FcgammaRIIA Genotypes Research Articles

Natural killer: dendritic cell activation using anti-CD137 mAb improves cetuximab mediated innate and adaptive immune responses in head and neck cancer (TUM7P.948)

Abstract EGFR-specific mAb cetuximab mediated activation of NK by FcγRIIIa cross-linking is important for anti-tumor immunity.Following cetuximab activation,NK express costimulatory receptor CD137, which can be ligated to improve activity of cetuximab-activated NK,which promote DC maturation and CD8+ T-cell priming, leading to tumor antigen spreading and Th1 cytokine release through NK-DC cross-talk. We show that the clinically available CD137 agonist mAb augments cetuximab-mediated ADCC in FcγRIIIa-V/F donors,but not in poor binding FcγRIIIa-F/F.We show that cetuximab-activated NK induce CD137 expression on DC, which can be further stimulated by CD137 mAb, leading to enhanced DC maturation and cross-presentation capacity.In a prospective phase II trial of neoadjuvant cetuximab in stage III/IV HNC patients, intratumoral activated NK cells also upregulated CD137, which was influenced by FcγRIIIa-V/F polymorphism. Moreover, cetuximab treatment induces CD137 expression on intratumoral activated CTL.We show that FcγRIIIaV/F polymorphism on NK cells greatly influences their induction of CD137 expression, as does the EGFR receptor density on HNC.Thus, careful selection of HNC patients in combination immunotherapy using cetuximab plus CD137 mAb may be necessary, using EGFR level of expression and FcgammaRIIIa genotype, to optimize NK:DC priming of tumor antigen specific CTL.Results suggest a beneficial effect of combination of cetuximab and CD137 mAb in currently designed clinical trials.

Immunoglobulin IgG Fc-receptor polymorphisms and HLA class II molecules in Guillain-Barré syndrome

To analyze host genetic factors immunoglobulin G Fc receptors (FcgammaRs) and human leukocyte antigen (HLA) class II in GBS patients. FcgammaRIIA, IIIA and IIIB polymorphisms were studied in 80 each GBS patients and healthy controls by allele specific PCR. HLA class II DRbeta1 and DQbeta1 typing was performed at the two-digit level by PCR in randomly selected 54 GBS patients and 202 controls. FcgammaRIIA-H/H (56% vs 9%; P < 0.0001) and FcgammaRIIIA-V/V (40% vs 13%; P < 0.0001) genotypes, H131 allele frequencies (0.73 vs 0.26, P < 0.0001) and HLA DQbeta1*060x (OR, 1.96; 95% CI, 1.26-3.04; P < 0.01) were significantly increased in GBS than controls. DRbeta1*0701 alone (OR, 10; 95% CI, 45.90-2.25; P < 0.001) and together with FcgammaRIIA-H/H (OR, 11.03; 95% CI, 2.63-46.20; P < 0.001) was significantly associated with GBS patients having microbiological evidence of recent infection. The study indicates that homozygous FcgammaRIIA and FcgammaRIIIA genotypes and FcgammaRIIA H131 allele are associated with GBS. HLA class II molecule DRbeta1*0701 is identified as novel genetic risk factor for development of GBS in patients with preceding infection.

Association of the leukocyte immunoglobulin G (Fcγ) receptor IIIa‐158V/F polymorphism with inflammatory myopathies in Dutch patients

Leukocytes are involved in the pathogenesis of idiopathic inflammatory myopathies (IIMs). Immunoglobulin G (IgG) receptors (FcgammaR) link the specificity of IgG to the effector functions of leukocytes. Several FcgammaR subclasses display functional polymorphisms that determine in part the vigour of the inflammatory response. FcgammaRIIIa genotypes were differentially distributed among 100 IIM patients compared with 514 healthy controls with a significant increase of the homozygous FcgammaRIIIa-V-158 genotype (3 x 2 contingency table, chi(2) = 6.3, P = 0.04). Odds ratios (ORs) increased at the addition of each FcgammaRIIIa-V-158 allele, in particular among patients with non-specific myositis and dermatomyositis {OR 2.1 [95% confidence interval (CI) 1.1-4.3] and 2.7 (95% CI 1.1-6.4) for FcgammaRIIIa-V/F158 and FcgammaRIIIa-V/V158 genotypes, respectively, using FcgammaRIIIa-F/F158 as a reference group}. These data suggest that the FcgammaRIIIa-V-158 allele may constitute a genetic risk marker for IIM.

