Haplotype analysis of HLA‐A, ‐B antigens and ‐DRB1 alleles in south Indian HIV‐1‐infected patients with and without pulmonary tuberculosis

We have shown earlier the association of human leucocyte antigen (HLA)‐A11 with resistance and HLA‐B40 and ‐DR2 with susceptibility to HIV and HIV‐TB. In the present study, we have attempted to find out the HLA‐DR2 subtypes and the possible HLA‐A/‐B/‐DRB1 haplotype combinations that are associated with susceptibility or resistance to HIV and HIV with pulmonary tuberculosis (HIV+PTB+). HLA‐DR2 subtyping was carried out by polymerase chain reaction‐based sequence‐specific oligonucleotide probe method. Overrepresentation of HLA‐DRB1*1501 in HIV‐positive PTB‐negative (HIV+PTB–) patients (P = 0.004, P_c = 0.06) and ‐DRB1*1502 in HIV‐positive PTB‐positive (HIV+PTB+) patients (P = 0.019) was observed as compared to healthy controls. Haplotype analysis revealed an increased frequency of HLA‐A2‐DRB1*1501 haplotype in HIV+PTB– patients (P = 0.008) and HLA‐A2‐DRB1*1502 among HIV+PTB+ patients (P = 0.01) compared to healthy controls. The haplotypes B40‐DRB1*1501 and B40‐DRB1*04 were found to be moderately increased in HIV+PTB– and HIV+PTB+ patients (P < 0.05). The study suggests that HLA‐A2‐DRB1*1501 haplotype may be associated with HIV infection while HLA‐A2‐DRB1*1502 haplotype might be associated with susceptibility to PTB in HIV patients. Moreover, HLA‐B40‐DRB1*1501 and HLA‐B40‐DRB1*04 haplotypes may be associated with susceptibility to HIV infection and to PTB in HIV patients.     

Association of IL‐4 589 C/T promoter and IL‐4RαI50V receptor polymorphism with susceptibility to HIV‐1 infection in North Indians

The clinical course and outcome of HIV‐1 infection are highly variable among individuals. Interleukin 4 (IL‐4) is a key T helper 2 cytokine with various immune‐modulating functions including induction of immunoglobulin E (IgE) production in B cells, downregulation of CCR5 and upregulation of CXCR4, the main co‐receptors for HIV. Our objective is to investigate whether single‐nucleotide polymorphisms (SNPs) in the IL‐4 promoter 589 C/T and IL‐4 Rα I50V affect the susceptibility to HIV infection and its progression to AIDS in North Indian individuals. The study population consisted of 180 HIV‐1 seropositive (HSP) stratified on the basis of disease severity (stage I, II, III), 50 HIV‐1 exposed seronegative (HES), and 305 HIV‐1 seronegative (HSN) individuals. The subjects were genotyped for IL‐4 589 C/T promoter polymorphism and IL‐4 Rα I50V by polymerase chain reaction restriction fragment length polymorphism. The results showed that IL‐4 589 C/T was not associated with the risk of HIV infection and disease progression. However, the IL‐4Rα I50 allele and genotype was significantly increased in HSP compared to HSN and HSP and was associated with risk of HIV infection. The frequency of IL‐4Rα I50 allele in the HSP group was higher than in HSN (76.11 vs. 64.75%; P = 0.000; OR = 1.734) and HES (76.11% vs. 62.00%; P = 0.007; OR = 1.953). Homozygous IL‐4Rα I50I genotype was significantly increased in HSP group compared with HSN (58.88% vs. 44.26%; P = 0.002; OR = 1.804) and HES (58.88% vs. 42.00%; P = 0.038; OR = 1.978). The present study for the first time suggests an association of IL‐4Rα I50 allele with increased likelihood of HIV‐1 infection in North Indian population. Further studies are required to confirm these findings and understand the effect of IL‐4Rα polymorphism on the outcome of HIV‐1 infection. J. Med. Virol. 81:959–965, 2009. © 2009 Wiley‐Liss, Inc.     

