Fc Gamma Receptor Polymorphisms Research Articles

Association between Fc-Gamma Receptor Polymorphisms and Autoimmune Neutropenia in Early Childhood in Danish Patients

Background Copy number variation (CNV) in the genome is difficult to analyze with standard genotyping methods. CNV in the Fcγ receptor region (FCGR) is associated with risk of autoimmune disease. Genetic variation in Fc-gamma coding genes is also abundant, and several functional polymorphisms are described. Autoimmune neutropenia (AIN) primarily affects children under the age of five but can also affect adults. The disease is caused by autoantibodies reactive to neutrophil surface antigens, primarily the FCGR3B receptor. We investigated the association between common SNPs and CNV in Fcγ receptors and AIN. Aims Establish the association between CNV and genetic variation in Fc-gamma receptor coding genes in Danish patients. Methods 127 Danish AIN cases were compared with 610 healthy and unrelated Danish blood donors for FCGR2A-H166R, and with 919 Caucasians (1) for FCGR3A-V158F, FCGR2B-B2.4, FCGR2B-I232T and CNV. Molecular determination of copy number and genotypes was determined using Multiplex Ligation Probe Assay (MLPA) with the following SALSA MLPA probemixes: P110-C1 FCGR mix 1 and P111-C1 FCGR mix 2. Statistical analysis was performed with Fisher Exact test. Results The polymorphisms FCGR2A-166H, FCGR3A-158F, FCGR2B-232I were statistically significantly associated with a higher risk of AIN (Table 1). The presence of a FCGR2B-2B.4 promoter haplotype was associated with a significantly lower risk of AIN (OR=0.5). There was not observed a difference in the distribution of CNV for the Fc-gamma receptor genes (data not shown). Summary/Conclusion In our Danish cohort, we report an association between AIN and polymorphisms in Fc-gamma receptor 2A, 3A and 2B, indicating a significance of other Fc-gamma receptors than FCGR3B. We do not observe a difference in the distribution of CNV of the Fc-gamma receptor genes. 1) Nagelkerke SQ, Tacke CE, Breunis WB, Tanck MWT, Geissler J, Png E, Hoang LT, van der Heijden J, Naim ANM, Yeung RSM, Levin ML, Wright VJ, Burgner DP, Ponsonby A-L, Ellis JA, Cimaz R, Shimizu C, Burns JC, Fijnvandraat K, van der Schoot CE, van den Berg TK, de Boer M, Davila S, Hibberd ML,Kuijpers TW and the International Kawasaki Disease Genetics Consortium (2019) Extensive Ethnic Variation and Linkage Disequilibrium at the CGR2/3 Locus: Different Genetic Associations Revealed in Kawasaki Disease. Front. Immunol. 10:185. doi: 10.3389/fimmu.2019.00185 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adoptive immunotherapy overcomes genetic susceptibility to bloodstream infections due to fc-gamma receptor polymorphisms after liver transplantation

Single nucleotide polymorphisms (SNPs) in FCGR3A can predict the susceptibility of liver transplant (LT) recipients to bloodstream infections (BSI) and clinical outcomes following living-donor LT (LDLT). Here, we retrospectively analyzed the relationship of adoptive immunotherapy with activated natural killer (NK) cells from perfusate effluents of liver allografts against BSI following LDLT. Higher BSI incidence and lower survival were observed in LT recipients with FcγRIIIa (158F/F or F/V) (n=81) who did not receive adoptive immunotherapy (n=55) than in those who did (n=26) (BSI frequency, 36.4% vs. 11.5%; p =.033; log-rank p =.047). After matching patient background using propensity score, similar results were obtained (BSI ratio, 41.7% vs. 12.5%; p =.049; log-rank p=.039). The predominant BSI pathogens in patients who did and did not receive adoptive immunotherapy were gram-negative rods (n=3, 100%) and gram-positive cocci (GPC) (n=15, 65.2%), respectively. The proportion of NK cells administered to patients with BSI was significantly lower than that administered to patients without BSI (Number: 80.3 (29.9-239.2)× 106 cells vs. 37.1 (35.6-50.4)× 106 ; p=.033, percentage; 14.1 (13.3-17.8)% vs. 34.6 (16.5-47)%, p=.0078). Therefore, adoptive immunotherapy with NK cells was associated with the reduced post-transplant BSI related to GPCs due to FcγRIIIa SNP in LT recipients.

