Functional and clinical consequences of Fc receptor polymorphic and copy number variants

Abstract

Receptors for immunoglobulins (Fc receptors) play a central role during an immune response, as they mediate the specific recognition of antigens of almost infinite diversity by leucocytes, thereby linking the humoral and cellular components of immunity. Indeed, engagement of Fc receptors by immunoglobulins initiates a range of immunoregulatory processes that might also play a role in disease pathogenesis. In the circulation, five main types of immunoglobulins (Ig) exist – namely IgG, IgA, IgE, IgM and IgD and receptors with the ability to recognize and bind to IgG (Fcγ receptor family), IgE (FcεRI and CD23), IgA (CD89; Fcα/µR) and IgM (Fcα/µR) have been identified and characterized. However, it is astonishing that nearly all the known human Fc receptors display extensive genetic variation with clear implications for their function, thus representing a substantial genetic risk factor for the pathogenesis of a range of chronic inflammatory disorders.

The Fcγ receptor family

Immunoglobulin G (IgG) is the most abundant Ig class in serum, constituting over 75% of circulating immunoglobulin. It mediates key effector functions through interaction with Fcγ receptors, which are encoded by eight different genes, each with multiple transcriptional isoforms and located in a locus on the long arm of chromosome 1 (1q21–23). Fcγ receptors are related structurally and belong to the Ig protein superfamily with multiple Ig-like domains. Fcγ receptors are divided generally into three main classes: FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16), each with distinct structural and functional properties (Fig. 1).

Fig. 1.

Overview of the Fcγ receptor family. Mϕ, macrophages; DC, dendritic cells; PMN, polymorphonuclear leucocytes; IFN-γ, interferon-γ; G-CSF, granulocyte colony-stimulating factor; NK, natural killer.

FcγRI is a high-affinity receptor for monomeric IgG (Ka: 10⁹–10¹⁰/M) with three extracellular Ig-like domains expressed constitutively by monocytes and macrophages, as well as by many myeloid progenitor cells. Three genes coding for FcγRI have been characterized: FCGR1A, FCGR1B and FCGR1C[1]. However, it is generally accepted that only FcγRIa is capable of IgG binding, whereas FcγRIb and FcγRIc possibly represent truncated or soluble forms of the receptor, with poorly characterized function. The α ligand-binding chain of FcγRI associates with a disulphide-bonded dimer of FcR γ chain, a signal transducing polypeptide described originally as a component of the high affinity IgE receptor that associates with various Fc receptors. The γ chain carries an activatory signalling motif (immunoreceptor tyrosine-based activation motif: ITAM), which mediates signal transduction upon FcγRI engagement.

In contrast to FcγRI, the other two classes of Fcγ receptor, FcγRII and FcγRIII, display low affinity for monomeric IgG. They are capable of binding to aggregated IgG through multimeric low-affinity, high-avidity interactions, which are particularly important in the recognition and binding of antibody–antigen complexes during an immune response. IgG binding to low-affinity FcγR can trigger a range of effector and immunoregulatory functions, including degranulation, phagocytosis and regulation of antibody production [2]. Examination of the genomic organization of the FcγRII and FcγRIII locus suggests that these receptors arose as a consequence of multiple gene duplication and recombination processes, followed by gain-of-function mutations. FcγRII is encoded by three genes: FCGR2A, FCGR2B and FCGR2C. All the members of the FcγRII class share a characteristic structure unique to FcγRII, that includes functional signalling motifs in their cytoplasmic domains, namely ITAM for FcγRIIa and FcγRIIc and immunoreceptor tyrosine-based inhibition motif (ITIM) for FcγRIIb. FcγRII is expressed by diverse cell types: FcγRIIa by myeloid cells, including polymorphonuclear leucocytes, monocytes, macrophages, platelets and certain types of endothelial cells; FcγRIIb by B cells, monocytes and macrophages; while FcγRIIc expression is restricted solely to natural killer (NK) cells.