Identification of new variants within the two functional genes CCL3 and CCL3L encoding the CCL3 (MIP‐1α) chemokine: implications for HIV‐1 infection

The CC chemokine CCL3 is encoded by two functional genes, namely CCL3 and CCL3L, and has been identified as a key chemokine in HIV‐1 susceptibility and disease progression. The complete CCL3 and CCL3L genes and core promoters of 43 African mother–infant pairs (86 samples) and 28 Caucasian adults in South Africa were sequenced and extensively analysed for genetic variations. Africans were found to be more polymorphic in both genes with 25 single nucleotide polymorphisms (SNPs) in the CCL3 gene and 14 gene copy number single nucleotide polymorphisms (gcnSNPs) in the CCL3L gene, compared to nine CCL3 SNPs and eight CCL3L gcnSNPs in Caucasians. A total of 14 polymorphisms across the two genes were newly identified in this study, most (12/14) of which were exclusive to the African population. In addition, two indels were identified and characterized in the CCL3 and CCL3L genes of a small number of individuals. Of the numerous unique intragenic haplotypes found in the two genes, none were shared by the two population groups. A newly identified five‐SNP CCL3 haplotype (Hap‐C1) found in a high frequency in Caucasians, however, seems to be evolutionarily related to the most prevalent newly identified African seven‐SNP CCL3 haplotype (Hap‐A1). Hap‐A1 also includes an SNP in the core promoter region and previous CCL3 haplotypes that have been reported to be associated with HIV‐1 infection appear to be smaller haplotypes within Hap‐A1. We thus propose Hap‐A1 as a likely candidate for influencing levels of CCL3 production and in turn outcomes of HIV‐1 infection.     

Comprehensive analysis of HIV Gag‐specific IFN‐γ response in HIV‐1‐ and HIV‐2‐infected asymptomatic patients from a clinical cohort in The Gambia

Majority of HIV‐2‐infected individuals meet the criteria of long‐term non‐progressors. This has been linked to superior qualitative HIV‐2‐specific cellular immune responses that correlate with viral control. However, it is unknown whether this is due to frequent targeting of immunodominant Gag epitopes in HIV‐2 than HIV‐1 infection. We describe a comprehensive comparison of the magnitude, breadth and frequency of Gag responses and the degree of cross‐recognition of frequently targeted, immunodominant Gag peptides in a cross‐sectional study of asymptomatic HIV‐1‐ and HIV‐2‐infected individuals. Fresh PBMC from 20 HIV‐1‐ and 20 HIV‐2‐infected patients with similar CD4⁺ T‐cell counts (p=0.36) were stimulated with pools of HIV‐1 and/or HIV‐2 Gag peptides in an IFN‐γ ELISPOT assay. We found no difference in the cumulative magnitude of IFN‐γ responses (p=0.75) despite significantly lower plasma viral loads in HIV‐2‐infected people (p<0.0001). However, Gag211–290 was targeted with significantly higher magnitude in HIV‐2‐infected subjects (p=0.03) although this did not correlate with viral control. There was no difference in frequently targeted Gag peptides, the breadth, immunodominance or cross‐recognition of Gag peptide pools between the two infections. This suggests that other factors may control viral replication in HIV‐2 infection.     

Investigation of pre‐diagnostic virological markers for progressive multifocal leukoencephalopathy in human immunodeficiency virus‐infected patients

Progressive multifocal leukoencephalopathy (PML) is a severe neurological disorder due to JC virus (JCV) infection. Pre‐diagnostic biological markers and risk factors for PML are not well understood. We conducted a case–control study nested within the Multicenter AIDS Cohort Study to examine the association between JCV viruria and viremia and serum antibody to JCV capsids, in relation to subsequent PML diagnoses, 5 months to 12 years later. Other demographic and immunologic factors were also examined. The study population included 28 incident cases of PML, 26 matched HIV‐positive controls, and 50 HIV‐negative controls. Prevalence of JCV viruria was 37% in cases, 42% in HIV‐positive controls, and 28% in HIV‐negative controls (P = 0.43). Among persons with JCV viruria, persistent viruria was more common in cases (89%) than in HIV‐positive controls (33%) (P = 0.02). Presence of JCV viruria was not related to the time to PML diagnosis (OR: 1.03, 95% CI: 0.8–1.4); however, the urinary concentration of JCV DNA increased with proximity to the date of PML diagnosis in cases. JCV seropositivity did not differ between cases or controls (P = 0.42). Four cases tested JCV seronegative, including one case only 5 months prior to diagnosis with PML. JCV DNA was detected in the serum of one HIV‐positive control. Smoking was the only demographic variable analyzed associated with an increased risk for PML (MOR: 9.0, 95% CI: 1.2–394.5). The results suggest that persistent JCV viruria and increasing urinary concentration of JCV DNA may be predictive of PML for some patients. J. Med. Virol. 81:1140–1150, 2009. © 2009 Wiley‐Liss, Inc.     

