Human FcR polymorphism and disease.

The central role of Fc receptors in supporting an appropriate humoral immune system has been demonstrated by numerous ex vivo and in vivo studies, in both human and model animals. Often one allele enhances activation and/or net immune system activity while the second allele tends to be less effective in eliciting responses, such as clearance and processing of immune complexes or antibody opsonized particles. Thus, functional FcR polymorphisms may significantly influence effector cell functions, thus providing diversity in host responses pertinent to many infectious, inflammatory and autoimmune diseases. For many SNPs, however, especially when they are in noncoding regions, the direct impact on biological function is not known and the potential influence on pathophysiology is ambiguous. An understanding of these associations and their implications for disease processes awaits further insight into the pertinent genomic architecture of the overall immune response. Often working in synergy with the complement system, FcγR-mediated clearance of antibody-coated microbes and FcγR-triggered inflammatory cytokine release are important mechanisms in eliminating infectious agents. Since human IgG2 is relatively inefficient in initiating the complement cascade, the FcγRIIa-131H allele is the primary leukocyte receptor capable of effectively clearing IgG2-coated microbes, which is important in host defense against encapsulated bacteria such as Streptococcus pneumonia , Hemophilus influenza, and Neisseria meningitidis (Bredius et al. 1993 ; Jefferis and Kumararatne 1990 ; Endeman et al. 2009 ; Platonov et al. 1998 ; Jansen et al. 1999 ). In the context of Strep pneumonia pneumonia, the FcγRIIa-131R allele, which fails to bind IgG2, may be over-represented in bacteremic patients, and in one study, the most severely infected bacteremic patients, who died within 1 week of hospitalization, were all homozygous for the R131 allele (Yee et al. 2000 ). Similarly, the FcγRIIa-131R allele is associated with increased infection by Hemophilus influenza and Neisseria meningitidis in multiple bacterial respiratory diseases and sepsis (Endeman et al. 2009 ; Platonov et al. 1998 ; Sanders et al. 1994 ; Bredius et al. 1994 ; Yuan et al. 2005 ). Of note, FcγRIIa also binds C-reactive protein with allele sensitivity reciprocal to IgG2 (Stein et al. 2000 ). High levels of CRP during infection may contribute to the clearance of IgG2-coated microbes by the R131 allele by opsonizing encapsulated bacteria and subsequently activating the complement mediated clearance (Weiser et al. 1998 ), which may compensate, at least in part, for the lack of FcγR-IgG2 mediated clearance in patients with the R131 allele. Periodontitis, an infectious disease caused by pathogenic anaerobic bacteria in the periodontium and the corresponding host response, is influenced by a combination of behavioral, environmental and genetic factors. Several types of FcγR-bearing cells are found in periodontal tissues, including neutrophils, lymphocytes and dendritic cells (Yuan et al. 1999 ). Functional studies largely focused on neutrophils have demonstrated that neutrophils homozygous for the FcγRIIa-131H allele were more efficient in bacterial phagocytosis, degranulation and elastase release (Nicu et al. 2007 ). In the same study the homozygous FcγRIIa-H131 patients also showed more bone loss than those with the H/R or R/R allotypes. Kobayashi et al. has also reported that neutrophils carrying the FcγRIIIb-NA2 allele showed lower reactivity to IgG1/IgG3 coated periodontopathic bacteria and induced weaker oxidative burst (Kobayashi et al. 2000 ). Association studies calculating the clinical relevance of FcγR polymorphisms in periodontitis have reported mixed results, complicated by the difference in size and ethnicity of the population studied and the inconsistent definitions of disease stage and progression. A recent meta-analysis aggregating 17 studies reported modest association of FcγRIIa-131R with aggressive periodontitis in Asians, relatively strong association of