FcγRIIa Genotypes Research Articles

Modeling of clinical phenotypes in systemic lupus erythematosus based on the platelet transcriptome and FCGR2a genotype

BackgroundThe clinical heterogeneity of SLE with its complex pathogenesis remains challenging as we strive to provide optimal management. The contribution of platelets to endovascular homeostasis, inflammation and immune regulation highlights their potential importance in SLE. Prior work from our group showed that the Fcγ receptor type IIa (FcγRIIa)–R/H131 biallelic polymorphism is associated with increased platelet activity and cardiovascular risk in SLE. The study was initiated to investigate the platelet transcriptome in patients with SLE and evaluate its association across FcγRIIa genotypes and distinct clinical features.MethodsFifty-one patients fulfilling established criteria for SLE (mean age = 41.1 ± 12.3, 100% female, 45% Hispanic, 24% black, 22% Asian, 51% white, mean SLEDAI = 4.4 ± 4.2 at baseline) were enrolled and compared with 18 demographically matched control samples. The FCGR2a receptor was genotyped for each sample, and RNA-seq was performed on isolated, leukocyte-depleted platelets. Transcriptomic data were used to create a modular landscape to explore the differences between SLE patients and controls and various clinical parameters in the context of FCGR2a genotypes.ResultsThere were 2290 differentially expressed genes enriched for pathways involved in interferon signaling, immune activation, and coagulation when comparing SLE samples vs controls. When analyzing patients with proteinuria, modules associated with oxidative phosphorylation and platelet activity were unexpectedly decreased. Furthermore, genes that were increased in SLE and in patients with proteinuria were enriched for immune effector processes, while genes increased in SLE but decreased in proteinuria were enriched for coagulation and cell adhesion. A low-binding FCG2Ra allele (R131) was associated with decreases in FCR activation, which further correlated with increases in platelet and immune activation pathways. Finally, we were able to create a transcriptomic signature of clinically active disease that performed significantly well in discerning SLE patients with active clinical disease form those with inactive clinical disease.ConclusionsIn aggregate, these data demonstrate the platelet transcriptome provides insight into lupus pathogenesis and disease activity, and shows potential use as means of assessing this complex disease using a liquid biopsy.

IgG1 Is the Optimal Subtype for Treating Atherosclerosis by Inducing M2 Macrophage Differentiation, and Is Independent of the FcγRIIA Gene Polymorphism

In recent years, it has been established that atherosclerosis is an autoimmune disease. However, little is currently known about the role of FcγRIIA in atherosclerosis. Herein, we sought to investigate the relationship between FcγRIIA genotypes and the effectiveness of different IgG subclasses in treating atherosclerosis. We constructed and produced different subtypes of IgG and Fc-engineered antibodies. In vitro, we observed the effect of different subtypes of IgG and Fc-engineered antibodies on the differentiation of CD14+ monocytes from patients or healthy individuals. In vivo, Apoe-/- mice were fed a high-fat diet (HFD) for 20 weeks and administered injections of different CVI-IgG subclasses or Fc-engineered antibodies. Flow cytometry was used to assess the polarization of monocytes and macrophages. Although CVI-IgG4 reduced the release of MCP-1 compared to the other subtypes, IgG4 did not yield an anti-inflammatory effect by induction of human monocyte and macrophage differentiation in vitro. Furthermore, genetic polymorphisms of FcγRIIA were not associated with different CVI-IgG subclasses during the treatment of atherosclerosis. In vivo, CVI-IgG1 decreased Ly6Chigh monocyte differentiation and promoted M2 macrophage polarization. We also found that the secretion of IL-10 was upregulated in the CVI-IgG1-treated group, whereas V11 and GAALIE exerted no significant effect. These findings highlight that IgG1 is the optimal subtype for treating atherosclerosis, and CVI-IgG1 can induce monocyte/macrophage polarization. Overall, these results have important implications for the development of therapeutic antibodies.

To Determine the Genotyping of Fc-gamma Receptor FCGR2A Polymorphism as Genetic Susceptibility to Neonatal Sepsis: A Study from a Tertiary Center of North India.

