FcgammaR Polymorphisms Research Articles

C7 Deficiency and Meningococcal Infection Susceptibility in Two Spanish Families

In this work, we report the genetic basis of C7 deficiency in two different Spanish families. In family 1, by using exon-specific polymerase chain reaction and sequencing, a recently described mutation was found in homozygosity in the patient; a single base change in exon 15 (C2107T) leading to a stop codon that causes truncation of the C-terminal portion of C7 (Q681X). Patient's father, mother and sister were heterozygous for this mutation. Interestingly, patient's parents were not related. In family 2, a new single base mutation in exon 2 (G90A), leading to a stop codon that causes the premature truncation of C7 (W8X), was found in the patient, mother and sister 1. Additionally, patient 2, her father and sisters, displayed a missense mutation in exon 9 (G1135C) resulting in a change of aminoacid (G357R). Although sister 1 bore the same mutations in the C7 gene that patient 2, she remains asymptomatic. Because both mutations were found in the patient and her sister, we analyse other defence mechanisms such as FcgammaR polymorphisms as well as mannose-binding lectin alleles (MBL2 gene) and MBL levels. Results showed that both siblings bore identical combinations of FcgammaR allotypes and different MBL2 alleles, exhibiting patient 2 a MBL-insufficient genotype. Normal MBL levels were found in patient 1 and in two previously studied C7-deficient siblings, suggesting the involvement of other mechanisms of immunity distinct of FcgammaR variants and the MBL pathway, for the absence of meningococcal recurrent infections in certain C7-deficient individuals.

Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells

Immunotherapy with the EGFR-specific mAb cetuximab is clinically effective in 10-20% of patients with squamous cell carcinoma of the head and neck (SCCHN). Little information is available about the mechanism(s) underlying patients' differential clinical response to cetuximab-based immunotherapy, although this information may contribute to optimizing the design of cetuximab-based immunotherapy. Our understanding of these mechanisms would benefit from the characterization of the variables which influence the extent of cell dependent-lysis of SCCHN cells incubated with cetuximab in vitro. Therefore, in this study we have investigated the role of FcgammaR IIIa-158 genotype expressed by effector NK cells, cetuximab concentration, and EGFR expression level by SCCHN cells in the extent of their in vitro lysis and in the degree of NK cell activation. PBMC or purified CD56+ NK cells genotyped at IIIa codon 158 and SCCHN cell lines expressing different levels of EGFR have been used as effectors and targets, respectively, in antibody dependent cellular cytotoxicity (ADCC) assays. Furthermore, supernatants from ADCC assays were analyzed for cytokine and chemokine levels using multiplexed ELISA. We found that the extent of lysis of SCCHN cells was influenced by the EGFR expression level, cetuximab concentration, and FcgammaR polymorphism. Effector cells expressing the FcgammaR IIIa-158 VV allele were significantly (P < 0.0001) more effective than those expressing FcgammaR IIIa VF and FF [corrected] alleles in mediating lysis of SCCHN cells expressed higher levels of the activation markers CD69 and CD107a, and secreted significantly (P < 0.05) larger amounts of inflammatory cytokines and chemokines. IL-2 or IL-15 treatment increased cetuximab-mediated ADCC by poor binding FcgammaR IIIa 158 FF expressing NK cells. The importance of the FcgammaR IIIa-158 polymorphism in cytotoxicity of SCCHN cells by NK cells supports a potential role for immune activation and may explain patient variability of cetuximab mediated clinical responses. Cellular and secreted immune profiles and FcgammaR genotypes from patients' lymphocytes may provide clinically useful biomarkers of immune activation in cetuximab treated patients.

