgG3 and IgG4 with higher affinity relative to Several independent studies in multiple ethnic groups the 158F (176F) allele. In addition, the increased binding have reported the association of R131 with the suscept- capacity of the 158V allele results in more robust ibility to SLE and/or lupus nephritis in Dutch Cauca- downstream functional effects. Using peripheral blood sians, European-Americans, African-Americans and NK cells from genotyped donors, individuals homo- Koreans,48–50 whereas other studies have presented zygous for the 159V allele show higher calcium transi- inconsistent results.51–55 Karassa et al.56 did a meta- ents, higher induction of CD25 expression and more analysis of 17 published studies and inferred that the rapid when compared with donors homozy- R131 allele had 1.3-fold higher risk for SLE susceptibility gous for 159F.69,70 Consistent with a critical role for compared with the H131 allele. Besides contributing to FcgRIIIa in IC clearance, the lower IgG-binding allele, susceptibility, the FcgRIIa-R131 allele was also shown to 158F, is associated with SLE susceptibility in several be related to SLE severity.57 Haseley et al.57 found that the case–control studies in multiple ethnic groups (Cauca- presence of 131R/R was associated with renal involve- sian and African-American). ment in patients with IgG2 anti-C1q autoantibody- A role for FcgRIIIa in disease severity has also been positive nephritis. Inconsistencies between studies might shown. Within patients with renal disease, the higher be attributable to ethnic differences, disease heterogene- binding 159V allele is associated with development of ity (that is, subclass of autoantibodies) or to genotyping end-stage renal disease.71 This result, in conjunction with error. the SLE susceptibility studies of FCGR3A, shows that this gene can influence not only disease susceptibility but FCGR2B also disease progression. In patients with renal disease, A non-synonymous T/C SNP in the FCGR2B gene has progression to end-stage renal disease is associated with been identified that results in the change of an isoleucine the higher binding allele of FcgRIIIa, consistent with a (I) to threonine (T) substitution at position 187 in the role for this receptor in promoting more vigorous local transmembrane domain of the FcgRIIb protein.58,59 This inflammatory responses in the kidney. single amino-acid substitution has been shown to affect the inhibitory function of FcgRIIb on B cells. The 187T FCGR3B allele is excluded from lipid rafts and has a decreased Three different allotypic variants of FcgRIIIb, NA1, NA2 inhibitory potential toward BCR signaling.60,61 Likewise, and SH, have been identified through serological studies. the 187T allele has been reported to be associated with The sequence bases for these FCGR3B variants are now SLE in Asian populations, including Japanese, Chinese known (Figure 3). The six SNP differences underlying and Thais,59,62,63 but no association has been found in these three serologic allotypes include five non-synon- African-American or Caucasian in the United States or ymous SNPs and one synonymous SNP. The five amino- Europe.58,64 A meta-analysis of association of this variant acid changes are all in the first extracellular domain of in FCGR2B with SLE in three independent studies of FcgRIIIb (marked as black in Figure 3), with the amino- Asian populations showed an odds ratio of 2.45 for acid 65 change resulting in a loss of a glycosylation site in 187T/T vs 187I/I for SLE susceptibility.60 the NA2 allele.22,72 The enhanced functional capacity of In 2004, Su et al.65 identified a promoter haplotype that the NA1 allele is firmly established. Some studies have alters FcgRIIb promoter activity. The less frequent suggested differing binding affinities for IgG1 and IgG3 promoter haplotype (À386C-120A) showed increased between the FcgRIIIB-NA1 and FcgRIIIb-NA2 alleles, promoter activity and drove higher receptor expression with the NA1 allele showing higher binding. Alterna- in both transfected cell lines and on cells ex vivo from tively, the NA1 and NA2 alleles may interact differently genotyped donors than the more frequent haplotype with other cell surface receptors, such as the b2-integrin, (À386G-120T).65,66 The less frequent and more active CD11b/CD18. Interactions with other cell surface recep-

Genes and Immunity FccR and SLE XLiet al 385

Exons S1 S2 EC1 EC2 TMC

nt 141 nt 147 nt 227 nt 266 nt 277 nt 349 AGG CTC AAC GCT GAC GTC AGC CTT AGC GAT AAC ATC aa change 36R SS38L LL65N 78AD 82DN 106V