Early atherosclerosis and IgG2 to bacteria are associated with FcγRIIa genotype in non‐smokers

Involvement of low density lipoprotein (LDL) immune complexes (ICs) in atherogenesis has been proposed. Human FcgammaRIIa receptor (CD32) plays a crucial role in the phagocytosis of IgG(2) ICs and a functional point mutation 131His/Arg diminishes IgG(2) binding to the receptor. We examined FcgammaRIIa-131His/Arg polymorphism, IgG(2) antibody titres to oxidized low-density lipoprotein (OxLDL) and Streptococcus pneumoniae cell wall polysaccharide (CWPS) and subclinical atherosclerosis in a large cohort of Finnish subjects (n = 1041). Non-smoking subjects with homozygous 131His/His genotype had more premature atherosclerosis (P = 0.004) and higher IgG(2) to bacterial CWPS (P = 0.002) compared with other genotypes. Smoking subjects had significantly higher intima-media thickness (IMT) than that of non-smokers (P < 0.001) and genotype-dependent associations were indistinct. There was no association between FcgammaRIIa genotype and antibody titres to OxLDL. Our data demonstrate that FcgammaRIIa 131His/Arg polymorphism is associated with subclinical atherosclerosis in non-smoking subjects. Furthermore, FcgammaRIIa genotype is associated with IgG(2) titres to bacterial CWPS, but not to OxLDL. These data propose possible involvement of FcgammaRIIa receptor in atherogenesis.

Hyper‐reactive PMNs in FcγRIIa 131 H/H genotype periodontitis patients

Receptors for the Fc part of IgG (FcgammaRIIa) on polymorphonuclear leukocytes (PMN) mediate phagocytosis and cell activation. Previous results show that one of the genetic variants of the FcgammaRIIa, the 131 H/H, is associated with more periodontal breakdown than the R/R. This may be due to hyper-reactivity of the H/H-PMNs upon interaction with bacteria. To study whether the FcgammaRIIa genotype modifies the PMN reactivity in periodontitis patients. A cohort of 98 periodontitis patients was genotyped. From these, 10 H/H and 10 R/R consented to participate. PMNs were incubated with immune serum-opsonized Actinobacillus actinomycetemcomitans (A.a.). Phagocytosis, degranulation (CD63 and CD66b expression), respiratory burst and elastase release were assessed. Patients of the H/H genotype showed more bone loss than those with the H/R or R/R genotype (p=0.038). H/H-PMNs phagocytosed more opsonized A.a. than did R/R-PMNs (p=0.019). The H/H-PMNs also expressed more CD63 and CD66b than did the R/R-PMNs (p=0.004 and 0.002, respectively) and released more elastase (p=0.001). The genotyping results confirm previous reports that more periodontal destruction occurs in the H/H genotype than in the H/R or R/R genotype. The functional studies indicate a hyper-reactivity of the H/H-PMN in response to bacteria, which may be one of several pathways leading to more periodontal breakdown.

The FcγRIIa polymorphism influences production of interleukin‐1 by mononuclear cells

The functional bi-allelic polymorphism of immunoglobulin G (IgG) Fc receptor (FcgammaR) IIa influences the efficiency of human IgG2 binding. Our previous study showed that the high affinity FcgammaRIIa genotype (-H/H131) was associated with periodontitis risk. As interleukin-1 (IL-1) is one of the major causes of periodontal tissue destruction, it is hypothesized that the FcgammaRIIa-H/H131cross-linking could induce an increased IL-1 release by mononuclear cells. In this study, we evaluated the intracellular expressions of IL-1beta in CD14 positive cells upon stimulation with human IgG2 by flow cytometry. FcgammaRIIa-H/H131 subjects exhibited a higher percentage of IL-1beta-producing cells than FcgammaRIIa-R/H131 and -R/R131 subjects (P < 0.05). These results support the concept that FcgammaRIIa genotype may affect IL-1beta production, possibly leading to interindividual differences in periodontitis risk.