The other low-affinity Fcγ receptor, FcγRIII, is encoded by genes FCGR3A and FCGR3B. Although FcγRIIIa and FcγRIIIb share high levels of sequence homology, they exhibit distinct structural differences. FcγRIIIa is a transmembrane protein that associates with the FcRγ chain, whereas FcγRIIIb is processed post-translationally as a glycosylphosphatidylinositol (GPI)-anchored protein, lacking transmembrane and intracellular domains. This difference is thought to be the result of an original gene duplication of the ancestral gene followed by point mutation in the membrane proximal region of the extracellular domain that created a GPI-anchor signal sequence (serine at position 203 rather than the phenylalanine present in the transmembrane FcγRIIIa). The FcγRIIIa isoform is expressed widely by several leucocyte cell types, including macrophages, NK cells and subsets of T cells and monocytes, while FcγRIIIb is expressed constitutively only by neutrophils [2].

The Fcε receptor family

Although normally present in serum at very low levels, IgE may be up-regulated in certain individuals where it associated with atopy, and in immune responses to certain parasites where it is believed to play a protective role. Unlike Fcγ receptors, there are no structural similarities shared by the two classes of IgE receptors: FcεRI, representing the high-affinity receptor for IgE, and FcεRII (CD23), a lower-affinity receptor. FcεRI is a heterotetrameric structure that is comprised of one α subunit, one β subunit and a homodimer of the FcRγ subunit, encoded by FCER1A, MS4A2 and FCER1G genes, respectively. The α subunit mediates IgE binding and its structure resembles closely those of the Fcγ receptors, as it consists of two extracellular Ig-like domains with a transmembrane and a cytoplasmic region. The β subunit of FcεRI is a 4-α helix membrane-spanning protein with tyrosine phosphorylation motifs in its C-terminal cytoplasmic region. Recent studies have demonstrated that it exists in two splice variant forms, the β and β_T, the latter having a role in the cellular targeting of FcεRIa [3]. Finally, the γ subunit together with the β subunit facilitates signalling following engagement of FcεRIa. FcεRI is expressed constitutively by mast cells and basophils, whereas monocytes, eosinophils and dendritic cells express FcεRI, but only in its trimeric form (α,γ-γ), lacking the β subunit [3].

FcεRII (CD23) is the low-affinity receptor for IgE, having an affinity of approximately 10⁷/M. It is expressed constitutively by B cells and is involved in the regulation of IgE production by B cells – a role related to that of FcγRIIb. In addition, it has been demonstrated that several cell types, including eosinophils, neutrophils, macrophages, monocytes and T cells, up-regulate FcεRII expression upon treatment with interleukin (IL)-4 [4]. FcεRII can also bind and interact with other molecules, such as CD21, CD11b and CD11c, although the functional significance of these interactions is still being defined. FcεRII displays susceptibility to proteolytic cleavage by A disintegrin and metalloproteinase (ADAM) sheddases and soluble FcεRII has been reported to have mitogenic properties [5,6].

Receptors for IgM and IgA

A number of receptors specific for IgA and IgM have been characterized, including the polymeric immunoglobulin receptor (pIgR) and Fcα/µR. These two receptors bind to IgA and IgM with intermediate affinity and are encoded by the PIGR and FCAMR genes present at the same locus on chromosome 1 (1q32). Fcα/µR is expressed by mature B cells and macrophages, as well as in secondary lymphoid organs such as lymph nodes, intestine and appendix, and it is therefore anticipated that it possesses a range of immunoregulatory roles [7]. In contrast, pIgR is expressed predominantly on the basolateral surface of epithelial cells and is involved in the transport of mucosal IgA and IgM across the epithelia [8].

Although pIgR and Fcα/µR, along with several other molecules, can bind specifically to IgA, the only ‘classical’ Fc receptor specific for IgA is FcαRI (CD89) [9]. While the ligand-binding (α) chain of FcαRI is related structurally to those of FcγR and FcεRI it is a more distantly related member of the family, and the FCAR gene maps to chromosome 19, alongside genes for leucocyte Ig-like receptors and natural killer cell receptors (KIRs). Like many of the FcγR and FcεRI, the FcαRI a chain associates with a homodimer, the FcRγ chain, although it is often expressed in the absence of FcRγ chain pairing.