Pharmacokinetic study and Fcγ receptor gene analysis in two patients with rheumatoid arthritis controlled by low-dose infliximab

The main aim of this study is to investigate the pharmacokinetics of infliximab and Fcgamma receptor (FcgammaR) polymorphism in two patients with rheumatoid arthritis (RA) who were well controlled by low-dose infliximab. A 57-year-old woman (Patient 1) and a 67-year-old woman (Patient 2) had active RA despite methotrexate and prednisolone treatments. They improved after the addition of infliximab (3 mg/kg), but developed pneumonia and sepsis, respectively. Although the infliximab doses were reduced to 1.5 mg/kg and 1 mg/kg, respectively, clinical improvements were maintained. Blood samples were obtained at 1 h after infliximab administration and at eight weeks (just before the next dose). The elimination half-life was determined by the serum concentration of infliximab. We also analyzed the polymorphisms of FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB for the genomic DNA samples from the two patients and three controls. Amplification of the FcgammaR-genomic regions in allotype-specific polymerase chain reactions was used to distinguish the genotypes. Decresed clearance of infliximab was proven by a pharmacokinetic study of these patients under low-dose infliximab therapy. 131H/H (FcgammaRIIA) and 176F/F (FcgammaRIIIA) were detected in both patients. NA1/NA2 and NA2/NA2 (FcgammaRIIIB) were detected in Patients 1 and 2, respectively. These patients were well controlled over the long term by low-dose infliximab. The mechanism of the reduced clearance of infliximab might possibly be explained in part by the FcgammaR polymorphisms.

Fcγ Receptor Polymorphisms are not Associated with Autoimmune Addison's Disease

Polymorphisms in the low-affinity Fcgamma receptors (FcgammaR) modulate their capacity to bind IgG and the subsequent immune response. Different FcgammaR polymorphisms have been reported to be associated with susceptibility and severity of various autoimmune diseases. We wanted to investigate associations between FcgammaR polymorphisms and autoimmune primary adrenal failure (Addison's disease). We have genotyped 149 patients with Addison's disease and 89 healthy controls for common polymorphisms in the genes coding for FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb using polymerase chain reaction. Patients with Addison's disease and controls showed no differences in genotype distributions of FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb. The results indicate that different FcgammaR polymorphisms do not have an impact on immune responses involved in the development of autoimmune Addison's disease.

Investigation of Fcgamma RIIA and Fcgamma RIIIA Polymorphism in Multiple Sclerosis: A Case Control Study.

Multiple Sclerosis (MS), the most common demylinating disease of the CNS, is immunologically mediated in genetically susceptible individuals. Receptors for the Fc fragment of IgG (FcgammaR) might induce inflammatory responses through linking the humoral and cellular immune responses by targeting immune complexes to effector cells. Polymorphisms in some FcgammaR genes are associated with various infectious and autoimmune diseases, probably due to their effects on different binding capacities of encoded receptors for IgG containing immune complexes. To investigate the importance of FcgammaR polymorphisms in susceptibility to MS. One hundred and fifty MS patients and 136 age and sex matched controls were genotyped for FcgammaRIIA and FcgammaRIIIA gene polymorphisms using PCR-RFLP method. The allelic and genotypic frequencies of the FcgammaRIIA and FcgammaRIIIA did not differ significantly between the MS patients and controls. There was no association between allelic polymorphism of FcgammaRIIIA and severity of disease based on Expanded Disability Status Scale (EDSS) score. However, significant association between inherited FcgammaRIIA genotype and disease activity (p=0.001) or progression index was revealed (p=0.014). EDSS values showed that FcgammaRIIA (H/H) and (H/R) genotypes were associated with a lower EDSS score in relapsing-remitting MS and in the total MS population (p=0.001) but not (R/R) genotype. Considering the detrimental role of autoantibodies in the pathogenesis of MS, our results suggest that the inherited FcgammaRIIA alleles could affect the severity of MS by influencing the clearance rate of immune complexes and autoantibodies. The results of the present study add the FcgammaRIIA gene to the gene networks which determine the severity of MS in southern Iran.

