FcγRIIa Genotypes Research Articles

Use of Dendritic Cells and GM-CSF Adjuvant Are Associated with Anti-Idiotype Cellular Immune Response Following Idiotype Vaccination in Follicular Lymphoma Patients.

Vaccination with idiotype (Id) induces humoral and/or cellular anti-Id immune responses (IR). Recently, we found that anti-Id humoral IR and IgG Fc receptor FcγRIIIa (CD16) 158 Valine/Valine (V/V) correlated with better outcome in patients receiving Id vaccination (JCO 22:4717). Therefore, identifying factors that influence the development of anti-Id IR will provide important information on how to improve Id vaccination by aiming to increase IR. We examined the following factors for their possible effects on IR: prior induction chometherapy or not, prior fludarabine, clinical response to induction chemotherapy, the production method for Id protein, the immunologic adjuvants used during vaccination and the FcγR polymorphisms. One hundred and eighty follicular lymphoma patients who were treated with Id vaccination at Stanford Medical Center between 1988 and 2002 were included. One hundred and sixty four of them received induction chemotherapy, followed by Id vaccination, while 16 patients were treatment naive at the time of Id vaccination. Humoral and cellular IR were determined following Id vaccination by enzyme-linked immunosorbent assays and by T-cell proliferation assays, respectively, as described.Of these 180 patients, 65 (36%) developed humoral IR and 44 (24%) developed cellular IR after Id vaccination. The development of humoral IR was not affected by receiving induction chemotherapy or not, use of fludrarbine, responses to induction chemtherapy, Id protein production method, type of immunologic adjuvant, FcγRIIIa, FcγRIIa or FcγRIIb genotypes. On the other hand, the development of cellular IR was greatly enhanced by using either dendritic cells or GM-CSF as adjuvant compared to chemical adjuvant (chemical adjuvant: 12% vs dendritic cells: 34%, p=0.003; vs GM-CSF: 48%, p<0.0001) and in patients who received Id protein from molecular cloning (hybridoma: 17% vs molecular cloning: 44%, p=0.0004). However, there was no impact on cellular IR by: induction chemotherapy (23% vs 44%, p=0.072), use of fludrarbine (20% vs 24%, p=0.821), induction chemtherapy responses (CR/CRu: 25% vs PR: 18%, p=0.415), FcγRIIIa genotype (V/V: 27% vs F carrier: 16%, p=0.806), FcγRIIa genotype (H/H: 34% vs R carrier: 23%, p=0.316) and FcγRIIb genotype (I/I: 21% vs T carrier: 37%, p=0.061).A logistic regression analysis was performed to identify independent prognostic variables influencing the development of either humoral or cellular IR. Use of dendritic cells or GM-CSF adjuvant emerged as the only predictive factor independently predicting the development of cellular IR (odds ratio: 4.72, 95% CI: 1.88–11.85, p=0.001), while no predictive factor was identified for the development of humoral IR. This observation is consistent with the prevailing notion that dendritic cells and GM-CSF adjuvant can facilitate cellular IR immune response to various vaccines. It is interesting that PR patients after induction chemotherapy and fludarabine-treated patients had the same chance of developing humoral or cellular IR as did other patients. Therefore, these two groups of patients should not be excluded from subsequent vaccine trials on the assumption that they have impaired immune systems. It is also important to point out that none of these 180 patients received rituximab during induction therapy, which may significantly impair the ability to develop humoral IR.

Humoral Immune Response and Immunoglobulin G Fc Receptor Genotype Are Associated with Better Clinical Outcome Following Idiotype Vaccination in Follicular Lymphoma Patients Regardless of Their Response to Induction Chemotherapy.