Fc receptor genetic variation – implications for function

Single nucleotide polymorphisms (SNPs)

The vast majority of the Fc receptor encoding genes display genetic variation either in the form of SNPs or alteration in their copy number. Although many SNPs have been identified for Fc receptors, for most of them their precise impact upon receptor function remains unknown. Functionally relevant genetically determined SNPs can be categorized into three main types, based on the effect they have on receptor function: (i) augmenting the affinity of Fcγ receptors for particular IgG subclasses; (ii) altering the receptor function and consequently downstream effector events; and (iii) affecting transcriptional promoter activity or mechanisms that alter the levels of receptor expression (Table 1).

Table 1.

Functional effects of genetic variants of Fc receptors.

Receptor	Gene	Variant	Effect	Reference
FcγRIIa	FCGR2A	R131H	H131: higher affinity for IgG2	[12]
FcγRIIb	FCGR2B	I232T	T232: lower affinity for lipid rafts/decreased inhibitory activity	17,18
		−386G > C	−386C: higher promoter activity	[23]
		−343G > C	−343C: loss of AP-1 binding site/transcriptionally repressed	[24]
		−120T > A	−120A: higher promoter activity	[23]
FcγRIIc	FCGR2C	Q57X	Truncated non-functional protein	[21]
		−386G > C	−386C: increased promoter activity	[21]
		−120C > A	−120A: linked with higher transcriptional activity	[21]
		CNV		[21]
FcγRIIIa	FCGR3A	V158F	V158: higher affinity for IgG1 and 3, binds IgG4	[14]
		CNV		[35]
FcγRIIIb	FCGR3B	NA1/2	NA1: higher affinity for IgG1 and 3	[15]
		SH/A78D	Unknown – linked to the NA2 allele	[16]
		CNV		33,108
FcεRI α chain	FCER1A	−66T > C	−66T: higher promoter activity – additional GATA-1 binding site	[26]
		−315C > T	−315T: increased transcriptional activity – Sp1 site	[27]
		−335T > C	−335C: increased expression?	[109]
FcεRI β chain	MS4A2	−426T > C	−426C: increased promoter activity	[31]
		−654C > T	−654T: increased promoter activity-YY-1 binding	28,31
		−109C > T	−109T: unknown/higher receptor expression	[28]
		E237G	G237: associated with higher expression	[88]
		I181L	L181: unknown/higher expression?	[88]
		V183L	L183: unknown/higher expression?	[88]
FcεRII	FCER2	R62W	W62: resistant to proteolytic cleavage	[5]
pIgR	PIGR	A580V	V580: near endoproteolytic cleavage site/reduced efficiency of IgA release?	[8]
FcαRI	FCAR	S248G	G248: enhanced IgA-mediated responses; increased cytokine release	[19]

Ig: immunoglobulin.

One of the first functional SNP identified for Fc receptors was the R131H allelic variant for the low-affinity Fcγ receptor FcγRIIa. This point mutation (519G > A) results in an amino acid substitution [arginine (R) to histidine (H)] at position 131, which is located in the membrane proximal Ig-like domain of the extracellular region [10]. Recent crystallographic studies, along with previous mutational analyses, indicated that this region is involved in the receptor interface interacting with the Fc portion of IgG [11] and the R131H variant determines the affinity of FcγRIIa for human IgG2. In particular, while the R131 variant is not able to interact with hIgG2, H131 has been shown previously to bind and enable phagocytosis of hIgG2-coated particles [12]. The H131 variant might be particularly important in conditions characterized by high IgG2 antibody responses, where it may confer enhanced leucocyte activation by IgG2 and increased capacity for clearance of circulating IgG2 complexes.

SNPs affecting the binding affinity for IgG subclasses have also been characterized for FcγRIII. There are two co-dominantly expressed allelic variants of FcγRIIIa having either a valine (V) or a phenylalanine (F) at position 158. This single amino acid substitution has been demonstrated to increase the affinity of the V158 allotype for IgG1 and IgG3 compared to F158 and induce capacity for IgG4 binding [13,14]. Furthermore, IgG-induced NK cell activity has been found to be increased significantly in 158V/V rather than the 158F/F individuals.