Neonatal sepsis term is an infection of newborns <28 days of age. It is a common cause of death in developing countries. The receptor-gamma receptor FCGR2A has been shown to be associated with neonatal sepsis. It is an activating receptor found in many cell types such as monocytes, neutrophils, macrophages, platelets, and others. The receptor has a polymorphism (single-nucleotide polymorphism rs1801274) in its gene (FCGR2A) that encodes either a histidine (H) or arginine (R) at amino acid position 131. There are many studies showing the impact of these FCGR2A polymorphisms on sepsis. Our study aims to determine the prevalence of Fc-gamma receptor FCGR2A (rs1801274) polymorphism in neonatal sepsis and control in Eastern UP populations. We conducted a cross-sectional descriptive study of 590 patients (310 healthy individuals and 280 sepsis patients) to determine polymorphisms in the CD32A coding region in neonates. All individuals were genotyped for a variant at position 131 of the FcγRIIA gene. In our study, the prevalence of FcγRIIa polymorphism is more in neonates with sepsis than in noninfected neonates. It was observed that the heterozygous allele (AG) were significantly increased in septic neonates when compared to the normal. Our data indicate that FcγRIIA genotyping can be used as a marker of genetic susceptibility to sepsis.

FcγRIIa and FcγRIIIa genes polymorphism in Egyptian children with primary immune thrombocytopenia

IntroductionPhagocytosis of autoantibody-sensitized coated platelets through Fc gamma receptors on phagocytic cells is an important mechanism of thrombocytopenia in primary immune thrombocytopenia (ITP). ObjectiveWe aimed to investigate the contribution of the FcγRIIa and FcγRIIIa genes polymorphism to the risk of ITP and their association with disease characteristics in Egyptian children. MethodsA case control study was conducted on eighty children with primary ITP and eighty age and sex healthy matched subjects as a control group. The FcγRIIa and FcγRIIIa genes polymorphism was detected using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). ResultsWe found that the FcγRIIa‐131H and ‐131R allele frequencies were 51.3 % and 48.7%, respectively, in children with ITP, versus 75% and 25%, respectively, in controls (p = 0.002). The compound heterozygous HR genotype was significantly higher in ITP patients (p < 0.05). The FcγRIIIa-158F and ‐158V allele frequencies were 46.3% and 53.7%, respectively, in children with ITP, versus 70% and 30%, respectively, in controls (p = 0.002). The compound heterozygous VF genotype was significantly higher in ITP patients (p < 0.05). The combined HR/FV genotype was 47.5% in ITP patients, versus 10% in controls (p < 0.001). No significant difference was found between children with newly diagnosed ITP and those who developed chronic ITP, regarding the frequency distribution of the FcγRIIa and FcγRIIIa alleles and genotypes (p > 0.05). ConclusionThere is a possible association of the FcγRIIa and FcγRIIIa genes polymorphism with the risk for, and genetic susceptibility to ITP in Egyptian children, but large-scale studies are still needed to support our findings.

Immunoglobulin G in Normal Plasma Inhibits HIT Antibody-Mediated Platelet Activation: Implications for Therapeutic Plasma Exchange Treatment in HIT

Immunoglobulin G in Normal Plasma Inhibits HIT Antibody-Mediated Platelet Activation: Implications for Therapeutic Plasma Exchange Treatment in HIT

Striking a balance in an antibody network: A roadmap for HIV-1 vaccines.

With almost 2 million new HIV-1 infections in 2018, a highly effective vaccine is imperative. Vaccine-elicited HIV-1 antibodies contribute to protection through multiple nonneutralizing activities, but the exact mechanisms remain unknown. In this issue of the JCI, Neidich and associates sought to determine how antibodies contributed to reducing the risk of HIV-1 acquisition in a phase IIb preventative vaccine efficacy trial, HVTN 505. Their studies revealed that antibody-dependent cellular phagocytosis (ADCP) and FcγRIIa binding were strongly associated with reduced HIV-1 risk; however, HIV-1 envelope-specific IgG3, IgA; and host FcγRIIa genotype also influenced risk. This study highlights the intricate interactions between antibodies and innate immune functions in humans.