Recently, we found that anti-idiotype humoral immune response and FcγRIIIa 158 Valine/Valine (V/V) correlated with clinical outcome in follicular lymphoma patients receiving idiotype vaccination (JCO 22:4717). This result highlighted the importance of developing anti-tumor antibodies and hosting an efficient ADCC machinery. In the previous study, all 136 patients received induction chemotherapy and were in clinical remission at the time of idiotype vaccination. One important question is whether the outcome of these patients was correlated with their clinical response to induction chemotherapy. We, therefore, analyzed the impact of chemotherapy response on clinical outcome to determine if the better outcome associated with humoral immune response and V/V genotype applies to patients with different chemotherapy response. Induction cheomtherapies included chlorambucil, CVP, an adriamycin-containing regimen, or alternating CVP and fludarabine. Ninety patients (66%) achieved complete response or unconfirmed complete response (CR/CRu) and 46 patient (34%) achieved partial response (PR). The progression free survival at 4 years was 59% for CR/CRu patients and 41% for PR patients. The median time to progression (TTP) of 5.21 for CR/CRu patients was significantly longer than the 1.62 years for PR patients (p=0.004). Multi-variant analysis using the Cox Proportional Hazards Model showed that humoral IR, V/V genotype and CR/CRu were three independent positive predictors for progression free survival, while FcγRIIa genotype, FcγRIIb genotype, cellular IR, gender, age, B symptoms, time from diagnosis to therapy, use of adriamycin or use of fludarabine during induction chemotherapy had no impact. The relative benefit was 2.26 (95% CI, 1.36–3.76, p=0.0016) for humoral IR, 5.03 (95% CI, 2.06–12.25, p=0.0004) for V/V genotype and 2.01 (95% CI, 1.22–3.29, p=0.0057) for CR/CRu. The impact of humoral immune response and V/V genotype on CR/CRu or PR patients were then examined. In CR/CRu patients, the progression free survival at 4 years was 74% for patients with humoral immune response and/or V/V genotype while only 45% for patients without either, with median TTP not reached and of 3.46 years for the two groups, respectively (p=0.007). In PR patients, the benefit of having humoral immune response and/or V/V genotype was even more pronounced. The progression free survival at 4 years was 63% for patients with humoral immune response and/or V/V genotype and 21% for patients without either, with median TTP not reached after 8 years and of 1.31 years for the two groups, respectively (p=0.0004). This result suggests that having humoral immune response and/or V/V genotype was associated with longer TTP regardless of their response to induction chemotherapy. In fact, there is no difference in the TTP between CR/CRu and PR patients if they had humoral immune response and/or V/V genotype (TTP not reached in both groups, p=0.338). In contrast, in the group with neither humoral immune response nor V/V genotype, CR/CRu patients enjoyed much longer TTP than PR patients (TTP 3.46 year vs 1.31 years, p=0.0005). This result further confirms the strong association of clinical outcome with humoral immune response and with the functional activity of Fc receptor bearing cells in patients receiving idiotype vaccination. Our results also argue for the inclusion of PR as well as CR patients in idiotype vaccine trials, since the apparent benefit of immune response is even greater in PR patients.

Influence of FcγRIIA and MBL polymorphisms on severe acute respiratory syndrome

Polymorphisms of human Fc γ‐receptor IIA (FcγRIIA) and mannose‐binding lectin (MBL) genes have been associated with susceptibility to or severity of some infectious diseases. In order to investigate whether these genetic factors might influence susceptibility to infection with the severe acute respiratory syndrome‐associated coronavirus (SARS‐Cov) as well as the course and severity of the infection, we evaluated polymorphisms of FcγRIIA and MBL genes in DNA samples from a group of approximately 180 people from Hong Kong who were infected with SARS‐Cov. These included 132 patients who had moderate course of SARS infection (home subgroup), 26 patients with a severe course requiring treatment in an intensive care ward (ICU subgroup) and a subgroup of 22 patients who died from SARS (deceased subgroup). A total of 200 normal blood donors from the same region were used as controls. A significant association was found between the FcγRIIA‐R/R131 genotype and a severe course of SARS, with higher frequency of homozygosity for FcγRIIA‐R/R131 in the ICU subgroup of SARS patients when compared with controls (P = 0.03; odds ratio: 3.2; 95% confidence interval: 1.1–9.1). In comparison with controls, a significant difference in linear trend distribution of FcγRIIA genotypes was seen among the severe SARS patients (ICU and deceased subgroups) without co‐morbidity, and the incidence of FcγRIIA‐H/H131 was lower in these patients as well. There were no significant differences in MBL genotypes and allele frequencies among SARS patients and controls. The study reveals that in addition to age and co‐morbidity, FcγRIIA polymorphism of individuals may also influence outcome after infection with the SARS‐Cov.