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.

FcγRIIa (CD32) Polymorphism and Onchocercal Skin Disease: Implications for the Development of Severe Reactive Onchodermatitis (ROD)

The pathologic manifestations of Onchocerca volvulus infection depend on the interplay between the host and the parasite. A genetic single nucleotide polymorphism in the Fc gamma RIIa gene, resulting in arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses and may influence the clinical variations seen in onchocerciasis. This study investigated the relationship between this polymorphism and disease outcome. Fc gamma RIIa genotyping was performed on clinically characterized onchocerciasis patients (N = 100) and healthy controls (N = 74). Fc gamma RIIa genotype R/R131 frequencies were significantly higher among patients with severe dermatopathology (P < 0.001). Increased risk of developing this form was mostly associated with one tribe (Masalit) (OR = 3.2, 95% CI 1-9.9, P = 0.042). The H131 allele was found to be significantly associated with a reduced risk of having the severe form of the disease (adjusted OR = 0.26, 95% CI = 0.13-0.46, P < 0.001). Our findings suggest that the polymorphism influences the clinical outcome of onchocerciasis.

Association of Fc gamma receptor IIA polymorphisms with acute renal-allograft rejection.

Acute rejection is a leading cause of early renal-allograft failure. The human Fc gamma receptor IIA (FcgammaRIIA) forms an essential link between the humoral branch and the effector cells of the immune system. In this study, we examined FcgammaRIIA genotypes in renal-allograft recipients (rejectors) with acute graft rejection and in a number of control groups to investigate a possible association between FcgammaRIIA polymorphism and acute renal-allograft rejection. The distribution of the genotypes in the study patient group differed from the control groups. The frequency of homozygosity for FcagammaRIIA-R/R131 in the rejectors was significantly higher than that in the recipients (nonrejectors) with well-functioning renal allografts and in blood donors (P< 0.05). In comparison with the control groups, the rejectors displayed a higher R131 allele frequency (P< 0.05) and a lower H131 allele frequency (P< 0.05). These results reveal a significant association between FcgammaRIIA-R/R131 and acute renal-graft rejection, and it is likely that FcgammaRIIA polymorphisms could be useful markers for potential risk of rejection.

Polymorphism of Fc receptor IIa for immunoglobulin G is associated with placental malaria in HIV-1-positive women in western Kenya.

Genetic polymorphism of the Fc receptor IIa for immunoglobulin (Ig) G (Fc gamma RIIa) determines IgG subclass binding. Previous studies have shown that individuals with the IgG1/3-binding Fc gamma RIIa-Arg/Arg131 genotype are relatively protected against high-density malaria, whereas individuals with the IgG2-binding Fc gamma RIIa-His/His131 genotype are at increased risk for developing cerebral malaria. The present study was undertaken to examine the relationship between Fc gamma RIIa polymorphism and placental malaria (PM) in pregnant women of known human immunodeficiency virus (HIV)-1 status. Fc gamma RIIa genotype was determined in 903 pregnant women who had participated in a study designed to assess the effect that PM has on vertical transmission of HIV-1. Fc gamma RIIa polymorphism was assessed in relation to PM. Among HIV-negative women, there was no difference in the distribution of the Fc gamma RIIa polymorphism by PM status. However, among HIV-positive women, the frequency of the Fc gamma RIIa-His/His131 genotype was significantly higher in women with PM than in women without PM (31% vs. 22%, respectively [P=.032]). In multivariate analysis, the adjusted odds ratio for PM in HIV-positive women with the Fc gamma RIIa-His/His131 genotype versus women in the Fc gamma RIIa-His/Arg131 reference group was 1.72 (95% confidence interval, 1.11-2.69 [P=.016]). The present study suggests that the IgG2-binding Fc gamma RIIa-His/His131 genotype is associated with enhanced susceptibility to PM in HIV-positive women but not in HIV-negative women.