Human immune polymorphisms associated with the risk of cryptococcal disease.

Cryptococcus neoformans is an opportunistic fungal pathogen that can cause lethal cryptococcal meningitis in immunocompromised individuals such as those with HIV/AIDS. In addition, cryptococcal infections occasionally arise in immunocompetent individuals or those with previously undiagnosed immunodeficiencies. The course of cryptococcosis is highly variable in both patient groups, and there is rapidly growing evidence that genetic polymorphisms may have a significant impact on the trajectory of disease. Here, we review what is currently known about the nature of these polymorphisms and their impact on host response to C. neoformans infection. Thus far, polymorphisms in Fc gamma receptors, mannose‐binding lectin, Dectin‐2, Toll‐like receptors and macrophage colony‐stimulating factor have been associated with susceptibility to cryptococcal disease. Notably, however, in some cases the impact of these polymorphisms depends on the genetic background of the population; for example, the FCGR3A 158 F/V polymorphism was associated with an increased risk of cryptococcal disease in both HIV‐positive and HIV‐negative white populations, but not in Han Chinese patients. In most cases, the precise mechanism by which the identified polymorphisms influence disease progression remains unclear, although impaired fungal recognition and phagocytosis by innate immune cells appears to play a major role. Finally, we highlight outstanding questions in the field and emphasize the need for future research to include more diverse populations in their genetic association studies.

Are Fc Gamma Receptor Polymorphisms Important in HIV-1 Infection Outcomes and Latent Reservoir Size?

Fc gamma receptors (FcγR) are cell surface glycoproteins which trigger specific effector-cell responses when cross-linked with the Fc portions of immunoglobulin (IgG) antibodies. During HIV-1 infection, the course of disease progression, ART response, and viral reservoir size vary in different individuals. Several factors may account for these differences; however, Fc gamma receptor gene polymorphisms, which influence receptor binding to IgG antibodies, are likely to play a key role. FcγRIIa (CD32) was recently reported as a potential marker for latent HIV reservoir, however, this assertion is still inconclusive. Whether FcγR polymorphisms influence the size of the viral reservoir, remains an important question in HIV cure studies. In addition, potential cure or viral suppression methods such as broadly neutralizing antibody (bNAbs) may depend on FcγRs to control the virus. Here, we discuss the current evidence on the potential role played by FcγR polymorphisms in HIV-1 infection, treatment and vaccine trial outcomes. Importantly, we highlight contrasting findings that may be due to multiple factors and the relatively limited data from African populations. We recommend further studies especially in sub-Saharan Africa to confirm the role of FcγRIIa in the establishment of latent reservoir and to determine their influence in therapies involving bNAbs.

The Current Landscape of Antibody-based Therapies in Solid Malignancies.

Over the past three decades, monoclonal antibodies (mAbs) have revolutionized the landscape of cancer therapy. Still, this benefit remains restricted to a small proportion of patients due to moderate response rates and resistance emergence. The field has started to embrace better mAb-based formats with advancements in molecular and protein engineering technologies. The development of a therapeutic mAb with long-lasting clinical impact demands a prodigious understanding of target antigen, effective mechanism of action, gene engineering technologies, complex interplay between tumor and host immune system, and biomarkers for prediction of clinical response. This review discusses the various approaches used by mAbs for tumor targeting and mechanisms of therapeutic resistance that is not only caused by the heterogeneity of tumor antigen, but also the resistance imposed by tumor microenvironment (TME), including inefficient delivery to the tumor, alteration of effector functions in the TME, and Fc-gamma receptor expression diversity and polymorphism. Further, this article provides a perspective on potential strategies to overcome these barriers and how diagnostic and prognostic biomarkers are being used in predicting response to mAb-based therapies. Overall, understanding these interdependent parameters can improve the current mAb-based formulations and develop novel mAb-based therapeutics for achieving durable clinical outcomes in a large subset of patients.