FcγRIIIb is characterized by the presence of the human neutrophil antigen (HNA or NA), a polymorphic variant that comprises four non-synonymous and one synonymous mutation within the membrane distal Ig-like domain of the receptor. The four amino acid differences between the two NA allotypes (NA1 or HNA-1a and NA2 or HNA-1b) have an impact on the N-linked glycosylation of the receptor, and as a consequence affect the affinity for IgG subclasses. In particular, the NA1 allotype displays increased binding and phagocytosis of IgG1- and IgG3-coated particles and it has been shown to exhibit higher affinity for IgG3 compared to the NA2 allotype [15]. Apart from NA-1 and NA-2, the SH polymorphism (also termed as HNA-1c) has been added to the NA family of FcγRIIIb polymorphisms [16]. The SH allele determines the substitution of alanine at position 78 to aspartic acid (A78D) and is linked mainly to the NA2 allele; however, the precise role of this polymorphism in IgG binding is unknown.

In addition to the polymorphisms augmenting receptor affinity for IgG subclasses, SNPs that have a profound impact on the functional effector responses of Fc receptors following immunoglobulin binding have been described. For example, in the case of the inhibitory Fcγ receptor FcγRIIb, it has been demonstrated that a change of a non-polar isoleucine to a polar threonine at position 232 (I232T) within the transmembrane region could affect receptor activity. The T232 variant has been shown to be translocated less efficiently to membrane domains rich in cholesterol and sphingolipids, termed as lipid rafts [17,18]. As a consequence, reduced inhibitory activity was observed for the T232, due possibly to impaired interaction with protein kinases that reside preferentially in lipid raft membrane domains.

A recently identified functional polymorphism in FcεRII is the arginine (R) to tryptophan (W) substitution at position 62 (R62W). In contrast to the R62 variant, the W62 variant is resistant to proteolytic shedding following treatment with a broad range of different proteases, which might influence receptor function and mitogenic role [5]. Finally, a relatively common polymorphism identified in the coding region of FcαRI is associated with impaired capacity to trigger mechanisms such as cytokine release [19]. This polymorphism (844A > G) involves the change of serine 248 to glycine (S248G) within the cytoplasmic domain of the receptor's α chain [20]. IgA-mediated cross-linking of FcαRI on neutrophils from individuals homozygous for the G248 variant triggered significantly more IL-6 release than equivalent cross-linking of receptor on neutrophils from donors homozygous for the S248 variant. In fact, the G248 form, unlike the S248 variant, is capable of inducing cytokine release in the absence of the FcRγ chain. This capacity is presumed to be due, at least in part, to its ability to interact directly with the Src family member Lyn, an important component of the FcαRI signalling cascade.

A number of SNPs have been characterized that play a regulatory role in the expression of particular Fcγ and Fcε receptors. For example, within exon 3 of the FCGR2C gene, a single nucleotide substitution at position 202 results in the change of a glutamine residue to a stop codon at position 57 (Q57X), resulting in the production of a non-functional, truncated protein. Furthermore, NK cells from heterozygous 57Q/X donors displayed reduced expression compared to 57Q/Q donors, while homozygous 57X/X donors were negative for NK cell surface receptor expression [21].

Another determinant of the levels of receptor expression are SNPs within the upstream promoter sequences that may affect the transcriptional activity of the promoter. For example, two SNPs, −386G > C and −120T > A, have been identified within the almost identical promoter regions of the genes encoding the FcγRIIb and FcγRIIc receptors [21,22]. Using in vitro promoter activity assays, it has been shown that the less frequent −386C and −120A haplotypes exhibit enhanced transcriptional activity compared to the −386G and −120T ones, due mainly to the differential binding of GATA-4 and Yin-Yang 1 (YY-1) transcription factors [22,23]. In addition, genetic linkage was observed between the −386C and −120A alleles. Furthermore, an additional polymorphic site (G to C substitution at the –343 position; −343G > C) within the promoter of the FCGR2B gene enables the interaction of the YY-1 transcription factor, leading to transcriptional repression of FCGR2B via competition for binding with the c-Jun/AP-1 transcription complex [24,25]. Given the high sequence similarity between the FCGR2B and the FCGR2C gene promoters, the −343G > C polymorphism would also be predicted to be present within the FCGR2C promoter.