Fcγ-receptor IIA genotype and invasive pneumococcal infection

Streptococcus pneumoniae is a major cause of pneumonia, bacteraemia, meningitis, and acute otitis media, especially in young children, immunocompromised patients, and elderly. Fcγ-IIA receptor plays a crucial role in the phagocytosis of IgG2-opsonized bacteria since it is the sole receptor able to interact with IgG2 antibodies. Fcγ-RIIA exhibits allelic polymorphisms with different capacities for binding IgG2 and phagocytosis. In a prospective study, we genotyped Fcγ-RIIA in 55 Caucasian patients suffering from invasive pneumococcal disease and in 100 Caucasian controls. In contrast to previous reports, we found no association between Fcγ-RIIA genotype and invasive pneumococcal disease.

Fcγ receptor IIIA polymorphism as a risk-factor for coronary artery disease

Background: Inflammation is important in the pathogenesis of atherosclerosis. Polymorphisms of Fc receptors for IgG (FcγR) are associated with modifying effects of several infectious and autoimmune diseases. We have assessed the relationship between polymorphisms in three different FcγR genes and coronary artery disease (CAD). Methods and results: We genotyped for the FcγRIIA-R/H131, the FcγRIIIB-Na1/Na2, and the FcγRIIIA-F/V158 polymorphisms in 882 patients undergoing diagnostic coronary angiography. Significant CAD was defined as ≥50% lumen diameter stenosis in at least one coronary artery. In the analysis, no association was found between the FcγRIIA and FcγRIIIB genotypes and CAD, whereas the FcγRIIIA genotype was strongly related. Compared to those being heterozygous, or homozygous for the F allele, patients homozygous for the V allele had significantly reduced risk: OR, 0.53; (CI, 0.32–0.90). Additional adjustment for classical risk factors and sedimentation rate did not affect the results. The V/V genotype was also inversely related to the extent of CAD defined as no CAD, single, double or triple vessel disease ( P trend = 0.002). Conclusions: Our data provide evidence for an association between FcγRIIIA allelic variants and coronary atherosclerosis. Genetic variation in this IgG-receptor may influence the clearance of antibodies by monocyte-derived macrophages involved in the pathogenesis of CAD.

The FcγRIIa polymorphism in patients with chronic kidney graft rejection

The FcγRIIa receptors, which provide a crucial link between cellular and humoral components of the immune response, display allelic polymorphism. Individuals are homozygous for either arginine 131 (RR131) or histidine 131 (HH131) or are heterozygous for these two alleles (RH131). The HH131 genotype binds human IgG2 with high RR131 with low, and RH131 with intermediate affinity. The aim of the study was to evaluate the FcγRIIa polymorphism in patients with chronic kidney graft rejection. The study included 121 renal transplant recipients: 53 patients with long-term stable graft function and 68 with chronic allograft rejection. The distribution of FcγRIIa genotypes in patients with chronic kidney graft rejection did not differ significantly from that in patients with stable graft function. The results suggest that the FcγRIIa polymorphism is not an important genetic risk factor for chronic rejection of kidney allografts.

Association of Fcgamma receptor IIa genotype with chronic periodontitis in Caucasians.

Functional polymorphisms of immunoglobulin G (IgG) Fc receptors IIIa and IIIb (FcgammaRIIIa and FcgammaRIIIb) have been shown as risk factors for periodontitis. The aim of this study is to examine whether FcgammaRIIa polymorphism is associated with a disease risk as well. Baseline periodontal and general health examinations were carried out on 1,221 Caucasian adults. From these, 422 subjects with moderate to severe, or little or no periodontal disease were assigned to two groups according to their mean clinical attachment loss (CAL). Subjects with mean CAL > or = 2.94 mm were diagnosed with chronic periodontitis (n = 213, 62 never-smokers and 151 smokers). Subjects with mean CAL < or = 1.77 mm were considered as having little or no periodontal disease and designated as controls (n = 209, 125 never-smokers and 84 smokers). The FcgammaRIIa genotype for three bi-allelic polymorphisms (FcgammaRIIa-R/ R131, R/H131, and H/H131) was determined by means of allele-specific polymerase chain reactions. The distribution of FcgammaRIIa genotype between the patient and control groups was significantly different, with enrichment of the high ligand-binding genotype FcgammaRIIa-H/H131 in the patients (patients versus controls: 36.6% versus 25.4%; P = 0.04). Multivariate logistic regression model demonstrated that subject age and gender, smoking, and the FcgammaRIIa genotype were significantly associated with severity of chronic periodontitis. For smokers, a significant over-representation of FcgammaRIIa-H/H131 in the patient group compared to the control group (patients versus controls: 35.1% versus 19.0%; P = 0.03). Additionally, smokers with FcgammaRIIa-H/H131 exhibited significantly greater mean CAL (mean +/- SE: 3.44 +/- 0.16 mm) than those with FcgammaRIIa-R/H131 (2.91 +/- 0.14 mm) and R/R131 (2.82 +/- 0.16 mm) (P = 0.04). There was no association between FcgammaRIIa genotype and the disease susceptibility or severity in subjects who had never smoked. Our results suggest that the FcgammaRIIa-H/H131 genotype may be associated with chronic periodontitis risk (and disease severity) in Caucasian smokers. Further studies with families and studies of mechanisms are necessary to help establish the extent to which this is a genetic determinant of periodontal diseases.