Infant CD4 C868T polymorphism is associated with increased human immunodeficiency virus (HIV-1) acquisition

The C868T single nucleotide polymorphism (SNP) in the CD4 receptor encodes an amino acid change that could alter its structure and influence human immunodeficiency virus (HIV‐1) infection risk. HIV‐1‐infected pregnant women in Nairobi were followed with their infants for 1 year postpartum. Among 131 infants, those with the 868T allele were more likely than wild‐type infants to acquire HIV‐1 overall [hazard ratio (HR) = 1·92, 95% confidence interval (CI) 1·05, 3·50, P = 0·03; adjusted HR = 2·03, 95% CI 1·03, 3·98, P = 0·04], after adjusting for maternal viral load. This SNP (an allele frequency of ～15% in our cohort) was associated with increased susceptibility to mother‐to‐child HIV‐1 transmission, consistent with a previous study on this polymorphism among Nairobi sex workers.     

Meta‐analysis of association between obsessive‐compulsive disorder and the 3′ region of neuronal glutamate transporter gene SLC1A1

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive‐compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3′ end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male‐only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome‐wide association and meta‐analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non‐significant corrected P). Secondary analyses of male‐affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non‐significant corrected P). Findings of this meta‐analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta‐analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next‐generation sequencing may be beneficial in examining the potential role of rare variants in OCD. © 2013 Wiley Periodicals, Inc.     

Impact of variants of MMP‐7(‐181A>G) gene in susceptibility to the development of HIV‐associated neurocognitive disorder and its severity

The HIV‐1‐induced neurological toxicity has been associated with the deficiency of matrix metalloproteinases. Tat protein of HIV up regulates MMP‐7 release and activation, leading to neurotoxicity. The SNP ‐181A>G of MMP‐7 is known to have functional effects on its promoter activity. Therefore, we aimed to evaluate the association of variants of MMP‐7 ‐181A>G gene in HIV‐associated neurocognitive disorder (HAND). In the present case–control study, we recruited 50 HIV‐infected individuals with HAND, 130 HIV‐infected individuals without HAND and 150 unrelated healthy individuals. Polymorphism for MMP‐7 ‐181A>G gene was genotyped by PCR‐RFLP method. Frequency of ‐181GG and G allele of MMP‐7 did not differ significantly between patients with HAND and without HAND (8.0% vs 13.1%, p = 0.22 and 31% vs 38.1%, p = 0.21). Individuals with ‐181 AG, ‐181GG genotype, and G allele of MMP‐7 were found to have reduced the risk of development of HAND but not significant (50.0% vs 51.9%, p = 0.09, OR = 0.54; 13.1% vs 19.0%, p = 0.33, OR = 0.71 and 38.1% vs 44.9%, p = 0.09, OR = 0.75). Individuals in early HIV disease stage having ‐181AG genotype and ‐181AG + GG combined genotype of MMP‐7 were not associated with the development of HAND (OR = 1.27, p = 0.25 and OR = 1.25, p = 0.17). Tobacco and alcohol consumption among individuals with any genotype of MMP‐7 was not associated with the risk of development of HAND. In conclusion, individuals with ‐181GG genotype and G allele had no impact on susceptibility to the development of HAND and its severity.     

Investigation of linkage and association/linkage disequilibrium of HLA A‐, DQA1‐, DQB1‐, and DRB1‐alleles in 69 sib‐pair‐ and 89 trio‐families with schizophrenia

The hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib‐pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA‐ DRB1*11 (chi‐square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301—DQA1*501—DRB1*11 (chi‐square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 trios with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31. © 2002 Wiley‐Liss, Inc.     