the FcγRIIIb-NA1/NA2 polymorphism with both aggressive and chronic periodontitis, and a statistically insignificant relationship between the FcγRIIIa-F158 V and periodontitis (Song and Lee 2013 ). In studies of the distribution of the inhibitory FcγRIIb variants, significant enrichment of the FcγRIIb-232T allele in patients with aggressive periodontitis compared to both chronic periodontitis patient and healthy control groups occurs in Japanese periodontitis patients (Yasuda et al. 2003 ). Furthermore, the composite genotype of FcγRIIb-232T plus FcγRIIIb-NA2 was strongly associated with aggressive periodontitis. The large number of B cells (Yuan et al. 1999 ) and the elevated antibody level (Horino et al. 1989 ) in periodontal lesions, as well as our understanding of the biology of the FcγRIIb-232T allele make the link between FcγRIIb-232T and periodontitis biologically plausible. Besides the well-known polymorphisms, several other SNPs in the FcγR cluster have been identified in association with periodontitis. For example, the FCGR2B -nt645 + 25A/G (rs2125685) SNP in intron 4 was reported in Japanese patients and was related to changes in receptor expression level and severity of periodontitis (Sugita et al. 2012 ). A little studied SNP in FCGR3A (rs445509) was associated with chronic periodontitis in a Chinese population (Chai et al. 2010 ). Further study of these variants may elucidate their function and contribution to disease. Variants influencing Fc receptor function are also relevant in host defense mechanisms for virus infections. Dengue virus may co-opt Fcγ receptors for cell entry when the antibody-opsonized virus particles are phagocytized by FcγR-bearing myeloid cells, establishing infection in the phagocytes (Moi et al. 2010 ; Littaua et al. 1990 ; Garcia et al. 2011 ). Several studies have suggested the FcγRIIa-R131 allele may have a protective effect in Dengue virus infection (Loke et al. 2002 ; Garcia et al. 2010 ). The FcγRIIa-R131H SNP is one important factor in host defense, as it is also reported to be relevant in infections with A/H1N1 influenza (Zuniga et al. 2012 ), severe acute respiratory syndrome (SARS)- coronavirus (Yuan et al. 2005 ), and Epstein–Barr virus (Diamantopoulos et al. 2013 ). In human immunodeficiency virus (HIV) infection, patients with homozygous low affinity R131 allele showed the highest rate of disease progress (Forthal et al. 2007 ). The FcγRIIIa-V158F genotype also correlates with the development of Kaposi’s sarcoma in HIV-infected patients (Forthal et al. 2007 ; Lehrnbecher et al. 2000 ). The vasculitides are a group of disorders that involve inflammation of the blood vessels. Although the etiology of vasculitis is often not clear, vascular inflammation can be immunologically mediated, triggered by immune complexes, anti-neutrophil cytoplasmic antibodies, anti-endothelial cell autoantibodies as well as by cell-mediated processes. The classification of the vasculitides is typically based on the size of the affected vessel. Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis, is a type of neutrophil mediated vasculitis affecting small and medium sized vessels. GPA is often characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) (Nolle et al. 1989 ). Engagement of both ANCA target and Fc receptors on myeloid cells by ANCA elicits production of interleukin-8, a neutrophil chemotactic factor, and a series of effector programs such as oxidative burst, degranulation and release of neutrophil extracellular traps (NETs) (Ralston et al. 1997 ; Porges et al. 1994 ; Kessenbrock et al. 2009 ; Sangaletti et al. 2012 ). No clear association between GPA susceptibility and the FcγRIIa allotype has been demonstrated although some evidence suggests a relationship to the likelihood of relapsing disease (Edberg et al. 1997 ; Tse et al. 1999 , 2000 ). FcγRIIIb, the numerically predominant FcγR on neutrophils, is the major receptor interacting with anti-PR3 IgG ANCA (Kocher et al. 1998 ), and FCGR3B CNV has been associated with GPA (Fanciulli et al. 2007 ). The FcγRIIIb-NA1 allele, known to induce stronger