Nucleotide 141 147 227 266 277 349 FCGR3B*01 (NA1) G C A C GG FCGR3B*02 (NA2) C T G C A A FCGR3B*03 (SH) C T G A A A

Amino Acid 36 38 65 78 82 106 FCGR3B*01 (NA1) Arg Leu Asn Ala Asp Val FCGR3B*02 (NA2) Ser Leu Ser Ala Asn IIe FCGR3B*03 (SH) Ser LeuSer Asp Asn IIe

Figure 3 Genomic structure of the FCGR3B locus. The sequence basis and corresponding amino acids for the NA1, NA2 and SH alleles are shown. tors may be critical or essential to FcgRIIIb function. As alleles in two healthy individuals in 1990.75,76 An noted above, this receptor lacks a transmembrane and increased CN was later observed through the presence cytoplasmic domain and is anchored to the cell surface of all three alleles in three individuals.77 through a GPI linkage. In the absence of these domains, Association of FCGR3B CNV with SLE has been such inter-molecular interactions may be necessary for determined using a real-time PCR assay developed by FcgRIIIb to function, and glycosylation change between Aitman et al.78 Relative CN of o2 at the FCGR3B locus the NA1 and NA2 alleles may alter such interactions. was associated with risk for SLE (with and without In a Japanese population, the NA2 allele has been nephritis). Relative CN of 42 FCGR3B was not reported as a susceptibility factor for SLE.73 However, significantly associated with protection against SLE but this observation has not been replicated. More recently, a was significantly associated with protection against re-examination of the importance of variation—CNV—at Addison’s disease and Wegener’s granulomatosis in a the FCGR3B locus has suggested a role for decreased CN French population.79 Thesameassayhasbeenusedto of FCGR3B in SLE susceptibility (see below). show an association of FCGR3B CN with risk for glomerulonephritis and lupus nephritis: increased CN was protective and decreased CN was a risk factor.78 There Genome-wide association studies is evidence that CNV of FCGR3B is associated with alterations of surface expression on neutrophils, neutrophil A number of GWAS studies in SLE have now been adhesion and IC uptake by neutrophils.80 Deficiencies in reported. As noted above, SNP coverage in the low- these neutrophil functions could cause or contribute to the affinity Fcg receptor is poor, with some genes (FCGR2C characteristic buildup of ICs seen in SLE. and FCGR3B) receiving no coverage. Nonetheless, a statistically significant association at the non-synon- ymous H131/R131 variant (rs1801274) was noted in the CNV of the other FCGR genes in the 1q23 cluster recent GWAS performed by the International Consor- CNV has been reported for other FCGR genes, but no 45 tium on Systemic Lupus Erythematosus. The SNPs in association with SLE has been reported yet. CNVs of other FCGR genes previously associated with SLE were FCGR2C and FCGR3B have been reported to be linked.81 not represented on any of the arrays used in the recent CNV of FCGR2C, assessed by multiplex ligation-depen- GWAS studies. The presence of high sequence homology dent probe amplification, was determined to be asso- between the FCGR genes, with the presence of a ciated with idiopathic thrombocytopenic purpura.27 In segmental duplication in this region (Figure 2), precludes the same report, CNV of FCGR3A was also reported. any GWAS-based conclusions regarding association at CNV of the two remaining receptors in the chromosome the FCGR3A or FGR2B loci with SLE. In addition, 1q23 FCGR cluster, FCGR2A and FCGR2B, has yet to be association between SNP variants and SLE in this reported. Although CNV of the other FCGR genes has yet genomic region may also be confounded by the presence to be associated with SLE, if reported at all, the clear of known CNVs. significance of FCGR3B CNV in SLE, the evidence of more extensive CNV in the cluster, and the logical connection between FCGRs and the pathology of SLE CNV in the Fcc receptor cluster suggest that further study of CNV in the 1q23 FCGR FCGR3B CNV and SLE cluster is warranted. CNV of FCGR3B in SLE has been known since the 1990s, although it was not reported as such.74 Although FCGR3B is almost identical at the sequence level to Future directions FCGR3A, unique alleles in the 30-most exon have been used to detect FCGR3B CNV. Deficiency (that is, a CN of Efforts to characterize the joint contribution of zero) of FCGR3B was first observed as a lack of all three Fc receptor loci with additional genotypic and environ-