Genetic variants of immunoglobulin γ and κ chains influence humoral immunity to the cancer‐testis antigen XAGE‐1b (GAGED2a) in patients with non‐small cell lung cancer

GM (γ marker) allotypes, genetic variants of immunoglobulin γ chains, have been reported to be associated strongly with susceptibility to lung cancer, but the mechanism(s) underlying this association is not known. One mechanism could involve their contribution to humoral immunity to lung tumour‐associated antigens. In this study, we aimed to determine whether particular GM and KM (κ marker) allotypes were associated with antibody responsiveness to XAGE‐1b, a highly immunogenic lung tumour‐associated cancer‐testis antigen. Sera from 89 patients with non‐small cell lung cancer (NSCLC) were allotyped for eight GM and two KM determinants and characterized for antibodies to a synthetic XAGE‐1b protein. The distribution of various GM phenotypes was significantly different between XAGE‐1b antibody‐positive and ‐negative patients (P = 0·023), as well as in the subgroup of XAGE‐1b antigen‐positive advanced NSCLC (P = 0·007). None of the patients with the GM 1,17 21 phenotype was positive for the XAGE‐1b antibody. In patients with antigen‐positive advanced disease, the prevalence of GM 1,2,17 21 was significantly higher in the antibody‐positive group than in those who lacked the XAGE‐1b antibody (P = 0·026). This phenotype also interacted with a particular KM phenotype: subjects with GM 1,2,17 21 and KM 3,3 phenotypes were almost four times (odds ratio = 3·8) as likely to be positive for the XAGE‐1b antibody as the subjects who lacked these phenotypes. This is the first report presenting evidence for the involvement of immunoglobulin allotypes in immunity to a cancer‐testis antigen, which has important implications for XAGE‐1b‐based immunotherapeutic interventions in lung adenocarcinoma.     

The rs6983267 SNP and long non‐coding RNA CARLo‐5 are associated with endometrial carcinoma

The single nucleotide polymorphism (SNP) rs6983267 and cancer‐associated region long non‐coding RNA (CARLo‐5) are associated with various human cancers. This study aimed to investigate the expression of CARLo‐5 in endometrial carcinoma (EC) and its relationship with clinicopathological features and patient survival. The association of the rs6983267 SNP with EC risk and its involvement in the regulation of CARLo‐5 expression in EC were investigated. The rs6983267 SNP was genotyped by polymerase chain reaction (PCR) and ligase detection reaction in 543 EC patients and 584 controls. The expression of CARLo‐5 in 108 EC tissues and 66 normal endometrial tissues (NETs) was determined using quantitative real‐time PCR. The genotype and allele distributions of the rs6983267 SNP differed significantly between patients and controls. There was a significant correlation between the rs6983267 genotypes and lymph node metastasis of EC patients (P = 0.026). CARLo‐5 expression was significantly higher in EC tissues than in NETs (P < 0.001) and significantly associated with FIGO stage (P = 0.029) and lymph node metastasis (P = 0.030). Patients with high CARLo‐5 expression had significantly shorter overall survival than those with low CARLo‐5 expression (P = 0.003). The rs6983267 genotype was significantly correlated with CARLo‐5 expression (P < 0.05). In conclusion, CARLo‐5 was identified as a pro‐oncogenic lncRNA that may play an important role in EC progression and represent a prognostic marker for EC. The expression of CARLo‐5 was significantly correlated with the rs6983267 genotype associated with increased susceptibility to EC. Environ. Mol. Mutagen. 57:508–515, 2016. © 2016 Wiley Periodicals, Inc.     

Dimorphic HLA‐B signal peptides differentially influence HLA‐E‐ and natural killer cell‐mediated cytolysis of HIV‐1‐infected target cells

As a mechanism of self‐protection, signal peptides cleaved from human leukocyte antigen (HLA) class I products bind to HLA‐E before the complex interacts with the natural killer (NK) cell receptor CD94/NKG2A to inhibit NK‐mediated cell lysis. Two types of the signal peptides differ in their position 2 (P2) anchor residue, with P2‐methionine (P2‐M) having higher HLA‐E binding affinity than P2‐threonine (P2‐T). All HLA‐A and HLA‐C molecules carry P2‐M, whereas HLA‐B products have either P2‐M or P2‐T. Epidemiological evidence suggests that P2‐M is unfavourable in the context of HIV‐1 infection, being associated with accelerated acquisition of HIV‐1 infection in two African cohorts. To begin elucidating the functional mechanism, we studied NK‐mediated killing of CD4⁺ T cells and monocyte‐derived macrophages infected with two laboratory‐adapted HIV‐1 strains and two transmitted/founder (T/F) viruses. In the presence of target cells derived from individuals with the three HLA‐B P2 genotypes (M/M, M/T and T/T), NK‐mediated cytolysis was elevated consistently for P2‐T in a dose‐dependent manner for all cell and virus combinations tested (P = 0·008–0·03). Treatment of target cells with an anti‐HLA‐E monoclonal antibody restored NK‐mediated cytolysis of cells expressing P2‐M. Observations on cell lysis were also substantiated by measurements of HIV‐1 p24 antigen in the culture supernatants. Overall, our experiments indicate that the anti‐HIV‐1 function mediated by NK cells is compromised by P2‐M, corroborating the association of HLA‐B genotype encoding P2‐M with accelerated HIV‐1 acquisition.     