Plasma levels of the soluble form of the FcγRIIa receptor vary with receptor polymorphisms and are elevated in rheumatoid arthritis

Soluble forms of the low-affinity immunoglobulin receptor FcγRIIa (sFcγRIIa) lacking the cytoplasmic tail have been reported in plasma however the mechanism and functional consequences are unknown. This study aimed to evaluate mechanisms of FcγRIIa release compared to GPVI release from platelets, and examine whether genetic polymorphisms at positions 27 and 131 within FcγRIIa correlate with platelet FcγRIIa stability and function. Enzyme-linked immunosorbent assays (ELISAs) were used to measure plasma sFcγRIIa and sGPVI levels. FcγRIIa genotype at positions 27 and 131 was evaluated. sFcγRIIa levels were not significantly different between non-131HH and 131HH but were significantly lower in 27W than non-27W. Treatment of platelets with aggregated immunoglobulin (Ig) G induced release of FcγRIIa and GPVI, but only sGPVI release was statistically significant, required functional FcγRIIa, and was blocked by inhibitors of signaling pathways and metalloproteinases. This indicated that sFcγRIIa was not released from platelets by metalloproteolysis. sFcγRIIa levels were not correlated with sGPVI levels in healthy individuals however levels of sFcγRIIa and sGPVI in plasma from patients with rheumatoid arthritis (RA) were significantly elevated above levels found in healthy individuals. Elevated level of sFcγRIIa in RA patients may reflect active immune-based arthritis and be predictive of active inflammation.

Human low‐affinity IgG receptor FcγRIIA polymorphism H131R associates with subclinical atherosclerosis and increased platelet activity in systemic lupus erythematosus

Essentials Systemic lupus erythematosus (SLE) patients are at increased risk for premature CVD. Platelet activity, vascular dysfunction and carotid artery plaque are associated with FcγRIIA genotype in SLE. FcγRIIA genotype was not associated with platelet activity or carotid plaque in healthy controls. FcγRIIA represents a link that connects platelet activity, vascular health and CVD in SLE. SUMMARY: Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with an elevated risk of premature cardiovascular disease. Platelets express receptors contributing to inflammation and immunity, including FcγRIIA, the low affinity receptor of the Fc portion of IgG antibodies. The variation at a single amino acid substitution, H131R, in the extracellular binding domain alters the affinity for IgG, which may account for individual variation in platelet activity and platelet-mediated disease. Objectives This study was performed to investigate the association between FcγRIIA genotype, preclinical atherosclerosis, platelet reactivity and vascular health. Methods FcγRIIA was genotyped in 80 SLE patients and 30 healthy controls. Carotid ultrasound plaque, soluble E-selectin and platelet aggregability were evaluated in SLE and matched controls. Results Carotid plaque was significantly more prevalent in SLE patients carrying a variant allele compared to those with a homozygous ancestral allele (58% vs. 25%, P=0.04). In contrast, prevalent carotid plaque was not associated with genotype in controls. Consistently, SLE variant FcγRIIA carriers vs. ancestral allele carriers had a significant increase in the levels of soluble E-selectin, which was not observed in controls. Monocyte and leukocyte-platelet aggregation and platelet aggregation in response to submaximal agonist stimulation were significantly elevated in SLE patients with the variant vs. ancestral genotype. Conclusions Carotid ultrasound plaque, soluble E-selectin levels and platelet activity were more frequently prevalent in SLE patients carrying variant FcγRIIA. The interplay between FcγRIIA-mediated platelet activation and endothelial cells might represent a mechanism underlying the pathogenesis of cardiovascular disease in SLE patients.

IVIg and LPS Co-stimulation Induces IL-10 Production by Human Monocytes, Which Is Compromised by an FcγRIIA Disease-Associated Gene Variant.