NADPH oxidase (CYBA) and FcγR polymorphisms as risk factors for aggressive periodontitis: A case–control association study

Neutrophils (PMN) in aggressive periodontitis (AgP) patients have been reported to be hyperactive especially with regards to superoxide production. Polymorphisms in genes influencing PMN function have been proposed as candidate risk factors for AgP. The aim of this study was to test the association of specific gene polymorphisms affecting PMN functions with AgP. Two hundred and twenty-four patients with confirmed diagnosis of AgP and 231 subjects with healthy periodontium took part in the study. A blood sample was collected from subjects and genotypes for p22phox (CYBA) NADPH oxidase, FP, Fcalpha and Fcgamma receptors were analysed in a blind fashion. The C242T p22phox NADPH oxidase T allele was significantly associated with AgP in a multiple logistic regression model adjusting for confounders, and this was observed for all subjects [p = 0.002, odds ratio (OR) = 1.87, 95% confidence interval (CI) = 1.27-2.83] and Caucasians (p = 0.009, OR=2.07, 95% CI = 1.20-3.59). Concomitant presence of C242T p22phox NADPH oxidase T allele and FcgammaRIIIb NA1 homozygosity was associated with the generalized AgP phenotype in Caucasians (p = 0.001, OR = 30.35, 95% CI = 3.81-241.97). C242T p22phox NADPH oxidase and FcgammaR polymorphisms may predispose to AgP through a modulation of neutrophil superoxide production.

Fc gamma RIIa, IIIa and IIIb polymorphisms in Turkish children susceptible to recurrent infectious diseases

The efficacy of IgG-induced Fc gamma receptor (FcgammaR) function displays interindividual heterogeneity due to genetic polymorphisms of three FcgammaR subclasses: FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb. FcgammaR polymorphisms may contribute to disease susceptibility or may alter disease course. The aim of this study is to examine FcgammaR gene polymorphisms in Turkish children with recurrent respiratory tract infections and without well known humoral immunodeficiencies. For the patients in the study group (n=52), recurrent infection was defined as the presence of at least six infection episodes a year. Seventy-one healthy children with a maximum of two infections in a year were enrolled as the control group. Subjects in both groups had no abnormalities in serum immunoglobulins, IgG subsets and specific antibody levels. For FcgammaRIIa: H131H, H131R, R131R genotypes and 131R, 131H alleles; for FcgammaRIIIa: F158F, F158V, V158V genotypes and 158F, 158V alleles; and for FcgammaRIIIb: -NA1/NA1, NA1/NA2, NA2/NA2 genotypes and NA1, NA2 alleles were determined by using amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Compared with the control group, the FcgammaRIIa-R131R genotype and 131R allele were found to be significantly elevated in the study group, and FcgammaRIIa-H131H genotype and 131H allele in the study group were significantly lower than in the control group. Genotypes and alleles related with FcgammaRIIIa and FcgammaRIIIb gene polymorphisms did not show any significant difference between the study and control groups. FcgammaRIIa gene polymorphism (R131R) may increase the risk and susceptibility for recurrent infectious diseases in children.

FcγRIIa-131R allele and FcγRIIIa-176V/V genotype are risk factors for progression of IgA nephropathy

Fcgamma receptors (FcgammaRs) may play an important role in positive and negative regulation of immune cell responses and immune complex (IC) clearance. Mesangial IgG deposition and circulating IgG/IgA-IC in sera are observed in patients with IgA nephropathy (IgAN). Therefore, the pathological roles of IgG-IC in IgAN have been discussed. On the other hand, several studies have identified FcgammaR polymorphisms (FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb) that determine susceptibility to autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The objective of the present study was to clarify whether FcgammaR polymorphisms influence susceptibility to IgAN, clinical features or severity in patients with IgAN. Japanese patients with IgAN (n = 124) and healthy controls (n = 100) were genotyped for FcgammaR polymorphisms (FcgammaRIIa-131H or R, FcgammaRIIIa-176F or V and FcgammaRIIIb-NA1 or -NA2). The genotyping of these polymorphisms was performed using allele-specific polymerase chain reaction (PCR) methods. Associations among FcgammaR polymorphisms and susceptibility, age of onset, levels of serum immunoglobulins, intensity of glomerular IgG deposition and pathological severity were analysed. These three FcgammaR polymorphisms showed no significant differences in genotype and allele frequencies between the IgAN patients and healthy controls. Each FcgammaR polymorphism had no influence on age of onset, serum levels of IgG and glomerular IgG deposition in IgAN. However, FcgammaRIIa-131R (R/R or H/R) or FcgammaRIIIa-176V homozygous carriers (V/V) showed significantly more severe injury than FcgammaRIIa-131H homozygous (H/H) (P < 0.03) or FcgammaRIIIa-176F carriers (F/F or F/V) (P < 0.03), respectively. The present study shows that polymorphisms of FcgammaRIIa and FcgammaRIIIa influence the severity of IgAN in Japanese patients but not the incidence, suggesting that IgG-IC may play important roles in the progression and prognosis of this disease via FcgammaRs.