The FcγRIIa Polymorphism in Children with Atopic Diseases

Background: Fcγ receptor II (FcγRIIa) is the most widely distributed of the classes of FcR and is expressed in polymorphic forms on most types of hematopoietic cells. Recent data suggest that this polymorphism may be relevant to FcγRIIa function. This might be linked to variability in immune response and therefore related to the pathogenesis of atopic diseases. The aim of the study was to evaluate the FcγRIIa polymorphism in children with atopic diseases. Methods: In the study were included 140 atopic children, 77 with food allergy and 126 healthy subjects as the control group. The FcγRIIa polymorphism was determined using the polymerase chain reaction method. Results: The distribution of FcγRIIa genotypes in atopic children did not differ from that of healthy controls. Moreover, there was no association between the FcγRIIa genotypes and atopic diseases. Conclusion: It seems that the FcγRIIa polymorphism does not represent an important genetic risk factor for atopic diseases susceptibility.

Genetic variation in Fcγ receptor IIa protects against advanced peripheral atherosclerosis

Immune processes play a substantial role in atherosclerotic disease. The role in atherosclerosis of Fcgamma receptor IIa (FcgammaRIIa), a receptor for immunoglobulin G and for the inflammatory mediator C-reactive protein, is not yet clear. Since the R/H131 polymorphism in the FcgammaRIIa gene strongly influences binding to FcgammaRIIa, we investigated the association of the R/H131 polymorphism with advanced peripheral atherosclerosis. Within the Rotterdam Study, a population-based cohort study, we determined FcgammaRIIa genotype in 430 subjects with advanced peripheral atherosclerosis as indicated by the ankle-arm index, and 411 controls. Heterozygous and homozygous carriers of the H131 allele were protected against advanced peripheral atherosclerosis (age- and gender-adjusted odds ratio (OR) 0.77 (0.54-1.12) and 0.65 (0.44-0.98), respectively, P trend=0.04). This effect was most pronounced in subjects with modestly elevated levels of inflammation as indicated by the leukocyte count (OR 0.52 (0.29-0.93) and 0.45 (0.23-0.86), for heterozygotes and H131 homozygotes, respectively; P trend=0.02). This is the first study showing that the H131 allele of FcgammaRIIa protects against advanced peripheral atherosclerosis.

Association of the Fcγ receptor IIA-R/R131 genotype with myasthenia gravis in Dutch patients

Myasthenia gravis (MG) susceptibility is partially determined by allelic heterogeneity of immune-modulatory genes. IgG receptors (FcγR) link the humoral and cellular branches of the immune system, and regulate immune responses and inflammation. Three FcγR subclasses (FcγRIIa, FcγRIIIa, and FcγRIIIb) exhibit functional polymorphisms, which affect efficiency of FcγR-mediated functions. FcγRIIa genotypes, but not FcγRIIIa and FcγRIIIb genotypes, were differentially distributed among 107 MG patients as compared to 239 healthy controls ( P≪0.01), with a relative increase of the FcγRIIa-R/R131 genotype (Odds ratio 2.4, 95% confidence interval 1.4–3.9). These data suggest that the FcγRIIa-R/R131 genotype is a marker for susceptibility to MG.