Intravenous Immunoglobulin (IVIg) is used to treat autoimmune or inflammatory diseases, but its mechanism of action is not completely understood. We asked whether IVIg can induce interleukin-10 (IL-10) and reduce pro-inflammatory cytokine production in human monocytes, and whether this response is reduced in monocytes from people with an Fcγ receptor IIA (FcγRIIA) gene variant, which is associated with increased risk of inflammatory diseases and poor response to antibody-based biological therapy. IVIg increased IL-10 production and reduced pro-inflammatory cytokine production in response to bacterial lipopolysaccharide (LPS), which required FcγRI and FcγRIIB and activation of MAPKs, extracellular signal-regulated kinase 1/2 (ERK1/2), and p38. IL-10 production was lower and pro-inflammatory cytokine production was higher in monocytes from people with the FcγRIIA risk variant and the risk variant prevented IL-10 production in response to (IVIg+LPS). Finally, we show that IVIg did not induce MAPK activation in monocytes from people with the risk variant. Our results demonstrate that IVIg can skew human monocytes to an anti-inflammatory, IL-10-producing activation state, which is compromised in monocytes from people with the FcγRIIA risk variant. This research has profound implications for the use of IVIg because 25% of the population is homozygous for the FcγRIIA risk variant and its efficacy may be reduced in those individuals. In addition, this research may be useful to develop new therapeutic strategies to replace IVIg by cross-linking FcγRIs and FcγRIIBs to promote anti-inflammatory macrophage activation, independent of the FcγRIIA genotype.

IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) complicated by severe thrombocytopenia and thrombosis can pose significant treatment challenges. Use of alternative anticoagulants in this setting may increase bleeding risks, especially in patients who have a protracted disease course. Additional therapies are lacking in this severely affected patient population. We describe three patients with HIT who had severe thromboembolism and prolonged thrombocytopenia refractory to standard treatment but who achieved an immediate and sustained response to IVIg therapy. The mechanism of action of IVIg was evaluated in these patients and in five additional patients with severe HIT. The impact of a common polymorphism (H/R 131) in the platelet IgG receptor FcγRIIa on IVIg-mediated inhibition of platelet activation was also examined. At levels attained invivo, IVIg inhibits HIT antibody-mediated platelet activation. The constant domain of IgG (Fc) but not the antigen-binding portion (Fab) is required for this effect. Consistent with this finding, IVIg had no effect on HIT antibody binding in a solid-phase HIT immunoassay (platelet factor 4 enzyme-linked immunoassay). The H/R131 polymorphism in FcγRIIa influences the susceptibility of platelets to IVIg treatment, with the HH131 genotype being most susceptible to IVIg-mediated inhibition of antibody-induced activation. However, at high doses of IVIg, activation of platelets of all FcγRIIa genotypes was significantly inhibited. All three patients did well on long-term anticoagulation therapy with direct oral anticoagulants. These studies suggest that IVIg treatment should be considered in patients with HIT who have severe disease that is refractory to standard therapies.

Association of Fcgamma receptor type 2A and 3A genotypes with rheumatoid arthritis in Chinese population.

SNPs of FcγRs were implicated in pathogenesis of rheumatoid arthritis (RA) and treatment efficacy of TNF inhibitors (TNFi). This study aims to investigate the associations of FcγRIIa and FcγRIIIa genotypes with autoantibody production and treatment response to TNFi in Chinese patients with RA. FcγRIIa and FcγRIIIa polymorphisms were genotyped in 158 RA patients. Response to TNFi was evaluated in 18 patients at 3 and 6 months after treatment. FcγRIIa-131H allele was significantly increased in autoantibody-negative RA patients. FcγRIIa-131H/H+H/R was closely associated with differences in 28-joint disease activity score in patients at months 3 and 6 of TNFi treatment. FcγRIIa-131H allele may have a protective role in autoantibody production and might be a biomarker for predicting good response to TNFi in Chinese RA patients.

FcγRIIa defunctioning polymorphism in paediatric patients with renal allograft.