Ethnic variation of Fcγ receptor polymorphism in Sami and Norwegian populations

Receptors for the Fc domain of IgG (Fc gammaR) play a critical role in linking cellular and humoral immunity. The various Fc gammaR genotypes may contribute to differences in infectious and immune-related diseases in various ethnic populations. The Samis are the aboriginal inhabitants of Norway and Fennoscandinavia and differ ethnically from the Norwegians. The distribution of various immune-related diseases has been reported to differ between Sami and Norwegians. This is the first study to evaluate the distribution of Fc gammaR polymorphisms in a Sami population. Two hundred Samis were genotyped for polymorphisms in the Fc gammaRIIA, Fc gammaRIIIA and Fc gammaRIIIB genes. The genotype and allele frequencies were compared with those of 272 healthy Norwegians. The Sami and Norwegian Fc gammaRIIA, Fc gammaRIIIA and Fc gammaRIIIB genotypes differed significantly. The Samis had higher frequencies of the Fc gammaRIIa-H/H131, Fc gammaRIIIa-F/F158 and Fc gammaRIIIb-NA1/NA1 genotypes. The Fc gammaR genotypes were non-randomly distributed in both populations. These findings may be important for the prevalence of autoimmune and infectious diseases in the two populations.

Immunological Status in the Aetiology of Recurrent Otitis Media with Effusion: Serum Immunoglobulin Levels, Functional Mannose-Binding Lectin and Fc Receptor Polymorphisms for IgG

The objective was to study the role of serum immunoglobulin levels, mannose-binding lectin (MBL), and Fc gamma receptor (FcgammaR) polymorphisms on the development of recurrent otitis media with effusion (OME). Children aged between two and seven years with persisting OME received bilateral tympanostomy tubes and immunological parameters were investigated in relation with OME recurrence within six months after tube extrusion. No statistically significant differences in serum immunoglobulin levels were present between children with and without OME recurrence. In children with bilateral recurrence (n = 56), median levels of MBL were 1.39 mg/L compared to 2.48 mg/L in children with OME recurrence (n = 17) (p = 0.29). In addition, 34% of the children with bilateral recurrence were homozygous for the genotype FcgammaRIIa-R/R131, whereas less than 20% of the children with unilateral recurrence or those without recurrence were homozygous for this Fcgamma receptor (p = 0.26). Serum mannose-binding lectin and FcgammaRIIa-R/R131 polymorphism may play a role in the aetio-pathogenesis of recurrent OME.

FcγR polymorphisms: Implications for function, disease susceptibility and immunotherapy

Leukocyte Fcgamma receptors (FcgammaR) confer potent cellular effector functions to the specificity of IgG. FcgammaR-induced leukocyte functions, including antibody-dependent cellular cytotoxicity, phagocytosis, superoxide generation, degranulation, cytokine production and regulation of antibody production, are essential for host defense and immune regulation. The efficacy of IgG-induced FcgammaR function displays inter-individual heterogeneity due to genetic polymorphisms of three FcgammaR subclasses, FcgammaRIIa (CD32a), FcgammaRIIIa (CD16a), and FcgammaRIIIb (CD16b). FcgammaR polymorphisms have been associated with infectious and autoimmune disease, or with disease severity. FcgammaR polymorphisms may furthermore serve as markers for therapeutic efficacy and side-effects of treatment with monoclonal antibodies. In this review, FcgammaR function and the relevance of FcgammaR polymorphisms as prognostic markers for inflammatory disease and antibody-based immunotherapy are discussed.