No association of FcγRIIa, FcγRIIIa and FcγRIIIb polymorphisms with MS

Anti-myelin IgGs occur in the cerebrospinal fluid (CSF) and serum of multiple sclerosis (MS) patients, and can induce inflammatory effector functions in leukocytes by crosslinking IgG receptors (FcγR). The efficiency of FcγR-mediated inflammatory processes is affected by functional polymorphisms of three Fcγ receptors (FcγRIIa, FcγRIIIa, FcγRIIIb). The relevance of FcγR polymorphisms in MS was evaluated by studying the distribution of FcγRIIa, FcγRIIIa and FcγRIIIb genotypes in 432 MS patients and 515 healthy controls. No significant differences were found between MS patients and controls, or between subgroups of patients. We conclude that Fcγ receptor polymorphisms influence neither susceptibility nor clinical disease course of MS.

FcgammaRIIa and FcgammaRIIIb polymorphisms were not associated with meningococcal disease in Western Norway.

Fcgamma-receptor (FcyR) polymorphisms have been associated with acquisition and severity of invasive meningococcal disease. We studied FcgammaR polymorphisms in a population with a high incidence of meningococcal disease. Fifty meningococcal disease patients aged 14-60 years, with bacteriologically confirmed disease and without detected complement deficiency, together with 100 healthy adult controls were included in the study. Clinical and bacteriological data were collected prior to FcgammaRIIa and FcgammaRIIb genotyping, which was performed by polymerase chain reaction. The distribution of the FcgammaRIIa and FcgammaRIIIb allotypes and their allele frequencies were not significantly different amongst the patients and the controls. The combination FcgammaRIIa-R/R and FcgammaRIIb-Na2/Na2 was less common among patients than controls (OR = 0.11, Fisher's exact P = 0.05). No significant association was found between the two FcgammaRs and severity of disease, meningococcal serogroup, age groups or gender. In contrast to previous findings, our study indicates that in Norwegian teenagers and adults, the FcgammaRIIa and FcgammaRIIIb allotypes are not decisive for the acquisition or for the severity of meningococcal disease.

Clearance of red cells by monoclonal IgG3 anti-D in vivo is affected by the VF polymorphism of Fcgamma RIIIa (CD16).

Human red cells (RBC) coated with IgG anti-D are cleared from the circulation to the spleen by macrophages which express IgG receptors (Fcgamma R). Polymorphisms of Fcgamma RIIa and Fcgamma RIIIa affect IgG binding in vitro, and may alter the efficiency of clearance of immune complexes in vivo. In a RBC clearance study, 22 Rh D-negative subjects were given 100-400 micro g human monoclonal or polyclonal IgG anti-D i.m. followed 48 h later by 51Cr-labelled D+ RBC. The half lives of the infused D+ RBC were determined, together with the coating levels of anti-D on the D+ RBC. Fcgamma RIIA and FcgammaRIIIA genotyping was performed. Large ranges of phagocytosis and extracellular lysis of RBC in vitro, and of half lives of RBC in vivo, were observed. Clearance of RBC coated with monoclonal IgG3 anti-D (BRAD-3) was more rapid in five subjects homozygous for Fcgamma RIIIa-F/F158 than in three subjects expressing the Fcgamma RIIIa-V158 allele (P = 0.024). This effect was not observed, however, for those individuals given polyclonal anti-D. There was also no significant difference in the efficiency of RBC destruction in vitro or of RBC clearance in vivo between the subjects analysed for individual genotypes or alleles or combinations of alleles. In conclusion, the presence of the Fcgamma RIIIa-V158 allele compromised the efficiency of removal of RBC coated with IgG3 anti-D.