IntroductionFc gamma receptor (FcγR) IIa is considered the most widely distributed of the three classes of Fc receptors, and it expresses an allelic polymorphism. This type of polymorphism may modify the immune response and may be an important factor for some diseases. The aim of the study reported herein was to evaluate the association between the FcγRIIa polymorphism and susceptibility to both end-stage renal disease (ESRD) and acute kidney graft rejection (AR) in children who have undergone renal transplantation.Material and methodsThe study evaluated 70 children who had undergone transplantation and 60 healthy subjects. AR was observed in 25 children.ResultsFcγRIIa genotypes and alleles were significantly different between transplantation patients and the control group. The assessment for FcγR of the groups in which AR was present showed that there was only a risk of having an acute rejection in homozygous genotype RR.ConclusionsFcγRIIa RR genotype and allele frequency was increased in paediatric renal transplant recipients. The present findings showed that FcγRIIa genotype may be related to ESRD disease susceptibility, and FcγRIIa polymorphisms seemed to affect AR.

Fc Gamma Receptor IIA (CD32A) R131 Polymorphism as a Marker of Genetic Susceptibility to Sepsis

Sepsis is a devastating disease that can affect humans at any time between neonates and the elderly and is associated with mortality rates that range from 30 to 80%. Despite intensive efforts, its treatment has remained the same over the last few decades. Fc receptors regulate multiple immune responses and have been investigated in diverse complex diseases. FcγRIIA (CD32A) is an immunoreceptor, tyrosine-based activation motif-bearing receptor that binds immunoglobulin G and C-reactive protein, important opsonins in host defense. We conducted a study of 702 patients (184 healthy individuals, 171 non-infected critically ill patients, and 347 sepsis patients) to investigate if genetic polymorphisms in the CD32A coding region affect the risk of septic shock. All individuals were genotyped for a variant at position 131 of the FcγRIIA gene. We found that allele G, associated with the R131 genotype, was significantly more frequent in septic patients than in the other groups (p = 0.05). Our data indicate that FcγRIIA genotyping can be used as a marker of genetic susceptibility to sepsis.

Association of Fc gamma-receptors IIa, IIIa, and IIIb genetic polymorphism with susceptibility to chronic periodontitis in South Indian population.

Background and Objective:Fc gamma receptors (FcγRs) are the members of the immunoglobulin superfamily and may play a role in the pathogenesis of periodontitis. Genetic variation in these receptors and its link with various forms of periodontitis is being studied in different populations. The aim of the present study is to determine whether specific FcγRIIa, FcγRIIIa, and FcγRIIIb alleles and/or genotypes are associated with risk for susceptibility to generalized chronic periodontitis (GCP) in South Indian population.Materials and Methods:The study population consisted of 120 South Indian subjects; 60 with GCP and 60 periodontally healthy. Deoxyribonucleic acid (DNA) was extracted from samples collected by scrapping buccal epithelium. FcγRIIa and FcγRIIIa genotyping were performed by polymerase chain reaction (PCR) amplification of DNA with allele-specific primers followed by allele-specific restriction digestion of the products. However, FcγRIIIb genotyping was done by allele-specific PCR.Results:No significant difference in the distribution of FcγRIIa H/R and FcγRIIIa NA1/NA2 genotypes or their respective alleles was observed in GCP patients and healthy subjects. For FcγRIIIa F/V genetic polymorphism, the homozygous V/V genotype and V allele were significantly overrepresented in GCP patients while F/F genotype and F allele in controls.Conclusion:The present study demonstrates that FcγRIIIa V/V genotype, as well as V allele, could be a possible risk factor for chronic periodontitis in South Indian population.

Short communication: Fc gamma receptors IIa and IIIa genetic polymorphisms do not predict HIV-1 disease progression in Kenyan women.

Genetic polymorphisms of the Fc gamma receptors (FcγR) IIa and IIIa have been implicated in the rate of HIV-1 disease progression, but results are inconsistent. We aimed to determine the association between these polymorphisms and disease progression in a cohort of HIV-1 seroconverters from Mombasa, Kenya. Neither FcγRIIa nor FcγRIIIa genotypes were predictive of set point viral load, viral load increase, CD4 decline, or HIV-1 disease progression (time to CD4 count <200 cells/mm(3), death, or treatment initiation). Our results suggest that FcγR polymorphisms might not be an important indicator of viral control and disease progression in this population.