Similarly, within the promoter of the gene coding for the α chain of the FcεRI (FCER1A), a number of SNPs, including –66T > C, −315C > T and −335C > T, have been shown to regulate receptor expression through differential binding and transactivation of transcription regulatory factors. For example, the –66T variant displayed increased in vitro transcriptional activity compared to the −66C form, because the former has an additional GATA-1 binding motif [26]. Similarly, the C to T substitution at position −315 (also referred as −344) was associated with significantly higher promoter activity, an effect that was attributed to the binding of Sp1 transcriptional regulator [27]. Similar SNPs have been identified in the promoter regions of the gene encoding for the β chain of the FcεRI receptor [28–30]. Increased binding of YY-1 and consequently higher promoter activity has been observed for the −426C and −654T haplotypes, compared with the −426T and −654C haplotypes [31].

Copy number variation

Apart from SNPs, a number of recent studies have demonstrated that genes coding for Fcγ receptors exhibit variation in their copy numbers. Indeed, whole genome scans revealed that over 12% of the human genome is covered by copy number variation, accounting for a great proportion of genetic diversity between individuals (reviewed in [32]). In addition, astonishingly high variation has been noted within the Fcγ receptor locus (Fig. 2), but not within the loci where the genes coding for other Fc receptors are mapped. Copy number variation has been demonstrated for FCGR3B, FCGR2C and FCGR3A genes, but not for FCGR2A or FCGR2B. For FCGR3B, Willcocks and co-workers [33] have demonstrated recently an association between gene copy number and surface expression of FcγRIIIb in neutrophils. In addition, neutrophils isolated from donors with more than two gene copies displayed enhanced IgG-induced effector responses as well as increased cell adherence in IgG-coated surfaces compared with those from donors with less than two [33]. Similarly, NK cells from individuals with two or three copies of FCGR3A tend to express higher levels of receptor and exhibit greater antibody-dependent killing capacity than those from individuals with one copy of the gene [21]. Based on these findings, it is anticipated that higher copy numbers of the FcγRIIc gene may be associated with increased levels of surface receptor expression and potentiation of responses following stimulation with IgG. Although a number of studies have made use of well-validated complementary techniques for the assessment of copy number variation, there is controversy on the accuracy and sensitivity of some of these techniques, as they are still at an early stage of technical development.

Fig. 2.

Copy number variation of the Fcγ receptor locus revealed by genome-wide analysis. Array comparative genome hybridization data from the Whole Genome TilePath (WGTP) project of the Sanger Institute (based on Redon et al.[106], available at http://www.sanger.ac.uk/humgen/cnv/data/). Log intensity ratios from 270 HapMap samples for nine probes within the 1q23 region of chromosome 1, where the Fcγ receptor locus is mapped. Contrary to other probes, distinct clusters of intensity ratios within the Fcγ receptor probe (8H4) reveal extensive gene copy variation ranging from zero to more than three copies. Similar analyses of the same experimental dataset for the loci where other Fc receptor genes are mapped revealed minimal variation in intensity ratios among the HapMap individuals (data not shown). A notable exception was the FcαR locus (19q13) that displays significant variation, due probably to the close proximity of the FCAR gene with the KIR family genes, which have been described previously to exhibit extensive copy-number variation [107].

Fc receptor genetic variants as risk factors for chronic inflammatory diseases

The link between Fc receptor genetic variants and disease pathogenesis has been the subject for intensive investigation for a number of decades and it is accepted widely that they play a crucial role in the pathogenesis of a range of chronic inflammatory diseases, constituting significant genetic risk factors for disease development and prognosis. Based on the functional implications of the Fcγ receptor polymorphic and copy number variants, they can be categorized into either low- or high-responder variants. Low-responder polymorphic variants of Fcγ receptors, for example R131, F158 and NA2 for FCGR2A, FCGR3A and FCGR3B, respectively, as well as a low number of genomic copies, are associated usually with autoimmune pathologies that are characterized by the presence of circulating IgG complexes [34–36]. Reduced efficiency of IgG–Fc interactions with these low-responder variants may compromise clearance of IgG complexes from circulation, leading to their deposition in peripheral tissues; a process that initiates or exacerbates inflammatory processes with detrimental effects. Alternatively, high-responder variants are linked to chronic inflammatory disorders characterized by excessive or inappropriate leucocyte activation [37–39]. These variants may result in more efficient and prolonged Fc–IgG interactions. Reduced threshold for IgG-mediated cellular effector responses could promote leucocyte infiltration into tissues together with the release of histotoxic and cytotoxic compounds that amplify inflammatory cell-mediated tissue damage [40]. A number of chronic inflammatory diseases (summarized in Table 2) have been shown to be associated with Fcγ receptor genetic variants and include (but are not limited to) autoimmune pathologies, such as systemic lupus erythematosus (SLE) [14,17,22,24,25,36,41–60], rheumatoid arthritis [35,61–66], myasthenia gravis [67,68], certain neuropathies[69–72], acute allograft rejection [73] and vascular inflammatory and thrombotic disorders, such as coronary artery stenosis, peripheral atherosclerosis and vasculitis [37,38,74–81].