neutrophil activation than the NA2 allele (Salmon et al. 1990 ), has similar allele frequencies in GPA and healthy populations, suggesting no role in overall disease risk. However, the presence of the NA1 allele is associated with the development of severe renal damage in GPA patients (Neira et al. 1996 ; Kelley et al. 2011 ). The recent identification of IgA ANCA in GPA, in addition to IgG ANCA, led to the investigation of the involvement of FcαRI in GPA pathogenesis. Indeed, the FcαRI-248G variant, which induces an augmented inflammatory response to IgA, was associated with overall susceptibility to GPA, as well as predisposition to severe renal disease (Kelley et al. 2011 ). Kawasaki disease affects medium-sized blood vessels most commonly in children under 5 years of age. Genome wide association studies have identified an association between Kawasaki disease and the FCGR2A locus with the 131H variant conferring elevated disease risk (Shrestha et al. 2012 ; Onouchi et al. 2012 ). It is reasonable to speculate the FcγRIIa-131H bearing leukocytes are more pro-inflammatory in the setting of Kawasaki disease, although direct experimental evidence waits to be established. One might also anticipate an association between IgG receptor variants and intravenous immunoglobulin (IVIG), the only proven therapy for Kawasaki disease. Indeed, in Japanese patients, those with the FcγRIIa-131H allele responded more efficiently to IVIG administration. Patients with the 131R allele were more likely to develop coronary lesions even after treatment (Taniuchi et al. 2005 ). Consistent with the notion that tilting the immune system towards inflammation might be associated with disease expression, the FCGR2C -ORF SNP was recently reported to be enriched in Kawasaki disease patients (Breunis et al. 2013 ). Takayasu’s arteritis is a rare form of large vessel vasculitis. A recent GWAS in Turkish and North American Takayasu’s arteritis patients identified a noncoding SNP in the FCGR2A/FCGR3A locus (rs10919543) as a susceptibility marker, which appeared to have a regulatory effect on FCGR2A transcript expression (Saruhan-Direskeneli et al. 2013 ). Several other forms of chronic inflammatory diseases have been reported to have associations with the FCGR cluster. The FCGR2A/2C region has been related to susceptibility to ulcerative colitis, one sub-phenotype of inflammatory bowel disease, in two GWA studies (McGovern et al. 2010 ; Asano et al. 2013 ). In addition to the well-known FcγR-R131H variant, the rs10800309 variant in this locus awaits further work to determine potential functional relevance. Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by autoantibodies and immune complexes. Although the etiology of SLE is unknown, many genes play a role in the susceptibility to and severity of the disease, and GWAS and candidate genes studies have identified the FCGRs as important contributors to the SLE diathesis (Harley et al. 2009 ). A GWAS study of Europeans confirmed the association of FCGR2A (rs1801274; 519G > A encoding R131H) with SLE (International Consortium for Systemic Lupus Erythematosus 2008 ). This nonsynonymous SNP is a risk factor for lupus nephritis and systemic lupus erythematosus in African Americans (Salmon et al. 1996 ; Edberg et al. 2002 ), Caucasians (Manger et al. 2002 ; Karassa et al. 2002 ; Magnusson et al. 2004 ; Kyogoku et al. 2004 ) and Asians (Siriboonrit et al. 2003 ; Lee et al. 2002 ; Chu et al. 2004 ), as well as for myasthenia gravis in Caucasians (Weersma et al. 2010 ; van der Pol et al. 2003 ). Homozygosity for the transmembrane 187T variant of FcγRIIb is also associated with SLE susceptibility in Japanese (Kyogoku et al. 2002 ), Chinese (Chu et al. 2004 ) and Thais (Siriboonrit et al. 2003 ). Interestingly, the 187T allele has a lower frequency in European Americans and is not associated with SLE in either this ancestry group or in African Americans where the frequency of 187T is similar to that of Asians (Li et al. 2003 ; Magnusson et al. 2004 ). Whether this difference represents, less statistical power for detection of association