Association of FCγRIIA (CD32) polymorphism with susceptibility to brucellosis

Background: Brucellosis is the major bacterial zoonoses of global importance caused by Brucella spps. FC γRIIA receptor plays a central role in phagocytosis of IgG2-opsonized bacteria. FC γRIIA exhibits allelic polymorphisms with different capacities for binding IgG2 and phagocytosis. Cells expressing Fc γRIIa-H131, bind more efficiently to complexes of IgG2 than those expressing the Fc γRIIAR131 variant. The purpose of this study was to evaluate the association of FC γRIIA polymorphisms with susceptibility to or severity of brucellosis. Materials and Methods: In this study, we evaluated FC γRIIA polymorphisms (R/R131, R/H131, H/H131) in 67 patients with brucellosis and 67 age, sex and geographical matched healthy volunteers. FC γRIIA genotyping was performed by using a sequence-specific primer polymerase chain reaction (SSP-PCR). Results: The comparison of the FC γRIIA genotypes distribution in patients with brucellosis and controls showed a higher frequency in FC γRIIA-R/R131 homozygosity in patients than controls (47.8% vs. 28.4%). Logistic regression analysis showed that there is a significant correlation between R/R131 genotype and brucellosis (OR=2.3, 95%CI=1.3-4.2, P=0.04). Although the frequency of the FC γRIIA-R/R131 was higher in patients with chronic brucellosis compared with acute brucellosis, we did not find any statistically significant differences (53.8% vs. 46.3%, P=0.65). Conclusion: The result of this study showed that the homozygous genotype of FC γRIIA-R/R131 in patients with brucellosis may be associated with susceptibility to brucellosis as a genetic risk factor.

The proinflammatory effect of C-reactive protein on human endothelial cells depends on the FcγRIIa genotype

The stimulatory effects of CRP (C-reactive protein) on endothelial cells are mainly mediated via FcγRIIa. This receptor exists in two different allotypes bearing either arginine (R131) or histidine (H131) at the extracellular amino acid position 131 of the mature protein, but only FcγRIIa-R131 displays high avidity for CRP. This study investigated the role of the FcγRIIa genotype in CRP-stimulated endothelial cells. We tested the effects of CRP on expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the endothelial release of pro-inflammatory molecules as a function of the FcγRIIa-genotype (FcγRIIa-H/H131, FcγRIIa-H/R131, FcγRIIa-R/R131) in HUVEC (Human Umbilical Vein Endothelial Cells). HUVEC were grouped according to their FcγRIIa status by genotyping with an allele specific nested-PCR. The expression of ICAM-1, VCAM-1, and E-selectin on HUVEC was detected by flow cytometry. The release of soluble markers (sCD40L, IL-6, IL-8, MCP-1, tPA, sP-selectin, and sVCAM-1) was measured using a multiplex assay for flow cytometry. CRP-stimulated expression of ICAM-1 and E-selectin was dependent on the specific FcγRIIa-genotype, with most pronounced induction in HUVEC with the FcγRIIa-R/R genotype, followed by H/R and H/H. In accordance with this finding, the supernatants of stimulated HUVEC with the R/R genotype showed significantly higher levels of tPA, MCP-1, and IL-6. Our data show that CRP stimulates the expression of adhesion molecules and the release of soluble markers by HUVEC as a function of the FcγRIIa-genotype. These findings could be relevant in the context of risk stratification in patients with cardiovascular disease.