Linkage and association on 8p21.2‐p21.1 in schizophrenia

In the past decade, we and others have consistently reported linkage to a schizophrenia (SZ) susceptibility region on chromosome 8p21. Most recently, in the largest SZ linkage sample to date, a multi‐site international collaboration performed a SNP‐based linkage scan (～6,000 SNPs; 831 pedigrees; 121 from Johns Hopkins (JHU)), that showed the strongest evidence for linkage in a 1 Mb region of chr 8p21 from rs1561817 to rs9797 (Z_max = 3.22, P = 0.0004) [Holmans et al. 2009. Mol Psychiatry]. We have investigated this 8p21 peak region further in two ways: first by linkage and family‐based association in 106 8p‐linked European‐Caucasian (EUC) JHU pedigrees using 1,402 SNPs across a 4.4 Mb region surrounding the peak; second, by an independent case‐control association study in the genetically more homogeneous Ashkenazim (AJ) (709 cases, 1,547 controls) using 970 SNPs in a further narrowed 2.8 Mb region. Family‐based association analyses in EUC pedigrees and case‐control analyses in AJ samples reveal significant associations for SNPs in and around DPYSL2 and ADRA1A, candidate genes previously associated with SZ in our work and others. Further, several independent gene expression studies have shown that DPYSL2 is differentially expressed in SZ brains [Beasley et al. 2006. Proteomics 6(11):3414–3425; Edgar et al. 2000. Mol Psychiatry 5(1):85–90; Johnston‐Wilson et al. 2000. Mol Psychiatry 5(2):142–149] or in response to psychosis‐inducing pharmaceuticals [Iwazaki et al. 2007. Proteomics 7(7):1131–1139; Paulson et al. 2004. Proteomics 4(3):819–825]. Taken together, this work further supports DPYSL2 and the surrounding genomic region as a susceptibility locus for SZ. © 2010 Wiley‐Liss, Inc.     

Immune escape of γ‐herpesviruses from adaptive immunity

Epstein–Barr virus (EBV) and Kaposi's sarcoma‐associated herpesvirus (KSHV) are two γ‐herpesviruses identified in humans and are strongly associated with the development of malignancies. Murine γ‐herpesvirus (MHV‐68) is a naturally occurring rodent pathogen, representing a unique experimental model for dissecting γ‐herpesvirus infection and the immune response. These γ‐herpesviruses actively antagonize the innate and adaptive antiviral responses, thereby efficiently establishing latent or persistent infections and even promoting development of malignancies. In this review, we summarize immune evasion strategies of γ‐herpesviruses. These include suppression of MHC‐I‐restricted and MHC‐II‐restricted antigen presentation, impairment of dendritic cell functions, downregulation of costimulatory molecules, activation of virus‐specific regulatory T cells, and induction of inhibitory cytokines. There is a focus on how both γ‐herpesvirus‐derived and host‐derived immunomodulators interfere with adaptive antiviral immunity. Understanding immune‐evasive mechanisms is essential for developing future immunotherapies against EBV‐driven and KSHV‐driven tumors. Copyright © 2014 John Wiley & Sons, Ltd.     

APOBEC3B deletion impacts on susceptibility to acquire HIV‐1 and its advancement among individuals in western India

APOBEC3B deletion polymorphism has been associated with risk of HIV‐1 acquisition and its progression. Therefore, we aimed to investigate the association of APOBEC3B ins/del polymorphism with risk of acquisition of HIV‐1 and its progression. In the present case–control study, we enrolled a total of 150 HIV‐infected individuals and 150 healthy controls. Polymorphism for APOBEC3B gene was genotyped by PCR. APOBEC3B ID, DD genotypes, and D allele were associated with higher risk of acquisition of HIV‐1 (p = 0.004, OR = 4.96; p = 0.03, OR = 3.55; and p = 0.004; OR = 1.60). The individuals with ID genotypes and combined genotype ID+DD of APOBEC3B in the presence of tobacco and alcohol showed the higher risk of advancement of HIV disease; however, risk could not reach statistical significance (OR = 1.14, 95% CI: 0.59–2.18; OR = 1.33, 95% CI: 0.83–2.15 and OR = 1.44, 95% CI: 0.77–2.69; OR = 1.50, 95% CI: 0.94–2.40). Individuals in advanced HIV disease stage and ID genotype and combined genotype ID + DD of APOBEC3B were more likely to be associated with advanced HIV disease stage but risk could not reach significant (OR = 1.50, 95% CI: 0.94–2.40; OR = 1.27, 95% CI: 0.88–1.84). Individuals with ID and DD genotype of APOBEC3B had influence on susceptibility to acquisition of HIV‐1. This suggests that APOBEC3B deletion may attenuate innate cellular immunity against HIV‐1 and thus confer the host persistence for HIV infection.     