Fc receptor II polymorphism in Vietnamese patients with systemic lupus erythematosus

The polymorphism of the Fc receptor for IgG class IIA (Fc gammaRIIA) in Vietnamese patients with systemic lupus erythematosus (SLE) was examined by using the polymerase chain reaction (PCR) method with genomic DNA and allele-specific primers. In the frequency of Fc gammaRIIA genotypes, the homozygosity of Fc gammaRIIA-H131 was four (8.3%) of 48 SLE patients and 16 (37.2%) of 43 healthy controls (P < 0.01). The allele frequency of Fc gammaRIIA-H131 in SLE patients was also significantly lower than that in the controls (P < 0.05). The unusual distribution of Fc gammaRIIA polymorphism suggested that Fc gammaRIIA might be involved in the development of SLE in Vietnamese patients.

Fcgamma receptor polymorphisms in relation to periodontitis.

Evidence suggests functional relevance for polymorphisms in FcgammaR in relation to inflammatory and infectious diseases. The present aim was to investigate genetic polymorphisms in three FcgammaR in relation to susceptibility and severity of periodontitis. The study population consisted of 68 periodontitis patients and 61 controls (Northern European Caucasian background, mean ages 44 and 42 years, respectively). Among the patients, 12 subjects were diagnosed with aggressive periodontitis (AgP) and 56 individuals were diagnosed with chronic periodontitis (CP). Radiographic bone levels were scored for all teeth in the patients. Subjects were typed for the following genes (alleles): FcgammaRIIa (R131 or H131), FcgammaRIIIa (V158 or F158) and FcgammaRIIIb (NA1 or NA2). Hardy-Weinberg equilibrium criteria were fulfilled for the different genotypes at the three genes investigated. The frequency of the FcgammaRIIIa-V158 allele in the patient population (53%) was higher than in the control group (39%) (OR 1.73 [1.06-2.85], p=0.034). The V158 carriage rate in AgP was even higher (63%). The frequency of the FcgammaRIIa-H131 allele in the total periodontitis population was 58%; for AgP this was 79%, compared with 51% in the control population (OR 3.68 [1.29-10.5], p=0.013). Also, the frequency of the FcgammaRIIa-H/H131 genotype was significantly higher in AgP patients than in controls (OR 9.07 [1.29-63.56], p=0.026, adjusted for smoking status and other potential confounders). Moreover, patients with the FcgammaRIIa-H/H131 genotype had more severe radiographic bone loss than patients with the other FcgammaRIIa genotypes. The current study of relative small sample size suggests that the FcgammaRIIa-H/H131 genotype may be a putative susceptibility and severity factor, and the FcgammaRIIIa-V158 allele a putative susceptibility factor for periodontitis in Northern European Caucasians. These results need further verification and the biological importance of these findings needs further investigation.

Independent association of HLA-DR and FCgamma receptor polymorphisms in Korean patients with systemic lupus erythematosus.

To determine the distribution of HLA-DR type and FcgammaRIIa/IIIa polymorphisms, and to analyse the combined effects of these genes for susceptibility in Korean systemic lupus erythematosus (SLE) patients. A total of 299 SLE patients meeting 1982 ACR criteria and 144 Korean disease-free controls were enrolled. Genotyping for the FcgammaRIIa 131 R/H and FcgammaRIIIa 176 F/V was performed by polymerase chain reaction (PCR) of genomic DNA using allele-specific primers. HLA-DRB1 typing was performed by the PCR-SSOP method. There was significant skewing in the distribution of the three FcgammaRIIa genotypes between the SLE patients and the controls [P = 0.002 for R/R131 vs R/H131 and H/H131, relative risk (RR) 2.6 (95% CI 1.3-5.2)], but not in FcgammaRIIIa genotypes. HLA-DRB1*15 allele was significantly more prevalent among SLE patients than the control population [P < 0.02, RR = 1.7 (1.1-2.6)]. HLA-DRB1 genotypes or allele frequencies of the SLE patients with nephritis did not differ significantly from those of the SLE patients without nephritis. We analysed the combined effects of the two candidate genes on SLE susceptibility. HLA-DRB1*15 allele was a significant predictor of SLE in individuals who were not homozygous for FcgammaRIIa-R/R131 [RR = 2.1 (1.2-3.7), P < 0.008], and the FcgammaRIIa-R/R131 genotype vice versa [RR = 5.3 (1.9-15.4), P < 0.001]. However, an additive or synergistic effect of both susceptible genes on relative risk for SLE was not evident. Our results suggest that FcgammaRIIa-R/R131 homozygote and HLA-DRB1*15 allele are independent risk factors in Korean SLE patients without additive or synergistic effects.