Polymorphisms in Fc Gamma Receptors and Susceptibility to Malaria in an Endemic Population.

Repeated infections by Plasmodium falciparum result in a humoral response that could reduce disease symptoms and prevent the development of clinical malaria. The principal mechanism underlying this humoral response is that immunoglobulin G (IgG) binds directly to the parasites, thus causing their neutralization. However, the action of antibodies alone is not always sufficient to eliminate pathogens from an organism. One key element involved in the recognition of IgG that plays a crucial role in the destruction of the parasites responsible for spreading malaria is the family of Fc gamma receptors. These receptors are expressed on the surface of immune cells. Several polymorphisms have been detected in the genes encoding these receptors, associated with susceptibility or resistance to malaria in different populations. In this review, we describe identified polymorphisms within the family of Fc gamma receptors and the impact of these variations on the response of a host to infection as well as provide new perspectives for the design of an effective vaccine for malaria.

Effects of intravenous immunoglobulin therapy and Fc gamma receptor polymorphisms on BK virus nephropathy in kidney transplant recipients.

BK virus nephropathy (BKVN) is a major complication in kidney transplant patients. This study aimed to investigate the efficacy of intravenous immunoglobulin (IVIG) therapy against persistent BKVN and to evaluate the association between persistent BKVN and Fc gamma receptor (FcγR) single nucleotide polymorphisms (SNPs). A total of 86 patients out of 279 kidney recipients with BKVN were investigated in a single-center retrospective study. The majority of 86 patients were Hispanic and Asian (69.8% and 17.4%). Patients were treated with adjunctive IVIG or standard therapy (controls). Subgroup analysis was performed between IVIG responders and non-responders. BK virus copy number and serum creatinine (SCr) were measured to evaluate the impact of IVIG. We analyzed the association between the response to IVIG and genotype at FcγR3A (rs396991) and FcγR2A (rs1801274) SNPs. Viral load in IVIG non-responders was significantly higher than in responders at the time of diagnosis (219271.8 vs 29816.3copies/mL, P=.015) and after 6months of IVIG use (12789.5 vs 1369.5copies/mL, P<.001). However, analyses SNP of FcγR2A (OR=0.807, CI=0.435-1.496 P=.495) and FcγR3A (OR=0.997, CI=0.505-1.970, P=.993) SNPs showed no significant differences between the 2 groups. IVIG appears to lower BK DNA viral load significantly in patients with persistent BKVN. However, no associations were identified between BKVN and FcγR2A or FcγR3A SNPs.

Fc Gamma Receptor Polymorphisms Modulated the Vaccine Effect on HIV-1 Risk in the HVTN 505 HIV Vaccine Trial.

HIV Vaccine Trials Network (HVTN) 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection yet enhanced HIV infection risk for others. Here, we assessed whether and how host Fc gamma receptor (FcγR) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four FCGR2C single-nucleotide polymorphism [SNP] sites) (hazard ratio [HR] = 9.79, P = 0.035) but not among participants without the haplotype (HR = 0.86, P = 0.67); the interaction of vaccine and haplotype effect was significant (P = 0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3 FCGR3B SNPs) (HR = 2.78, P = 0.058) but not among participants without the haplotype (HR = 0.73, P = 0.44); again, the interaction of vaccine and haplotype was significant (P = 0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8+ T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an FCGR2A SNP and two FCGR2B SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination.IMPORTANCE By analyzing data from the HVTN 505 efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) vaccine regimen, we found that host genetics, specifically Fc gamma receptor genetic variations, influenced whether receiving the DNA/rAd5 regimen was beneficial, neutral, or detrimental to an individual with respect to HIV-1 acquisition risk. Moreover, Fc gamma receptor genetic variations influenced immune responses to the DNA/rAd5 vaccine regimen. Thus, Fc gamma receptor genetic variations should be considered in the analysis of future HIV vaccine trials and the development of HIV vaccines.

Associations between FCGR polymorphisms and immune thrombocytopenia: A meta-analysis.