Polymorphisms in pattern‐recognition genes in the innate immunity system and risk of non‐Hodgkin lymphoma

The pattern‐recognition pathway plays an important role in infection recognition and immune responses, and previous studies have suggested an association between genetic variation in innate immunity genes and non‐Hodgkin lymphoma (NHL). We evaluated NHL risk associated with genetic variation in pattern‐recognition genes using data from a case–control study of NHL conducted in Connecticut women. Single nucleotide polymorphisms (SNPs) in 27 pattern‐recognition genes were genotyped in 432 Caucasian incident NHL cases and 494 frequency‐matched controls. Unconditional logistic regression was used to compute odds ratios (ORs) for NHL and common NHL subtypes in relation to individual SNPs and haplotypes. A gene‐based analysis that adjusted for the number of tagSNPs genotyped in each gene showed a significant association with overall NHL for the MBP gene (P = 0.028), with the diffuse large B‐cell lymphoma (DLBCL) subtype for the MASP2 gene (P = 0.011), and with the follicular lymphoma (FL) subtype for DEFB126 (P = 0.041). A SNP‐based analysis showed that MBP rs8094402 was associated with decreased risks of overall NHL (allele risk OR = 0.72, P‐trend = 0.0018), DLBCL (allele risk OR = 0.72, P‐trend = 0.036), and FL (allele risk OR = 0.67, P‐trend = 0.021), while MASP2 rs12711521 was associated with a decreased risk of DLBCL (allele risk OR = 0.57, P‐trend = 0.0042). We also observed an increased risk of FL for DEFB126 rs6054706 (allele risk OR = 1.39, P‐trend = 0.033). Our results suggest that genetic variation in pattern‐recognition genes is associated with the risk of NHL or specific NHL subtypes, but these preliminary findings require replication in larger studies. Mol. Mutagen. 2013. © 2012 Wiley Periodicals, Inc.     

Programmed death (PD)‐1 molecule and its ligand PD‐L1 distribution among memory CD4 and CD8 T cell subsets in human immunodeficiency virus‐1‐infected individuals

Human immunodeficiency virus (HIV)‐1 causes T cell anergy and affects T cell maturation. Various mechanisms are responsible for impaired anti‐HIV‐1‐specific responses: programmed death (PD)‐1 molecule and its ligand PD‐L1 are negative regulators of T cell activity and their expression is increased during HIV‐1 infection. This study examines correlations between T cell maturation, expression of PD‐1 and PD‐L1, and the effects of their blockade. Peripheral blood mononuclear cells (PBMC) from 24 HIV‐1⁺ and 17 uninfected individuals were phenotyped for PD‐1 and PD‐L1 expression on CD4⁺ and CD8⁺ T cell subsets. The effect of PD‐1 and PD‐L1 blockade on proliferation and interferon (IFN)‐γ production was tested on eight HIV‐1⁺ patients. Naive (CCR7⁺CD45RA⁺) CD8⁺ T cells were reduced in HIV‐1 aviraemic (P = 0·0065) and viraemic patients (P = 0·0130); CD8 T effector memory subsets [CCR7^‐CD45RA^–(T_EM)] were increased in HIV‐1⁺ aviraemic (P = 0·0122) and viraemic (P = 0·0023) individuals versus controls. PD‐1 expression was increased in CD4 naive (P = 0·0496), central memory [CCR7⁺CD45RA^– (T_CM); P = 0·0116], T_EM (P = 0·0037) and CD8 naive T cells (P = 0·0133) of aviraemic HIV‐1⁺versus controls. PD‐L1 was increased in CD4 T_EMRA (CCR7^‐CD45RA⁺, P = 0·0119), CD8 T_EM (P = 0·0494) and CD8 T_EMRA (P = 0·0282) of aviraemic HIV‐1⁺versus controls. PD‐1 blockade increased HIV‐1‐specific proliferative responses in one of eight patients, whereas PD‐L1 blockade restored responses in four of eight patients, but did not increase IFN‐γ‐production. Alteration of T cell subsets, accompanied by increased PD‐1 and PD‐L1 expression in HIV‐1 infection contributes to anergy and impaired anti‐HIV‐1‐specific responses which are not rescued when PD‐1 is blocked, in contrast to when PD‐L1 is blocked, due possibly to an ability to bind to receptors other than PD‐1.     