Fcgamma receptor IIIA polymorphism as a risk factor for acute poliomyelitis.

Poliomyelitis is a viral infection that causes flaccid paralysis in approximately 1% of cases. The Fc receptors for immunoglobulin G (FcgammaR) are associated with modifying effects of several infectious and autoimmune diseases. To assess the influence of FcgammaR polymorphisms on the acute and late course of poliomyelitis, 110 Norwegian patients with well-defined histories of acute poliomyelitis were genotyped, of whom 50 suffered from the postpolio syndrome (PPS). In comparison with healthy control subjects without a history of poliomyelitis, significantly fewer patients had the FcgammaRIIIA genotype V/V (P<.01). However, this genotype was not an independent risk factor for PPS. The FcgammaRIIA and IIIB genotypes and allele frequencies did not differ between the patients and control subjects. The FcgammaRIIIA V/V genotype may lower the risk for contracting acute poliomyelitis through better clearance of poliovirus.

Relevance of Fcgamma receptor and interleukin-10 polymorphisms for meningococcal disease.

The contribution of individual Fcgamma receptor (FcgammaR) subclasses to meningococcal phagocytosis was studied. In addition, functional FcgammaR polymorphisms were determined in 50 patients with meningococcal disease (MD), in 183 first-degree relatives of MD patients, and in 239 healthy control subjects, to study the association of FcgammaR genotypes with disease. Efficient internalization of opsonized Neisseria meningitidis serogroup B was mediated via multiple FcgammaR subclasses on phagocytes. Accordingly, a low-efficiency combination of FcgammaRIIa-R/R131, FcgammaRIIIa-F/F158, and FcgammaRIIIb-NA2/2 genotypes was increased significantly in relatives of patients with MD, compared with healthy control subjects (P<.05; odds ratio, 2.6; 95% confidence interval, 1.1-6.3). FcgammaRIIa and FcgammaRIIIa genotype distributions differed between patients with sepsis and those with meningitis. Combined genotypes of FcgammaRIIa and interleukin-10 -1082, which was previously reported as being associated with MD outcome, were distributed randomly in control subjects but not in relatives of patients with MD (P<.01). These data provide further evidence for the association of polymorphic genes on chromosome 1 and MD.

The Fcgamma receptor IIIA-158F allele is a major risk factor for the development of lupus nephritis among Caucasians but not non-Caucasians.

To determine whether inheritance of Fcgamma receptor (FcgammaR) alleles conferring lower affinity for IgG binding increases the risk of developing lupus nephritis. We compared the frequency of low-affinity alleles of two FcgammaR polymorphisms (FcgammaRIIA and FcgammaRIIIA) among 235 patients with systemic lupus erythematosus (SLE) and proven nephritis (nephritis patients) and among 352 SLE patients with no evidence of renal disease (non-nephritis control subjects). The ethnic distribution of patients in the study was 49% Caucasian, 20% Hispanic, 17% Asian/Pacific Islander, 12% African American, and 2% from other ethnic groups. All patients were genotyped for the FcgammaRIIA-131R/H and FcgammaRIIIA-158V/F polymorphisms. We used contingency table analysis to compare allele and genotype distributions for nephritis patients and nonnephritis control subjects, including ethnic-specific strata. Multivariate logistic regression analyses included sex and disease duration as covariates. Univariate and multivariate analyses demonstrated a striking association between the low-affinity FcgammaRIIIA-158F allele and FF genotype and the risk of nephritis among Caucasians, but not among non-Caucasians (multivariate odds ratio [OR] 2.6 for Caucasians with FF genotype), (P = 0.0017). This association was even stronger among Caucasians with severe nephritis (OR 4.4, P < 0.0001). In contrast, inheritance of the low-affinity FcgammaRIIA-131R allele (and RR genotype) was not associated with an increased risk of lupus nephritis among any of the ethnic groups examined. The FcgammaRIIIA-158F allele is a major risk factor for the development of lupus nephritis among Caucasians, but not among non-Caucasians. These results suggest that ethnic variation is critical in defining the specific genetic factors underlying the pathogenesis of SLE, and they have important prognostic and therapeutic implications as well.