Table 2.

Association of Fcγ receptor variants with chronic inflammatory diseases.

Gene	Variant	Disease	Reference
FCGR2A	H131	GBS	[72]
	R131	Acute renal allograft rejection, APS, giant cell arteritis, HIT, ITP, IgA nephropathy, lupus nephritis, MG severity, peripheral atherosclerosis, RA severity, RF, SLE, WG	[34,36,38,39,41–44,46,47,49,52,57,64,66,68, 73,74,77,80–82,110–118]
FCGR2B	−120A	SLE, CIDP	[22,71]
	−343C	SLE	[24,25]
	−386C	SLE, CIDP	[22,71]
	T232	SLE	[17,53,57–60]
FCGR2C	High CNV	ITP	[21]
FCGR3A	F158	Coronary artery stenosis, giant cell arteritis, lupus nephritis, SLE, WG	[14,37–39,46,50–53,82,83,119]
	V158	ACPA-positive RA, allergic rhinitis, bronchial asthma, HIT, ITP, IgA nephropathy severity, rheumatoid factor production, RA	[35,61–63,65,75,78,110,120,121]
FCGR3B	NA1	ANCA vasculitis, ITP, MG severity	[67,76,79]
	NA2	GBS severity, lupus nephritis, SLE	[55–57,69,70]
	High CNV	ANCA-positive vasculitis	[33]
	Low CNV	SLE, lupus nephritis	[33,86,108]

ACPA: anti-citrullinated protein/peptide antibodies; ANCA: anti-neutrophil cytoplasmic antibodies; APS: anti-phospholipid syndrome; CIDP: chronic inflammatory demyelinating polyneuropathy; CNV: copy number variation; GBS: Guillain–Barré syndrome; HIT: heparin-induced thrombocytopenia; Ig: immunoglobulin; ITP: idiopathic thrombocytopenia purpura; MG: myasthenia gravis; NA: neutrophil antigen; RA: rheumatoid arthritis; RF: rheumatic fever; SLE: systemic lupus erythematosus; WG: Wegener's granulomatosis.

Although there is substantial evidence for the role of Fcγ receptor variants with susceptibility to all these diseases, SLE represents a prototype, multi-organ, antibody-mediated autoimmune disorder, characterized classically by elevated circulating IgG complexes. SLE has been shown to be associated strongly with almost all known Fcγ receptor polymorphic and copy number variants. Several groups have reported an increased frequency of the low-responder allele of FcγRIIIa, F158 among SLE patients [14,46,50–53,82,83]. Furthermore, this allele displays preferential segregation with affected individuals from multiplex SLE families, indicating clearly that it represents a significant risk factor for SLE susceptibility [84]. For FcγRIIa, the R131 allele has been shown to be associated with SLE in several ethnic groups, an observation that was confirmed further by recent meta-analyses [36,49]. Similarly, increased frequency among SLE patients of the low-responder allele of FcγRIIIb, NA2 has been reported widely [55–57]. It should be noted that there have been several reports that describe the lack of association of these polymorphisms with SLE, due possibly to the high genetic variation of these polymorphisms in populations of different origin [50,51,56,85]. In addition, although autoantibodies of all three major subclasses (IgG1, IgG2 and IgG3) can be detected in SLE patients, heterogeneity of the antibody subclass responses and differential clinical exacerbations among these patients could also constitute an additional determinant that accounts for the lack of association between particular Fcγ receptor polymorphisms with disease susceptibility.