Several studies already explored associations between Fc gamma receptor (FCGR) polymorphisms and immune thrombocytopenia (ITP), but the results of these studies were not consistent. Consequently, we conducted a meta-analysis of relevant studies to better analyse the effects of FCGR polymorphisms on individual susceptibility to ITP. PubMed, Web of Science, Embase and CNKI were searched for eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Totally 17 studies were eligible for analyses (1200 cases and 1723 controls). Significant associations with ITP were observed for FCGR3A F158V polymorphism in dominant (P<0.0001, OR=0.47, 95% CI 0.39-0.57), recessive (P<0.0001, OR=2.03, 95% CI 1.58-2.61), overdominant (P<0.0001, OR=1.42, 95% CI 1.19-1.69) and allele (P<0.0001, OR=0.58, 95% CI 0.51-0.65) models in overall analyses. But we did not observe any significant associations with ITP for FCGR2A H131R and FCGR2B I232T polymorphisms in overall analyses. Subgroup analyses by ethnicity yielded similar positive results for FCGR3A F158V polymorphism in both Asians and Caucasians. Furthermore, subgroup analyses by type of disease revealed that FCGR2A H131R polymorphism was significantly associated with childhood-onset ITP, and FCGR3A F158V polymorphism was significantly associated with both childhood-onset and adult-onset ITP. In summary, our findings suggested that FCGR2A H131R polymorphism may serve as a potential genetic biomarker of childhood-onset ITP, while FCGR3A F158V polymorphism may serve as a potential genetic biomarker of both childhood-onset and adult-onset ITP.

The Association of FCGR2A and FCGR3A polymorphisms with outcomes in cetuximab treated metastatic colorectal cancer patients: CCTG and AGITG CO.20 trial analysis.

633 Background: We previously reported that the Fc-gamma receptor (FCGR) germline polymorphism in the FCGR2A gene (rs1801274; His (H) to Arg (R) substitution) but not FCGR3A (rs396991; Phe (F) to Val (V)) was associated with cetuximab benefit on overall survival (OS) in metastatic colorectal cancer patients (CCTG CO.17 trial). We performed a validation of these results in CO.20, a randomized trial of cetuximab+placebo vs. cetuximab+brivanib for metastatic, chemotherapy refractory, wild type K-RAS colorectal cancer. Methods: After genotyping DNA extracted from whole blood, the polymorphism relationships with OS and progression-free survival (PFS) were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. Results: Of 592/725 (82%) K-RAS wild type patients with available DNA and genotyping, those carrying the higher affinity FCGR2A H/H genotype (N = 165; 28%) had improved OS (HR 0.53; 95%CI:0.41-0.68) and PFS (HR 0.65; 95%CI:0.51-0.83) compared to those carrying the lower affinity R/R genotype (N = 128; 22%), corresponding to median absolute benefits of 3.7 (OS) and 3.3 months (PFS). The H/R genotype (N = 299; 50%) had intermediate outcomes. No significant associations were found between FCGR3A genotype and OS or PFS. No interaction between FCGR polymorphisms and treatment arm was observed. Patients carrying the double wild type combination of FCGR2A H/H and FCGR3A F/F genotypes (N = 45; 7.6%) had significantly better outcomes than other patients, particularly those carrying the rare (N = 11; 2%) R/R+ V/V genotype combination, corresponding to median absolute benefits of 12.5 (OS; HR 0.33 95%CI:0.16-0.68) and 4.5 (PFS; HR 0.45 95%CI:0.22-0.92) months. There were no significant associations between FCGR polymorphisms and either any grade of 3/4 toxicity or skin rash. Conclusions: In KRAS-wild type, cetuximab-treated patients, FCGR2A polymorphism was independently replicated to be associated with clinical outcome without affecting toxicity profiles. Additionally, in this large dataset, FCGR3A appears to modulate the relationship between FCGR2A polymorphism and outcome.