Fcgamma receptor polymorphisms in systemic lupus erythematosus: association with disease and in vivo clearance of immune complexes.

Fc receptors for IgG (FcgammaR) play a prominent role in the clearance of immune complexes in systemic lupus erythematosus (SLE). Polymorphisms of FcgammaR have been proposed as genetic factors that influence susceptibility to SLE. We analyzed 3 functional FcgammaR polymorphisms in a strictly Caucasian population of SLE patients, and determined the influence of these polymorphisms on the clearance of immune complexes in vivo. Genomic DNA was isolated from 230 Caucasian patients with SLE and 154 controls. Amplification of FcgammaR-genomic regions in allotype-specific polymerase chain reactions was used to distinguish the genotypes. In addition, we analyzed the FcgammaR genotypes of 13 patients with SLE who participated in a study determining the half-life of IgG-coated erythrocytes in the blood. We found a strong trend toward skewing of FcgammaRIIa, with an enrichment of the homozygous FcgammaRIIa-R/R131 genotype in patients compared with controls. We did not find a correlation between this genotype and the development of lupus nephritis. However, we established that the half-life of IgG-coated erythrocytes in the blood was prolonged in patients expressing the FcgammaRIIa-R/R131 genotype. The homozygous FcgammaRIIIa-F/F158 genotype was found more frequently in patients with arthritis and/or serositis. In Caucasian populations, the R/H polymorphism of FcgammaRIIa is a minor determinant in susceptibility to SLE, whereas the V/F polymorphism of FcgammaRIIIa is associated with a set of disease manifestations. Notably, the R/H polymorphism of FcgammaRIIa affects the clearance of immune complexes in vivo, which may influence the course of a disease such as SLE.

The Fcgamma receptor genotype as a risk factor for generalized early-onset periodontitis in Japanese patients.

Genetic polymorphisms of immunoglobulin G (IgG) Fc receptors (FcgammaR) were recently shown to be associated with recurrence rates of adult periodontitis (AP). The purpose of this study was to evaluate whether FcgammaR polymorphisms are also associated with generalized early-onset periodontitis (G-EOP) in Japanese patients. Thirty-eight Japanese patients with G-EOP and 83 Japanese patients with AP were identified according to established clinical criteria, including measurements of probing depth, clinical attachment level, and alveolar bone level. FcgammaR genotypes for 3 bi-allelic polymorphisms were determined in these G-EOP and AP patients and 104 race-matched healthy controls by means of allele-specific polymerase chain reactions. There was a significant difference in the distribution of FcgammaRIIIb genotypes between G-EOP patients and healthy controls (P = 0.02). Additionally, a significant over-representation of FcgammaRIIIb-NA2 allele was observed in G-EOP patients as compared to AP patients and controls (P= 0.02, P= 0.009, respectively). Moreover, we found a strong association between G-EOP and the composite genotype comprising FcgammaRIIIb-NA2 and FcgammaRIIIa-158F (G-EOP versus controls: odds ratio 2.4, 95% CI 1.0-6.0, chi2 = 4.13, P= 0.04). This study indicates that the FcgammaRIIIb-NA2 allele and possibly FcgammaRIIIa-158F could be associated with susceptibility to G-EOP in Japanese patients.

Fcgamma receptor polymorphisms in Wegener's granulomatosis: risk factors for disease relapse.