A novel PCR-based method for direct Fcγ receptor IIIa (CD16) allotyping

Leukocyte IgG receptors (FcγR) are important immune-response modulating molecules. FcγRIIIa is expressed on macrophages, NK-cells and γδ-T cells and exhibits a genetically determined, functional polymorphism at nucleotide 559. This allelic difference predicts either a phenylalanine (F158) or valine (V158) at amino acid 158 in the membrane-proximal extracellular domain, and has been shown to be associated with autoimmune and infectious diseases. Published methods to determine FcγRIIIa genotypes are cumbersome. Therefore, we developed a novel, rapid and reliable PCR-based method to determine FcγRIIIa genotypes. Comparison of genotyping results with direct FcγRIIIa sequencing of 60 blood donors showed 100% accuracy of this new method. Since genotype frequencies of FcγR polymorphisms depend strongly on race and ethnicity, we compared FcγRIIIa genotype frequencies of 176 Caucasian Dutch and 104 Japanese blood donors. Interestingly, these frequencies were not significantly different ( P>0.1), in contrast to the FcγRIIa and FcγRIIIb genotype frequencies ( P<0.001).

Human Fc gamma receptor IIA (FcgammaRIIA) genotyping and association with systemic lupus erythematosus (SLE) in Chinese and Malays in Malaysia.

SLE is an autoimmune and polygenic disorder characterized by an accumulation and deposition of immune complexes. Several studies have indicated differential impact of FcgammaR polymorphism genotypes in different ethnic groups studied. The Fc receptor for IgG class IIA gene (FcgammaRIIA) occurs in two allelic forms. The allele FcgammaRIIA-H131 encodes a receptor with a histidine at the 131 amino acid position; the other allele FcgammaRIIA-R131 encodes an arginine. This polymorphism is believed to determine the affinity of the receptor for hIgG2 in immune complexes. FcgammaRIIA-H131 has a higher capacity for hIgG2 compared to FcgammaRIIA-R131 as measured by in vitro studies of insoluble immune complex clearance. We have investigated the polymorphism for FcgammaRIIA using a novel polymerase chain reaction-allele specific primer (PCR-ASP) method designed specifically to distinguish the two allelic forms. Our studies were based on 175 Chinese and 50 Malays SLE patients as well as 108 and 50 ethnically matched healthy controls for the respective groups. Analysis of the data (chi2 test with Yates correction factors and odds ratios) revealed that there were no significant differences between SLE patients and controls. We have not found evidence of a protective effect conferred by FcgammaRIIA-H131 in the ethnic groups studied.

A Naturally Occurring Mutation in FcγRIIA: A Q to K127 Change Confers Unique IgG Binding Properties to the R131 Allelic Form of the Receptor

FcγRIIa is widely expressed on hematopoietic cells. There are two known allelic polymorphic forms of FcγRIIa, FcγRIIa-R131 and FcγRIIa-H131, which differ in the amino acid at position 131 in the second Ig-like domain. In contrast to FcγRIIa-R131, FcγRIIa-H131binds hIgG2 but not mIgG1, and this differential binding has clinical implications for host defense, autoimmune disease, immunohematologic disease, and response to therapeutic monoclonal antibodies. We identified a novel FcγRIIA genotype in a healthy individual homozygous for FcγRIIA R/R131 in whom a C to A substitution at codon 127 changes glutamine (Q) to lysine (K) in one of the two FcγRIIA genes. This individual's homozygosity for FcγRIIA-R/R131 leads to the prediction that the receptors on her cells would not bind hIgG2. Monocyte and neutrophil phagocytosis of hIgG2-opsonized erythrocytes was significantly higher (P &lt; .05) for cells from this K/Q127, R/R131 individual than for Q/Q127, R/R131 donors. Platelet aggregation stimulated by an mIgG1 anti-CD9 antibody in this individual was significantly different (P &lt; .05) from Q/Q127, H/R131 and Q/Q127, H/H131 donors and similar to Q/Q127, R/R131. Our data show that the K127/R131 receptors have a unique phenotype, binding both hIgG2 and mIgG1. Further functionally significant mutations in human Fcγ receptors and possible novel mechanisms for inherited differences in disease susceptibility should be sought with unbiased screening methods.