FC gamma receptor polymorphisms in patients with immune thrombocytopenia

ABSTRACTIntroduction: Immune thrombocytopenia (ITP) is an autoimmune blood disease of unknown etiology. The aim of our study was to investigate a possible role of FCGR2A and FCGR3A polymorphisms in the development of primary ITP.Methods: We analyzed 125 adult patients with ITP and 120 healthy controls. Genotyping was performed by using PCR-RFLP methods.Results: Our results showed significantly higher frequency of high-affinity FCGR3A-158V allele in patients with ITP compared with control subjects (47.2% versus 37.5%; p = 0.037). We did not find significant differences in the genotype distribution or allele frequencies for FCGR2A-131H/R between patients and controls, p = 0.652 and p = 0.478. In the groups of patients with unresponsive and responsive ITP we found significantly different genotype distribution and allele frequencies for FCGR3A, p = 0.036 and p = 0.008 respectively. There was no significant difference in genotype and allele frequencies for FCGR2A between these two groups of patients. Our results confirmed that the combination of high-affinity FCGR2A-131H and FCGR3A-158V allele was more common in patients with ITP than in controls (55% versus 40%; p = 0.024).Conclusion: Our results suggest possible role of FCGR3A polymorphism in the etiology, development and clinical outcome of ITP, but larger prospective studies are needed to confirm these results.

Fc-Gamma Receptor Polymorphisms Are Associated with Susceptibility to and Recovery from Pediatric Immune Thrombocytopenia

Introduction: Immune thrombocytopenia (ITP) in children is a rare autoimmune disorder characterized by isolated thrombocytopenia. Platelet specific autoantibodies are often present leading to accelerated clearance of opsonized platelets by Fc-gamma receptor (FcγR) bearing phagocytes, particularly in the spleen. Both activating FcγRs as well as the inhibitory FcγRIIb are subject to genetic variation that affects their function. This includes mutations resulting in loss of expression; for example only the FCGR2C*ORF with an open reading frame leads to FcγRIIc expression. On myeloid and natural killer cells, FcγRIIc expression enhances IgG-mediated activation. Similarly, functional FcγRIIb polymorphisms also exist (FCGR2B*232I/T), with the FCGR2B*232T variant being functionally impaired in downregulating activating FcγRs and the B-cell receptor. We evaluated whether FcγR polymorphisms are associated with occurrence of ITP, response to intravenous immunoglobulin (IVIg) therapy and recovery in children with newly diagnosed ITP.Patients and methods: Children aged 3 months-16 years with newly diagnosed ITP, a platelet count below 20x109/L and with mild to moderate bleeding were included in the randomized multicenter TIKI trial (Therapy with or without IVIg for Kids with acute ITP; NTR study ID TC1563). Patients were randomized to receive either a single dose of IVIg (0.8 g/kg) or to receive careful observation and medical treatment only in case of severe bleeding. At diagnosis, blood samples were taken to perform the multiplex ligation-dependent probe amplification (MLPA) assay, assessing copy number variations and detecting all known FcγR polymorphisms.Results: From May 2009 until May 2015, 180 newly diagnosed patients were enrolled in this part of our study. ITP patients showed an FcγR profile different from that of healthy controls, with an overrepresentation of FCGR2C*ORF (31.7% versus 19.6%, p=0.007) and its associated promoter 2B.2, a higher allele frequency of FCGR3A*158V (41.4% versus 32.8%; p=0.019), and less often FCGR3B-HNA1a (9.4% versus 18.1%, p=0.032). In the observation group (n=81), all children with complete recovery at 1 week (n=17) were homozygous for 232I in FCGR2B (p=0.016). In patients randomized to receive IVIg, complete response rate after one week was 68.4%; complete responders were either homozygous FCGR2B*232I or heterozygous FCGR2B*232I/232T. No complete responses to IVIg were seen in the three patients with the homozygous FCGR2B*232T genotype (p=0.03). In patients with a homozygous FCGR2B*232I genotype combined with the 2B.4 promoter haplotype, complete response rate was significantly higher than in patients lacking this combination (93.3% versus 64.6%, respectively; p=0.03).Conclusion: Functional FcγR polymorphisms in FCGR2C, FCGR3A and FCGR3B genes are associated with newly diagnosed ITP in children. Furthermore, the less functional 232T-FcγRIIb isoform is associated with the lack of early recovery, either with or without IVIg treatment. FcγR profiles can be regarded as a risk factor to develop ITP during childhood. FcγR profiles are associated with the clinical course and response to IVIg treatment suggesting that determination of the FcγR profile can be of additional value in patient counselling and decision algorithms whether or not to start IVIg treatment in ITP. DisclosuresNo relevant conflicts of interest to declare.

Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD2 antibody ch14.18/CHO show higher ADCC levels and improved event-free survival

ABSTRACTPolymorphisms in Fc-gamma-receptor (FCGR) genes as well as killer cell immunoglobulin-like receptor (KIR) and KIR ligand (KIRL) repertoires may influence antitumor effects of monoclonal antibodies (mAb). Here, we systematically analyzed high- and low-affinity FCGR2A and -3A genotypes as well as stimulating and inhibitory KIR/KIRL combinations in 53 neuroblastoma (NB) patients treated by long-term infusion (LTI) of anti-GD2 IgG1 Ab ch14.18/CHO using validated real-time PCR methods.Patients with high-affinity FCGR2A and -3A genotypes showed a higher level of Ab-dependent cell-mediated cytotoxicity (ADCC) on day 8 after the start of ch14.18/CHO and superior event-free survival (EFS) compared to patients with low FCGR genotypes. Similar observations were made for patients with stimulatory KIR/KIRL haplotype B (combination of KIR genes including activating receptor genes) compared to inhibitory haplotype A (a fixed set of genes encoding for inhibitory receptors, except 2DS4) and stronger effects were found in patients when haplotype B and high-affinity FCGRs were combined. Surprisingly, independent analysis of KIRs showed a major role of activating KIR 2DS2 for high ADCC levels and prolongation of EFS. The greatest effect was observed in 2DS2-positive patients that also had high-affinity FCGR2A and -3A genotypes.In summary, the presence of the activating KIR 2DS2 has a major effect on ADCC levels and survival in NB patients treated by LTI of ch14.18/CHO and may therefore be a useful biomarker in combination with FCGR polymorphisms for Ab-based immunotherapies.

Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia.

Recent studies in adult lymphoma patients have indicated a correlation between polymorphisms of Fc gamma-receptors (FcγRs, encoded by the respective FCGR genes) and the response to rituximab treatment. In vitro, cells expressing FcγRIIIa-158V mediate antibody-dependent cellular cytotoxicity (ADCC) more efficiently than cells expressing FcγRIIIa-158F. The impact of the FCGR2A-131HR polymorphism is unclear. In this study, the FCGR polymorphisms FCGR3A-158VF and FCGR2A-131HR were analyzed in pediatric patients with mature aggressive B cell non-Hodgkin lymphoma/leukemia (B-NHL). Pediatric patients received a single dose of rituximab monotherapy. Response was evaluated on day 5 followed by standard chemotherapy for B-NHL. Among 105 evaluable patients, a response to rituximab was observed in 21% of those homozygous for FcγRIIa-131RR (5/24) compared to 48% of patients who were HH and HR FcγRIIa-131 allele carriers (18/34 and 21/47, respectively; p=0.044). Among patients with the FCGR3A-158 polymorphism, those homozygous for the FF genotype had a significantly favorable rituximab response rate of 59% (22/37) compared to 32% in patients who were FcγRIIIa-158VV and FcγRIIIa-VF allele carriers (2/9 and 20/59, respectively; p=0.022). A stringent phase II response evaluation of children and adolescents with B-NHL after one dose of rituximab monotherapy showed a significant association between the rituximab response rate and FCGR polymorphisms. These findings support the hypothesis that FCGR polymorphisms represent patient-specific parameters that influence the response to rituximab.

Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis.