A number of polymorphisms within the FCGR2B coding and promoter regions that are linked to the development of SLE have been identified. Many of these variants exhibit decreased activity or expression of FcγRIIb that would probably affect B cell function and antibody production, as well as the activity of other cell types such as monocytes and macrophages. A notable example is the transmembrane polymorphism T232, which displays lower affinity for lipid rafts, and as a consequence it exhibits decreased inhibitory activity and has been shown to be associated with SLE, at least in Asian populations [17,53,57–60]. Similarly, the −343C allele that displayed repressed FCGR2B promoter activity was enriched among SLE patients, compared to disease-free controls [24,25]. Other SNPs within the promoter of FCGR2B are −386G > C and −120T > A, which exhibit genetic linkage. Interestingly, Su and colleagues reported that the frequency of the −386C and −120A alleles, which exhibit enhanced transcriptional activity, was increased in Caucasian patients with SLE compared to ethnically matched controls [22]. The functional relevance of this finding remains to be determined, but one possibility is that these polymorphisms (−386G > C, −120T > A) might be linked genetically to other as-yet unidentified polymorphisms associated with SLE, or their over-representation in the SLE cohort to be due to their low haplotype frequency in the tested population. Finally, variation in the copy number of FCGR3B has been identified as an additional determinant for the development of SLE. In two independent studies, low copy numbers of the FCGR3B gene was associated strongly with SLE, as the percentage of individuals with less than two genomic copies of FCGR3B was significantly higher in the SLE compared to the control study cohort [33,86]. Reduced surface expression of FcγRIIIb in these individuals may compromise the clearance of IgG complexes, increasing the risk for the development of SLE.

Apart from Fcγ receptors, polymorphism within FcαRI has been associated with SLE, in that the proinflammatory G248 allele has been found to be enriched in SLE populations [19] (Table 3). In addition, several Fcε receptor polymorphisms have been linked with the development of allergy-related chronic inflammatory diseases, and new associations continue to be reported [87](Table 3). In particular, polymorphisms within the gene coding for the β subunit of the FcεRI (MS4A2) have been shown to be associated strongly with atopy, asthma, airway hyperresponsiveness, allergic rhinitis, serum IgE levels, atopic asthma and atopic dermatitis [28–30,88–97]. The extent of the impact of these polymorphisms on receptor function and properties is under investigation. Many atopy-associated SNPs within the promoter of FCER1A have been reported to determine transcriptional activity and subsequently receptor expression. In particular, the −66T, −315T and −335C alleles, which differ in their frequency between atopic and non-atopic subjects, at least in some populations, were associated strongly with increased serum IgE [26,27,98]. As the levels of IgE in circulation are correlated greatly with the surface expression of FcεRI, these polymorphisms might affect receptor expression directly or indirectly and consequently the effectiveness of IgE-mediated cellular responses.

Table 3.

Role of IgE, IgA and IgM receptor SNPs in disease pathogenesis.

Receptor	SNP	Disease	Reference
FcεRI α chain	−66T > C	Atopy, high IgE levels in asthma	[26]
	−315C > T	Aspirin-intolerant chronic urticaria, high IgE levels	[98]
	−335T > C	High IgE levels	[109]
FcεRI β chain	E237G	Atopic asthma, high IgE levels, atopy, airway hyperresponsiveness, allergic rhinitis, asthma	[88,90–97,122]
	I181L	Atopy, asthma	[88,89]
	−109C > T	High IgE levels	[28–30,95]
FcαRI	S248G	SLE	[19]
pIgR	A580V	IgA nephropathy	[8]

Ig: immunoglobulin; SLE: systemic lupus erythematosus; SNP: single nucleotide polymorphism.

In summary, Fc receptors have a key role in the regulation of immune cell function and the polymorphic and copy number variants identified so far undoubtedly contribute to the development of a number of chronic inflammatory diseases. Apart from these diseases, Fc receptor polymorphisms have also been shown to be associated strongly with susceptibility to pathogens, constituting a major genetic risk factor for a number of infectious diseases[99–103]. Furthermore, recent advances in the therapeutic use of intravenous immunoglobulins have highlighted the role of Fc receptor polymorphisms in the clinical outcome and therapeutic responsiveness [104,105]. One of the future challenges is to determine the precise role of the different classes of human Fc receptors in the control of innate and acquired immune responses and define how the observed genetic variation contributes to disease pathogenesis.

Disclosure

The authors declare no competing financial interests.