A Naturally Occurring Mutation in FcγRIIA: A Q to K127 Change Confers Unique IgG Binding Properties to the R131 Allelic Form of the Receptor

AbstractFcγRIIa is widely expressed on hematopoietic cells. There are two known allelic polymorphic forms of FcγRIIa, FcγRIIa-R131 and FcγRIIa-H131, which differ in the amino acid at position 131 in the second Ig-like domain. In contrast to FcγRIIa-R131, FcγRIIa-H131binds hIgG2 but not mIgG1, and this differential binding has clinical implications for host defense, autoimmune disease, immunohematologic disease, and response to therapeutic monoclonal antibodies. We identified a novel FcγRIIA genotype in a healthy individual homozygous for FcγRIIA R/R131 in whom a C to A substitution at codon 127 changes glutamine (Q) to lysine (K) in one of the two FcγRIIA genes. This individual's homozygosity for FcγRIIA-R/R131 leads to the prediction that the receptors on her cells would not bind hIgG2. Monocyte and neutrophil phagocytosis of hIgG2-opsonized erythrocytes was significantly higher (P < .05) for cells from this K/Q127, R/R131 individual than for Q/Q127, R/R131 donors. Platelet aggregation stimulated by an mIgG1 anti-CD9 antibody in this individual was significantly different (P < .05) from Q/Q127, H/R131 and Q/Q127, H/H131 donors and similar to Q/Q127, R/R131. Our data show that the K127/R131 receptors have a unique phenotype, binding both hIgG2 and mIgG1. Further functionally significant mutations in human Fcγ receptors and possible novel mechanisms for inherited differences in disease susceptibility should be sought with unbiased screening methods.

Fcγ Receptor IIA H/R131 Polymorphism in Patients with Antiphospholipid Antibodies

A role for Fcgamma receptor in the pathophysiology of thrombosis in APS has been hypothesized. The polymorphism of this receptor, FcgammaRIIA H/R131, is associated with the binding affinity for human IgG2 (i.e. FcgammaRIIA-H131 isoform has a higher affinity than FcgammaRIIA-R131). Since anti-beta2 glycoprotein I antibodies (anti beta2GPI), which play a major pathogenic role in APS, show IgG2 dominant distribution, we investigated the prevalence of receptor isoforms in patients with antiphospholipid antibodies (aPL) by a PCR-RFLP method. We studied 100 Caucasian patients with aPL (57 primary APS, 32 secondary APS to SLE and 11 other diseases with aPL) and 41 healthy controls. H131/H131, H131/R131 and R131/R131 genotypes were found in 21 (21%), 50 (50%) and 29 (29%) in the patient group, and 9 (22%), 23 (56%) and 9 (22%) in control group, respectively. Thus there was no statistically significant difference in the prevalence of each genotype in these groups. None of the clinical manifestations of primary APS (arterial/venous thrombosis, recurrent pregnancy loss and thrombocytopenia) was significantly correlated with any FcgammaRIIA genotype. In conclusion, FcgammaRIIA polymorphism did not correlate with the manifestations of APS, and FcgammaRIIA genotype is not a genetic marker of APS.

Relationship between Fc receptor IIA polymorphism and infection in children with sickle cell disease

OBJECTIVE: Despite penicillin prophylaxis and vaccination, infection with encapsulated organisms remains a leading cause of morbidity and death in children with sickle cell disease. The role of Fc receptors in the clearance of encapsulated organisms is well documented. The His(H)-Arg(R) polymorphism at amino acid 131 of the FcγRIIA receptor alters binding affinity for human IgG2 and influences infection with encapsulated organisms in children without sickle cell disease. We hypothesized that the genotype for high-affinity human IgG2 binding (H/H 131) is underrepresented in children with sickle cell disease who had encapsulated organism infection. DESIGN: We studied 60 black children with sickle cell disease from four participating centers who had a history of encapsulated organism infection. Genomic DNA from peripheral blood was subjected to amplification by polymerase chain reaction and to sequence analysis for identification of the FcγRIIA genotype, and the genotype distribution was then compared with our data from ethnically matched control subjects. RESULTS: Contrary to our hypothesis, the H/H 131 genotype was over represented in all individuals ( p = 0.046) and in particular in the 11 individuals with a history of Haemophilus influenzae type b infection (64% H/H 131, 27% H/R 131, 9% R/R 131; p = 0.002), in comparison with ethnically matched control subjects (14% H/H 131, 60% H/R 131, 26% R/R 131). In the 51 individuals with a history of Streptococcus pneumoniae infection, the genotype distribution was not statistically significantly different from that of the control population. CONCLUSIONS: The H/H 131 FcγRIIA genotype is overrepresented in black children with sickle cell disease and a history of H. influenzae type b infection but not in those with S. pneumoniae infection. (J P EDIATR 1996;128:813-9)