To determine relevant Fc-gamma receptor (FcγR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found. Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcγRII and FcγRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLE patients and 919 healthy Caucasian controls. Expression of FcγRs on leukocytes was assessed using flow cytometry. In multivariable analysis, low copy number of CNR1 (including FCGR3B; odds ratio (OR) 2.04; 95% CI: 1.29, 3.23), FCGR2A-131RR (OR 2.00; 95% CI: 1.33, 2.99), and the 2B.4 haplotype of FCGR2B (OR 1.59; 95% CI: 1.13, 2.24), but not FCGR2C open reading frame, were significantly (all P < 0.01) and independently associated with susceptibility to SLE. The 2B.4 haplotype was negatively associated with LN and led to surface expression of FcγRIIb on neutrophils and monocytes. This study is the first to investigate the most relevant and functional single nucleotide polymorphisms and copy number variations of FcγRII and FcγRIII polymorphisms in one study population, enabling the determination of the individual contribution of each polymorphism in multivariable analysis. Three polymorphisms were shown to be independently associated with susceptibility to SLE. The novel findings of a negative association of the 2B.4 haplotype with LN, and increased expression of FcγRIIb on neutrophils and monocytes as a result of this 2B.4 haplotype warrant future research in the role of these cells and FcγRs in the pathogenesis of SLE and LN.

FCGR2A and FCGR3A Genotypes in Human Immunodeficiency Virus Mother-to-Child Transmission.

Background. Fc-mediated effector functions have been suggested to influence human immunodeficiency virus (HIV) acquisition and disease progression. Analyzing the role of host Fc gamma receptor (FcγR) polymorphisms on HIV outcome in mother-to-child transmission (MTCT) will increase our understanding of how host genetics may alter immune responses in prevention, therapy, and disease. This study analyzed the impact of FCGR2A and FCGR3A genotypes on MTCT in a cohort in which Fc-mediated antibody functions are predictive of infant HIV outcome. Methods. Human immunodeficiency virus-positive mothers and their infants from a historical MTCT cohort were genotyped for FCGR2A and FCGR3A. We assessed the impact of these genotypes on transmission and acquisition of HIV and disease progression using χ(2) tests, survival analyses, and logistic regression. Results. Among 379 mother-infant pairs, infant FCGR2A and FCGR3A genotypes were not associated with infant HIV infection or disease progression. Maternal FCGR2A was not associated with transmission, but there was a trend between maternal FCGR3A genotype and transmission (P = .07). When dichotomizing mothers into FCGR3A homozygotes and heterozygotes, heterozygotes had a 64.5% higher risk of transmission compared with homozygotes (P = .02). This risk was most evident in the early breastfeeding window, but a trend was only observed when restricting analyses to breastfeeding mothers (hazards ratio, 1.64; P = .064). Conclusions. Infant FCGR2A and FCGR3A genotypes were not associated with HIV infection or disease progression, and, thus, host FcγR genotype may not significantly impact vaccination or therapeutic regimens that depend on Fc-mediated antibody functions. Maternal FCGR3A genotype may influence early breastfeeding transmission risk, but more studies should be conducted to clarify this association and its mechanism.

Possible mechanisms for intravenous immunoglobulin-associated hemolysis: clues obtained from review of clinical case reports.

Intravenous immunoglobulin (IVIG) is an efficacious treatment modality for a number of conditions and is usually well tolerated with few reports of serious adverse events; however, the administration of IVIG may occasionally result in clinically significant hemolysis. The literature was reviewed for case reports and case series of IVIG-associated hemolysis. The cases were scrutinized for clues as to the possible mechanism(s) of the hemolysis. Review of the 129 individual cases reported in the literature identifies clinical features shared by the majority of patients. These features included non-O blood group patients and treatment with high-dose IVIG as an immune-modulating agent for an underlying inflammatory or immune-mediated disorder. Other patient factors such as secretor phenotype, soluble ABH substance, and Fcgamma receptor polymorphisms may also play a role. It is known that high-dose IVIG given to non-O blood group patients with underlying inflammatory and/or immune-mediated disorders is associated with increased risk of hemolysis. This review reveals additional patient characteristics in cases of IVIG-associated hemolysis, including underrepresentation of D- and group B cases, higher incidence in pediatric Kawasaki disease and unique at-risk patient groups including allogeneic stem cell transplant recipients with group A donor in a group O recipient, and patients in whom soluble AB substance is removed by plasma exchange at the same time as receiving IVIG.

Fc-Gamma receptor polymorphism and gene expression of peripheral blood mononuclear cells in patients with HER2-positive metastatic breast cancer receiving single-agent trastuzumab.