Association analysis of −416 G>C polymorphism of T‐cell immunoglobulin and mucin domain‐1 gene with asthma in Iran

TIM (T‐cell immunoglobulin (Ig) and mucin domain)‐1, one of the members of TIM family, expresses on Th2 cells and promotes the production of Th2 signature cytokines. This can increase a series of responses in these cells which could be one of the causes of asthma or asthma‐related phenotypes. The aim of this study was to investigate whether a TIM‐1 promoter single nucleotide polymorphism (SNP), ?416 G>C, is associated with asthma in Iranian population. In this case–control study, existence of the ?416 G>C polymorphism was assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) in 300 patients with asthma (97 atopic, 203 nonatopic) and 309 healthy volunteers. Additionally, the relationship between these polymorphism genotypes and total serum IgE levels in this Iranian population was evaluated. We discovered a significant association between the ?416 G>C polymorphism and atopic asthma susceptibility in the population, but this SNP showed no connection with nonatopic asthma (P < 0.05). However, our results showed significant relation between this polymorphism and serum IgE level (P < 0.05). Our results suggest that ?416 G>C polymorphism in TIM‐1 gene could be a predisposing factor for atopic asthma in Iranian population, and CC genotype of this SNP can be associated with increased level of IgE in patients with asthma in the same population.     

Bacillus‐derived poly‐γ‐glutamic acid attenuates allergic airway inflammation through a Toll‐like receptor‐4‐dependent pathway in a murine model of asthma

Background Asthma is an inflammatory disease of the airways that is mediated by Th2 responses. Poly‐γ‐glutamic acid (γ‐PGA) is an extracellular polymeric compound that is synthesized by Bacillus cells. Previously, we found that γ‐PGA promoted Th1 cell development in a manner dependent on antigen‐presenting cells, but inhibited Th2 cell development. Objective To investigate the effect of γ‐PGA on dendritic cells (DCs), and its potential for treating Th2‐mediated allergic asthma. Methods Wild‐type, Toll‐like receptor (TLR)‐2 deficient, and TLR‐4‐defective mice were used. DCs derived from the bone marrow and extracted from the lung were stimulated with γ‐PGA and assayed for the expression of signalling molecules, costimulatory molecules, and cytokines. Mice were sensitized and challenged with ovalbumin (OVA) to induce asthma. They were repeatedly injected intranasally with γ‐PGA before and during the challenge period, and inflammation and structural remodelling of the airways were examined. Results γ‐PGA selectively signalled conventional DCs to activate NF‐κB and mitogen‐activated protein kinase, leading to the up‐regulation of CD86, CD40, and IL‐12, but not IL‐10 and IL‐6. These effects of γ‐PGA were dependent on TLR‐4 and independent of TLR‐2. Importantly, the intranasal administration of γ‐PGA to OVA‐sensitized/challenged mice reduced the airway hyperresponsiveness and allergic inflammation such as leucocyte influx, goblet cell hyperplasia, eosinophilia, and Th2 cytokine production. In addition to lowered IgE titres, the treatment of mice with γ‐PGA significantly reduced the multiplication and Th2 polarization of mediastinal lymph node T cells upon allergen‐specific restimulation. These anti‐asthmatic effects of γ‐PGA were also abolished in TLR‐4‐defective mice. Conclusions and Clinical Relevance Our data indicate that γ‐PGA activates DCs to favour Th1 cell induction through a TLR‐4‐dependent pathway and alleviates pathologic symptoms in a Th2‐biased asthmatic model. These findings highlight the potential of γ‐PGA for the treatment of asthma and other allergic disease in which Th2 polarization plays an important role. Cite this as: K. Lee, S.‐H. Kim, H. J. Yoon, D. J. Paik, J. M. Kim and J. Youn, Clinical & Experimental Allergy, 2011 (41) 1143–1156.