IGKC and FcγR genotypes and humoral immunity to HER2 in breast cancer

Immunoglobulin κ constant (IGKC) gene has recently been identified as a strong prognostic marker in several human solid tumors, including breast cancer. Although the mechanisms underlying the IGKC signature are not yet known, identification of tumor-infiltrating plasma cells as the source of IGKC expression strongly suggests a role for humoral immunity in breast cancer progression. The primary aim of the present investigation was to determine whether the genetic variants of IGKC, KM (κ marker) allotypes, are risk factors for breast cancer, and whether they influence the magnitude of humoral immunity to epidermal growth factor receptor 2 (HER2), which is overexpressed in 25–30% of breast cancer patients and is associated with poor prognosis. Using a matched case–control design, we genotyped a large (1719 subjects) study population from Japan and Brazil for KM alleles. Both cases and controls in this study population had been previously characterized for GM (γ marker) and Fcγ receptor (FcγR) alleles, and the cases had also been characterized for anti-HER2 antibodies. Conditional logistic regression analysis of the data showed that KM1 allele additively contributed to the risk of breast cancer in the Japanese subjects from Nagano: Compared to KM3 homozygotes, KM1 homozygotes were almost twice as likely to develop breast cancer (OR=1.77, CI 1.06–2.95). Additionally, KM genotypes—individually and in particular epistatic combinations with FcγRIIa genotypes—contributed to the magnitude of anti-HER2 antibody responsiveness in the Japanese patients. This is the first report implicating KM alleles in the immunobiology of breast cancer.

Polymorphisms of FcγRIIA, FcγRIIIA and FcγRIIB in patients with immune thrombocytopenia and their clinical significance

This study was aimed to investigate the correlation of FcγR polymorphisms with the susceptibility, severity and efficacy of immunotherapy for patients with immune thrombocytopenia (ITP). PCR and DNA sequencing were used to determine the polymorphisms of FcγRIIA, FcγRIIIA and FcγRIIB in 44 ITP patients, and in 97 healthy control subjects. The results indicated that FcγRIIIA-158V/F polymorphisms between patients and controls were statistically significantly different (P = 0.015); among FcγRIIIA genotypes, the frequency of 158V/V homotype was higher in ITP (P = 0.005). However, the FcγRIIA-131H/R or FcγRIIB-232T/I polymorphisms were not significantly different between patients and controls; there were no correlation of FcγRIIA, FcγRIIIA and FcγRIIB genotype frequencies with the platelet counts or the courses of ITP; among the 38 ITP patients who received treatments, the complete response (CR) rate was 42% (16/38), and partial response (PR) rate was 34% (13/38). The therapeutic response was significantly different between FcγRIIIA-158V/V homotype and 158F/V heterotype (P = 0.034). The CR of patients with 158V/V homotype was obviously lower than that of patients with 158F/V, but the frequencies of FcγRIIA and FcγRIIB genotypes not correlated with the responsiveness to treatment. The CR rate of 6 patients treated with rituximab was 67%, and PR rate was 17%. The overall response rate was as high as 84%, the adverse reactions were not observed. It is concluded that the polymorphism of FcγRIIIA-158V/F, but not FcγRIIA-131H/R or FcγRIIB-232T/I, correlates with the patient susceptibility and therapeutic response of ITP.

Association of Fcγ receptor IIIa genotype with the rate of HIV infection after gp120 vaccination

AbstractWe determined whether polymorphisms in Fcγ receptor (FcγR) IIa or FcγRIIIa genes were associated with outcomes in Vax004, a trial testing recombinant gp120 vaccination in preventing sexually acquired HIV infection. Male subjects (n = 1725), including infected and uninfected vaccinees and placebo recipients, were genotyped. We observed no association between FcγRIIa genotype and infection rate in vaccinees or placebo recipients. However, FcγRIIIa genotype was associated with infection rate among vaccinees (P = .035). Exploratory analyses revealed that vaccinees homozygous for the FcγRIIIa V allele in the lowest behavioral risk group had a greater rate of infection than low risk vaccinees with at least 1 F allele (hazard ratio [HR] = 3.52; P = .002). No such association was seen among vaccinees with high-risk behaviors or among placebo recipients in either risk stratum. Vaccinated low-risk VV subjects had a greater infection rate than low-risk VV placebo recipients (HR = 4.51; P = .17) or low-risk placebo recipients with any genotype (HR = 4.72; P = .002). Moreover, low-risk VV vaccinees had infection rates similar to individuals with high behavioral risk, irrespective of genotype. Our results generate the hypothesis that recombinant gp120 vaccine may have increased the likelihood of acquiring HIV infection in individuals with the VV genotype (present in ∼ 10% of the population) at low behavioral risk of infection.