Genes and Immunity FccR and SLE XLiet al 386 mental factors will expedite our understanding of SLE reactive oxygen species and serine proteases, which pathogenesis and importantly, its natural history. promote differences in receptor phagocytotic and bind- ing capacity, respectively. It is conceivable that additional Heritable indices of SLE severity and progression microenvironmental factors, including infectious agents, Recent advances in sequencing and sex hormones, C-reactive protein and mannose-binding marker density, together with estimating unknown phase lectin that correlates with the SLE diathesis, influence Fc and accounting for population stratification in large receptor function. Such modifying effects may under- case–control association studies, have become key score the variation in Fcg receptor gene associations elements for identifying heritable risk factors for lupus observed with disease and lupus nephritis. This is susceptibility. However, longitudinal studies will be particularly noteworthy because the pleiotropic effects essential to facilitate our understanding of the genetic of these inflammatory molecules act locally to perturb markers involved in influencing disease severity and Fcg receptor-mediated IC clearance, leading to chronic progression, which is characterized by flare, chronically inflammation of the glomeruli, fibrinoid necrosis and active disease and quiescence. Such characterization reduced renal capacity, consistent with lupus nephritis. would facilitate an evaluation of the effectiveness of a prognostic index for SLE. Conclusion Fc receptor co-expression and function Immune surveillance is redundant and is reflected by the The study of Fcg receptors in SLE has a rich heritage co-expression of multiple ITAM- or ITIM-containing Fc dating back over 30 years to the initial Fcg receptor- receptors on the same cell. The co-expression of multiple mediated clearance studies. Our knowledge of the stimulatory ITAM-dependent Fc receptors provides a diversity of Fcg receptor structure and function has mechanism by which the joint effect conceivably results developed substantially since that time. On the basis of in a synergistic activation of effector cells and enhanced this increase in knowledge about these receptors, many efficiency for IC clearance. Alternatively, in cells that pivotal mechanistic and genetic studies have reinforced co-express inhibitory ITIM- and ITAM-dependent Fc the functional importance of these receptors in the receptors, the magnitude of the effector cell response pathogenesis of SLE. As we develop additional tools to upon IgG isotype cross-linkage is attenuated, reflecting assess genomic variants in this region, we will undoubt- an antagonistic joint effect. Thus, the SLE diathesis may edly be surprised by the diversity of variation among reflect the relative difference in the magnitude of ITAM- these genes and gain increased insight into the role of Fcg and ITIM-dependent effects on the activation of effector receptors in SLE. cells, which in turn may be influenced by the genetic heterogeneity observed in the genes that encode the Fc receptors. The delineation of individual stimulatory and Conflict of interest inhibitory effects of Fc receptor gene loci or haplotypes may advance our understanding of the combined effects The authors declare no conflict of interest. of these receptors on the risk of, or time to, SLE and related sequelae or clinical manifestations. Acknowledgements Gene-by-gene interactions In addition to the Fcg receptors, strong and consistent We thank Dr Robert P Kimberly for his continued gene associations were shown across diverse populations support. Travis Ptacek was supported by the UAB for human leukocyte antigens,70,72,82,83 components of the Hughes Med-Grad Fellowship Program. Our work is classical complement activation system belonging to the supported by grants RO1-AR42476, RO1-AR33062 and major histocompatibility complex class III region70,72,83,84 P01-AR49084 from NIH-NIAMS and by 1UL1RR025777 and more recently, the type I interferon regulatory from the NIH National Center for Research Resources. factor-5 (IRF5),69,85–87 the protein tyrosine phosphatase, PTPN22,69,75,78,88–90 ITGAM, PXK and KIAA1542.45 De- spite strong associations with SLE, these susceptibility loci do not sufficiently contribute to the risk of this References complex phenotype alone. The joint effects of deleterious 1 Sestak AL, Shaver TS, Moser KL, Neas BR, Harley JB. 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