Several studies have recently identified polymorphisms of receptors for the Fc fragment of IgG (FcgammaR) as genetic factors influencing susceptibility to multiple autoimmune and infectious diseases. This genetic predisposition could also influence the expression of Wegener's granulomatosis (WG), a systemic autoimmune disease with chronic nasal carriage of Staphylococcus aureus as an important risk factor for disease relapses. Therefore, we analyzed 3 functional FcgammaR polymorphisms from 91 patients with WG and 154 controls for a possible relationship with disease expression and occurrence of relapses. FcgammaR phenotypes were determined using amplification of FcgammaR-genomic regions in allotype-specific polymerase chain reactions. Of particular interest in the analysis were 2 allotypic forms of FcgammaRIIa (R131 or H131) and 2 allotypic forms of FcgammaRIIIa (V158 or F158), all of which are functionally different. Analysis of FcgammaR phenotypes demonstrated that patients with WG were more prone to disease relapse in the first 5 years after diagnosis if they were homozygous for both the R131 form of FcgammaRIIa and the F158 form of FcgammaRIIIa (relative risk 3.3, 95% confidence interval 1.6-6.8). These polymorphisms are both associated with decreased FcR-mediated clearance, which may be relevant to the chronic nasal carriage of S aureus. Both the R/H131 polymorphism of FcgammaRIIa and the V/F158 polymorphism of FcgammaRIIIa represent heritable risk factors for the development of disease relapses in WG.

IgG receptor polymorphisms: risk factors for disease.

Two groups of receptors for immunoglobulin G (FcgammaR) can be distinguished. Endothelial cells and placental syncytiotrophoblasts express an MHC class I-like FcgammaR important for regulation of IgG half-life and IgG transport, respectively. FcgammaR expressed on leukocytes constitute a heterogeneous family of membrane bound and soluble proteins. The various FcgammaR (sub) classes of this family differ in ligand affinity and specificity, which is determined by primary structure, glycosylation, association with signaling subunits, and environmental factors (such as serine proteases). The finding that polymorphisms of FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb critically affect interaction with antibodies has prompted analysis in patients which provided tantalizing evidence for the relevance of FcgammaR polymorphisms as risk factors for a number of infectious and autoimmune diseases.

Relevance of immunoglobulin G Fc receptor polymorphism to recurrence of adult periodontitis in Japanese patients.

Polymorphonuclear neutrophil (PMN) phagocytic function has been shown to be impaired in some patients with periodontitis. PMN constitutively express members of two immunoglobulin G receptor (Fc gammaR) classes: Fc gammaRIIa (CD32) and Fc gammaRIIIb (CD16). Both receptors exhibit genetically determined structural and functional biallelic polymorphisms, which have been shown to influence PMN phagocytic function. In this study, we assessed the relevance of these Fc gammaR polymorphisms to susceptibility to adult periodontitis and recurrence rate. The distribution of Fc gammaRIIa and Fc gammaRIIIb genotypes of 100 Japanese patients with adult periodontitis during follow-up was compared to the distribution of genotypes in 105 race-matched healthy controls. No significant skewing of distributions of Fc gammaRIIa and Fc gammaRIIIb genotypes was observed between patients and controls. Notably, however, a significant overrepresentation of the Fc gammaRIIIb-NA2 allotype was found in patients with disease recurrence (P < 0.05; odds ratio, 4.29; 95% confidence interval, 1.19 to 16.24). Moreover, the annual rate of recurrence was significantly higher in patients with the Fc gammaRIIIb-NA2/NA2 and Fc gammaRIIIb-NA1/NA2 genotypes than in Fc gammaRIIIb-NA1/NA1 individuals (P < 0.05). Fc gammaRIIa-R/R131 individuals also exhibited higher recurrence rates, though the difference was not statistically significant (P = 0.06). These results suggest that the Fc gammaRIIIb-NA2 allotype represents a risk factor for recurrence of adult periodontitis.