FcgammaRIIA polymorphisms in Streptococcus pneumoniae infection.

Invasive pneumococcal disease continues to be a major cause of morbidity and mortality among children and adults worldwide. Effective host defence against Streptococcus pneumoniae depends on immunoglobulin G-mediated phagocytosis of the bacteria and it has been shown in vitro that the FcgammaRIIA polymorphism (FcgammaRIIA-R131 vs FcgammaRIIA-H131) determines the capacity of immunoglobulin G2-mediated phagocytosis via this receptor. In this study, we evaluated FcgammaRIIA polymorphisms in children with pneumococcal sepsis and a number of control groups in order to investigate a possible association of FcgammaRIIA genotypes with Streptococcus pneumoniae infection. The distribution of the genotypes differed in these populations. The frequency of homozygosity for FcgammaRIIA-R/R131 in the patients was significantly higher than that in the healthy random donor population (43%vs 21%, P < 0.05). The frequencies of FcgammaRIIA-H/H131 were similar among all groups of individuals, while the incidence of the heterozygous FcgammaRIIA-R/H131 was lower (35%vs 52%, P < 0.05). Thus, it appears that the FcgammaRIIA-H131 polymorphic form, even in the heterozygous form, may be protective for pneumococcal sepsis and children with FcgammaRIIA-R/R131 genotype could be more at risk of infection with invasive Streptococcus pneu-moniae.

Identification of IgG subclasses and C-reactive protein in lupus nephritis: the relationship between the composition of immune deposits and FCgamma receptor type IIA alleles.

To characterize the subclass composition of IgG deposited in lupus glomeruli, to examine its relationship to allelic polymorphisms of IgG receptors (Fcgamma receptors [FcgammaR]), and to determine whether C-reactive protein (CRP), a ligand for FcgammaRIIa, is present in these immune deposits. Renal biopsy samples from 80 patients with lupus nephritis were examined by light microscopy and indirect immunofluorescence with IgG-subclass-specific monoclonal antibodies. FcgammaRIIA genotypes were determined using allele-specific polymerase chain reaction. Immunostaining for CRP was performed on lupus and nonlupus glomerulonephritis specimens. IgG2 and IgG3 were the predominant subclasses in immune deposits in all World Health Organization classes of nephritis. The frequency of genotypes containing the low-binding IgG2 allele, FcgammaRIIa-R131, was significantly greater than expected in patients with class III or class IV nephritis and in patients with intense IgG2 deposition. CRP, a ligand with particular affinity for FcgammaRIIa-R131, was consistently present in the renal immune deposits of lupus nephritis specimens. FcgammaRIIA genes are associated with proliferative renal disease and may contribute to disease pathogenesis. FcgammaRIIa-R131, the variant with low affinity for IgG2, has high affinity for CRP. Thus, FcgammaRIIa-R131 may contribute to impaired removal of circulating immune complexes, as well as efficiently triggering phagocyte activation and the release of inflammatory mediators within glomeruli.