in these groups or an epistatic effect is not certain. The FcγRIIb-187T allele may be a risk factor for anti-GBM disease in Chinese (Zhou et al. 2010 ) while a promoter haplotype, 2B.4 (−386C −120A), which alters FCGR2B gene expression is associated with SLE (Su et al. 2004 ). In a second patient population, homozygosity of the −386C allele alone (also referred to as −343C) affirmed an association of promoter variants with SLE (Blank et al. 2005 ). CNV in this receptor cluster, including the FCGR2C -ORF allele, may be associated with SLE in patients of European and African ancestry (Li et al. 2013 ). The low IgG binding FcγRIIIa-158F is associated with SLE and with lupus nephritis (Wu et al. 1997 ; Karassa et al. 2002 ; Jonsen et al. 2007 ; Dong et al. 2013 ) in multiple ancestry groups including Europeans, African Americans (Edberg et al. 2002 ; Koene et al. 1998 ), Chinese (Chu et al. 2004 ), and Japanese (Kyogoku et al. 2002 ). Interestingly, homozygosity for the high IgG binding –158 V allele is a significant predictor of end-stage renal disease in a multiethnic group of SLE patients (Alarcon et al. 2006 ). Both FcγRIIIb CNV and NA1/NA2 alleles may be associated with SLE in UK Caucasians (Willcocks et al. 2008 ), Thais (Siriboonrit et al. 2003 ), Japanese (Hatta et al. 1999 ), and Spanish (Gonzalez-Escribano et al. 2002 ). The −169C > T SNP (rs7528684) in FCRL3 , which alters an NFκB binding site and is associated with FCRL3 mRNA and surface protein expression, is associated with autoimmunity in some ethnic groups. Associated with SLE, RA, and AITD in Japanese (Kochi et al. 2005 ; Gibson et al. 2009 ), this variant is not associated with these conditions in other ethnicities suggesting that it is not a general autoimmunity risk factor (Chistiakov and Chistiakov 2007 ). The −169C > T SNP is not associated with SLE in Chinese (You et al. 2008 ), Koreans (Choi et al. 2006 ), or Mexican patients with childhood-onset SLE (Ramirez-Bello et al. 2013 ), but the association with the presence of autoantibodies in Polish SLE patients suggests a possible role in production of autoantibodies (Piotrowski et al. 2013 ). Results of meta-analyses differ on whether the −169C > T is associated with SLE in different ethnicities (Breunis et al. 2013 ; Mao et al. 2010 ; Song et al. 2013 ), and the mechanism(s) through which this variant may contribute to SLE remains unclear. Evidence for the contributions of the classical low-affinity Fcγ receptors to Rheumatoid Arthritis suggests that several polymorphisms may be associated with RA manifestations in different ethnic groups, although associations are not always consistent. While GWAS indicated that FCGR2A is associated with RA (Raychaudhuri et al. 2009 ), candidate gene studies suggest the FCGR3A is associated with RA (Morgan et al. 2000 ; Morgan et al. 2003 ) and a role for FCGR2C is unclear. The −169C > T promoter SNP in FCRL3 is associated with RA in Caucasians and Chinese (Thabet et al. 2007 ; Eike et al. 2008 ; Maehlen et al. 2011 ; Wu et al. 2010 ), with JIA in Mexicans (Ramirez-Bello et al. 2013 ), and with JIA in Norwegian patients (Eike et al. 2008 ). This SNP has been correlated with increased FCRL3 surface expression on Tregs of patients with erosive RA (Bajpai et al. 2012 ), and the −169CC genotype may be correlated with radiographic severity in Korean RA patients (Han et al. 2012 ). A more detailed review of Fc receptor associations and reheumatoid arthritis is discussed in Chapter XX. The rs2777963T > C, rs14335A > G and rs10489674C > T polymorphisms in FCRL4 have been associated with susceptibility and severity of ankylosing spondylitis (AS) in Han Chinese (Zeng et al. 2012 ). Similarly, in FCRL5 two nonsynonymous SNPs, rs12036228C > T and rs6427384T > C in exon 5 and exon 7, respectively, and their C-T haplotype were found to be associated with ankylosing spondylitis in HLA-B27 positive Han Chinese, suggesting a role in AS (Tang et al. 2009 ). However, the role, if any, of these SNPs in FCRL4 and 5 expression or function is unclear. Several studies have found association between autoimmune