The aim of this study was to investigate gene expression in the peripheral blood mononuclear cells (PBMCs) of patients with HER2-positive breast cancer receiving trastuzumab. We also evaluated the effect of Fc-gamma receptor genotype on trastuzumab-driven gene expression. Gene expression was assessed by microarray analyses before and after administration of single-agent trastuzumab in 34 patients with metastatic HER2-positive breast cancer who were genotyped for Fc-gamma receptor (FcGR) IIA H131R and FcGRIIIA V158F. Gene set enrichment analysis (GSEA) was used to identify the gene sets that were significantly enriched after administration of trastuzumab in patient cohorts categorized by FcGR variant. At baseline three non-immune-related gene sets were identified only in patient cohort of FcGRIIA non-H/H variant. Thirty gene sets were identified in the cohort of FcGRIIIA V/V variants, while no gene set was identified in FcGRIIIA non-V/V variants one week after starting trastuzumab. Eleven gene sets were identified in FcGRIIA H/H variants 8 week after starting trastuzumab, but none in non-H/H variants. Immune-related gene sets were significantly down-regulated after administration of trastuzumab. The response of PBMCs to trastuzumab markedly varied with polymorphisms in FcGRIIA and FcGRIIIA. These results indicate that FcGR polymorphisms contribute to the systemic immune reaction triggered by trastuzumab. Further investigations are needed to clarify the biological effects of FcGR variation on the mechanism of trastuzumab activity.

Biomarkers Related to Carotid Intima-Media Thickness and Plaques in Long-Term Survivors of Ischemic Stroke.

Lifestyle risk factors, inflammation and genetics play a role in the development of atherosclerosis. We therefore studied Fc gamma receptor (FcγR) polymorphisms, interleukin (IL)-10 polymorphisms and other biomarkers related to carotid intima-media thickness (cIMT) in patients with ischemic stroke at a young age. Patients were evaluated 12 years after stroke occurrence. Patients (n = 232) 49 years of age or younger with an index stroke between 1988 and 1997 were retrospectively selected. Blood samples were taken at a first follow-up 6 years after the stroke. At a second follow-up, additional arterial events were registered for 140 patients, new blood samples were taken, and measurements of cIMT and blood pressure (BP) were performed. Unadjusted logistic regression analysis showed that cIMT ≥1 mm was associated with age, male gender, additional arterial events, BP, cholesterol, sedimentation rate, haemoglobin, triglycerides, creatinine, glycolysed haemoglobin (HbA1c) and FcγRIIIB-NaII/NaII. Adjusted backward stepwise logistic regression showed significance for age (odds ratio (OR) 1.13, 95 % confidence interval (CI) 1.04 to1.23, p = 0.003), male gender (OR 4.07, 95 % CI 1.15 to 14.5, p = 0.030), HbA1c (OR 6.65, 95 % CI 1.21 to 36.5, p = 0.029) and FcγRIIIB-NaII/NaII (OR 3.94, 95 % CI 1.08 to 14.3, p = 0.037). In this long-term follow-up study of patients with ischemic stroke at a young age, FcγRIIIB-NaII/NaII was identified as a possible contributing factor for cIMT ≥1 mm together with known risk factors, such as age, male gender, systolic BP, additional arterial events and HbA1c.

Host immunity to Cryptococcus neoformans.

Cryptococcosis is caused by the fungal genus Cryptococcus. Cryptococcosis, predominantly meningoencephalitis, emerged with the HIV pandemic, primarily afflicting HIV-infected patients with profound T-cell deficiency. Where in use, combination antiretroviral therapy has markedly reduced the incidence of and risk for disease, but cryptococcosis continues to afflict those without access to therapy, particularly in sub-Saharan Africa and Asia. However, cryptococcosis also occurs in solid organ transplant recipients and patients with other immunodeficiencies as well as those with no known immunodeficiency. This article reviews innate and adaptive immune responses to C. neoformans, with an emphasis on recent studies on the role of B cells, natural IgM and Fc gamma receptor polymorphisms in resistance to cryptococcosis.