Platelet FcγRIIA HIS131ARG polymorphism and platelet function: antibodies to platelet-bound fibrinogen induce platelet activation

The His131Arg polymorphism of platelet FcgammaRIIA affects the binding affinity of certain IgG subclasses. The Arg131 allele has been associated with (auto)immune thrombocytopenia and heparin-induced thrombocytopenia in some studies. Because FcgammaRIIA can transmit platelet activation signals, we studied platelet responsiveness from 73 healthy donors to determine if this polymorphism modulated platelet function. Platelet function was studied by agonist and shear-induced activation, and standard aggregation. FcgammaRIIA was genotyped by allele-specific PCR. Compared with His131, the Arg131 allele was associated with significantly greater binding of activation-dependent antibodies. This effect was most prominent for the receptor-induced binding site (RIBS) antibodies F26 (P < 0.0001) and RIBS1 (P = 0.0057), and the ligand-induced binding site antibody LIBS1 (P = 0.0367). Unexpectedly, Arg131-positive platelets did not show greater fibrinogen binding, platelet aggregation or shear-induced platelet activation. We considered whether enhanced Fc binding and FcgammaRIIA cross-linking were responsible for those discrepancies. The increased binding of the two RIBS antibodies to the Arg131 isoform was abolished by blocking FcgammaRIIA, and the FcgammaRIIA genotype effect on F26 IgG binding was lost when F26 F(ab')2 fragments were used. Furthermore, intact F26 and RIBS1 IgG directly and specifically induced P-selectin expression, and this effect was greatest in Arg131-positive platelets. We concluded that (a) the His131Arg polymorphism of FcgammaRIIA does not affect intrinsic platelet reactivity; (b) RIBS antibodies are able to cross-link FcgammaRIIA and activate platelets, and this activation has a modest effect on Arg131 platelets; and (c) flow cytometric based platelet assays may need to compensate for this FcgammaRIIA His131Arg effect on platelet activation.

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.

Fcgamma receptor IIIA polymorphism in Korean patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by the presence of various autoantibodies and the deposition of immune complex, which is cleared by Fcgamma receptors. Genotype analysis was done to investigate whether the FcgammaRIIIA-176F/V polymorphism is a risk factor for SLE in Koreans. We genotyped 145 Korean SLE patients and 75 control subjects for FcgammaRIIIA-176F/ V. After amplifying a 1.7-kb fragment containing the Fcgamma/RIIIA-176F/V polymorphic site using two FcgammaRIIIA gene-specific primers, we performed a nested polymerase chain reaction (PCR) for allele-specific genotyping at position 559 in FcgammaRIIIA. FcgammaRIIIA genotype or allele distribution was not significantly different between lupus patients and controls, and also between lupus nephritis patients and healthy controls. Neither creatinine clearance, 24 h urine proteinuria, number of American College of Rheumatology (ACR) criteria, nor the Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index was different according to the genotype. In conclusion, FcgammaRIIIA-176F/V polymorphism is not associated with SLE in Koreans.

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.

Involvement of Fc gamma receptor polymorphism in the therapeutic response of idiopathic thrombocytopenic purpura.

Clearance of autoantibody-sensitized platelets through Fc gamma receptors on phagocytic cells is one of the main mechanisms of thrombocytopenia in idiopathic thrombocytopenic purpura (ITP). We examined the Fc gamma RIIA-131R/H and Fc gamma RIIIA-158V/F polymorphisms in 104 adult chronic ITP patients, and in 59 healthy control subjects using polymerase chain reaction-based allele-specific restriction analysis. The frequency of Fc gamma RIIA genotypes (131H/H, H/R, R/R) was not significantly different between patients and controls, and did not correlate with the responsiveness to treatment. In contrast, among Fc gamma RIIIA genotypes, frequency of 158F/F homotype was smaller in ITP (P < 0.05). Furthermore, in Fc gamma RIIIA-158V/V homotype, the complete remission (CR) rate with medication (treatment with corticosteroid or other immunosuppressive agents) was significantly higher (60%) than that in 158V/F (10%) or 158V/F plus 158F/F, (P < 0.01, P < 0.05). Conversely, the CR rate after splenectomy in 158F/F and 158V/F types (64.3% and 54.6%) was higher than in 158V/V (25%). Our results indicate that the polymorphism of Fc gamma RIIIA, but not Fc gamma RIIA, influences the response to treatment in ITP.