endocrinopathies and SNPs in FCRL family members, although potential underlying mechanisms remain elusive. In a recent study of Type 1 Diabetes (T1D) the C-allele of FCRL1 rs4971154 was strongly associated with the presence of the IA-2A autoantibody in serum suggesting a role in production of autoantibodies (Mao et al. 2010 ). Although the FCRL3 −169C > T SNP was not associated with T1D in several studies of Caucasians (Eike et al. 2008 ; Owen et al. 2007 ; Duchatelet et al. 2008 ), a recent study of 8,506 T1D patients in the United Kingdom found a strong negative association between the C allele and anti-IA-2A autoantibody- positive T1D (Mao et al. 2010 ). The mechanism of association remains unclear. In autoimmune thyroid disease, Owen et al. found modest association of the 3’UTR C > A SNP rs2282288 with Grave’s Disease in Europeans (Owen et al. 2007 ). The −169TT promoter genotype of rs7528684 was associated with remission in Japanese AITD patients (Inoue et al. 2012 ), and with protection against Grave’s Disease in Chinese (Gu et al. 2010 ). A potential role for FCRL3 in production of autoantibodies is supported by the observations that the rs11264798C > G and rs7528684C > T SNPs are associated with thyroid peroxidase autoantibody (TPOA) positivity in GD and anti- IA-2A positivity in T1D (Plagnol et al. 2011 ), while the rs7522061T > C SNP is associated with anti-876 ZnT8A positivity (autoantibody to the zinc transporter 8 in islet cells) in T1D patients (Howson et al. 2012 ). The FCRL3 −169C > T SNP (rs7528684) has been associated with multiple sclerosis in a Spanish cohort (Martinez et al. 2007 ; Matesanz et al. 2008 ). While the T allele of the nonsynonymous coding SNP (rs7522061), which results in the N28D change, was found to be protective in Spanish, the G allele was a risk factor for MS in patients in the United Kingdom (Matesanz et al. 2008 ). Despite its association with many autoimmune disorders in different ethnicities, the −169C > T SNP appears not to be associated with risk for ulcerative colitis, Crohn’s disease or primary sclerosing cholangitis (Eike et al. 2008 ), or with Inflammatory Bowel Disease (Martinez et al. 2007 ). Allergic diseases are a type of hypersensitivity characterized by mast cell activation and IgE-mediated inflammation. The high-affinity IgE receptor expressed on mast cells, FcεRI, has long been considered a candidate gene in allergic diseases. Multiple studies have established a consistent genetic association between allergies and the promoter variants of FcεRI α-chain. The −66T > C and/or the −315C > T SNPs are associated with atopic dermatitis, chronic urticaria, asthma, and high serum IgE levels (Hasegawa et al. 2003 ; Potaczek et al. 2006 ; Kim et al. 2006 ; Bae et al. 2007 ; Zhou et al. 2012 ; Niwa et al. 2010 ). The −66T > C SNP was highlighted as the strongest hit in two GWA studies with high IgE levels (Weidinger et al. 2008 ; Granada et al. 2012 ). These genetic findings may be explained by functional studies that have demonstrated that both SNPs amplify transcription activity, increasing FcεRI expression on mast cells and basophils (Hasegawa et al. 2003 ; Kanada et al. 2008 ), and the well-established observation that surface FcεRI expression correlates positively with circulating IgE levels (MacGlashan 2005 ). Similarly, several SNPs in the FcεRI β-chain are associated with allergic inflammatory diseases such as atopy, asthma, and nasal allergy (Nishiyama et al. 2004 ; Zhang et al. 2004 ; Laprise et al. 2000 ; Nagata et al. 2001 ; Li and Hopkin 1997 ; Hizawa et al. 2000 ; Kim et al. 2006 , 2007 ; Yang et al. 2014 ). Functional properties of these SNPs are not known. The low-affinity IgE receptor on B cells, FcεRII (CD23), is important in regulating IgE production and B cell differentiation. The R62W alteration in the FCER2 gene, that yields increased IgE binding and augmented ERK signaling (Chan et al. 2014 ), is associated with elevated serum IgE levels and an increased risk of severe asthma exacerbation in children (Laitinen et al. 2000 ; Koster et al. 2011 ; Tantisira et al. 2007 ). A promoter SNP in the FCER2 gene, rs3760687, associated with increased total serum IgE (Sharma et al. 2014 ), may alter the activity of the transcription factors Sp1 and Sp3, leading to modulation of FcεRII expression (Potaczek et al. 2009 ). Even though IgE and IgE receptors have been known to be the major players in allergic inflammation, allergen-specific IgG and FcγRs also play a role (Kaneko et al. 1995 ; Jonsson et al. 2012 ; Williams et al. 2012 ; Lau et al. 2005 ; Bruhns et al. 2005 ). In a candidate gene study, both the FcγRIIa-R131H and the FcγRIIb-I187T SNPs have been associated with atopy (Wu et al 2014 ). In this context, it is conceivable that FcγRIIa-H131 allele may clear allergen-IgG2 immune complexes more efficiently, preventing inflammation and tissue damage. Whether allergen-specific IgG2 levels vary in accordance with FcγRIIa polymorphisms is unknown. Furthermore, the FcγRIIb-187T allele may not be as effective in negatively regulating BCR function, resulting in increased B cell IgE production. Crosstalk between FcγRIIb and FcεRI on mast cells is also a possibility.

The efficacy of therapeutic monoclonal antibodies used in autoimmune diseases to induce ADCC and deplete autoreactive B lymphocytes from circulation depends, at least in part, on the strength of the interaction of activating FcγRs with the therapeutic antibody on the opsonized target cells. The FcγRIIIa -158F/V polymorphism influences the efficacy of rituximab treatment, which targets the CD20 surface protein on B cells, with patients homozygous for the high binding -158 V allele showing the best response (Robledo et al. 2012 ; Cooper et al. 2012 ). The precedent that alleles which alter binding and function of FcγRIIa and FcγRIIIa may affect the efficacy of antibody therapy is an important principle in antibody-based therapeutics. A more extensive discussion of the role of Fc receptors in the use of therapeutic antibodies is presented in Chapter XX, “FcR and therapeutic antibodies”.

Genetic variations in human Fc receptors, through their impact on antibody-mediated mechanisms, contribute to individual and population-based host defense and susceptibility to a range of human diseases. Fc receptor polymorphisms modulate the effectiveness of immune system in defense against invading pathogens by regulating immune cell activities. They also impact the handling of immune reactants and the threshold of immune tolerance. Complex clinical phenotypes, such as autoimmunity or allergy, involve multiple genetic and environmental factors, and the subtle regulatory effects of various naturally occurring polymorphisms are compounded in their impact over time. Accurate assessment of the contributions of Fc receptor polymorphisms to immune system function and clinical phenotype requires a careful understanding of the genomic structure, sequence homology, and known physiological responses of Fc receptors in addition to well phenotyped study populations for adequately powered association studies. Such studies have provided important insights into pathogenetic mechanisms and potential novel therapeutic approaches.

Highly homologous in their extracellular sequences, members of the Fc receptor family have both structural differences as well as allelic variations which impact biological properties and their respective roles in pathophysiology. Investigation over the last two decades has demonstrated regulatory and/or coding single nucleotide polymorphisms (SNP) that change receptor biology through one of three mechanisms: quantitative receptor expression, ligand affinity, or signaling capacity. Emerging data have also demonstrated copy number variation (CNV) in the classical low affinity Fc receptors for IgG. Many of the SNPs and CNVs are associated with pathogenesis, severity, and/or treatment outcome in a range of immune-mediated diseases. Signaling and biology of Fc receptors are discussed in Chapter X and Y. In this chapter, we discuss the germ line variations in the genes encoding Fc receptors and how these variations impact receptor function and association with disease.