Cytotoxic T Lymphocyte-associated Antigen-4 Gene Research Articles

Cytotoxic T lymphocyte‐associated antigen‐4 (CTLA-4) gene polymorphisms in a cohort of Egyptian patients with immune thrombocytopenia (ITP)

BackgroundImmune thrombocytopenia (ITP) is characterized by immune response dysregulations. Cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) plays a central role in immune checkpoint pathways and preventing autoimmune diseases by regulating immune tolerance. We aimed to explore the potential association between CTLA-4 gene polymorphisms and ITP as well as study their impact on the response to therapy.MethodsWe investigated two CTLA-4 single‐nucleotide polymorphisms (SNPs; rs: 231775 and rs: 3087243) using real-time PCR as well as the plasma levels of CTLA-4 by ELISA in 88 patients with ITP and 44 healthy participants (HC).ResultsCTLA-4 (rs: 3087243) A > G polymorphism analysis showed most HC had the homozygous AA genotype, which was statistically significant compared to patients with ITP. Plasma levels of CTLA4 were statistically lower in patients with acute ITP. There was no correlation between CTLA-4 (rs: 231775 and rs: 3087243) A/G SNPs were not correlated to the response to all lines of therapy assessed (corticosteroids, thrombopoietin receptor agonists, splenectomy, and rituximab).ConclusionCTLA-4 CT 60 A/G may affect the susceptibility of ITP, but both CTLA-4 + 49 A/G and CT60 A/G did not impact the response of patients with ITP to different lines of therapy.

Correlation of CTLA-4 polymorphism and the risk of gastric cancer in a Chinese Bai population.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is involved in the regulation of immune responses mediated by T cells. This study aimed to explore the correlation between CTLA-4 gene polymorphisms and the risk of gastric cancer (GC) in the Bai minority population of southwestern China. A total of 422 GC patients and 397 healthy controls (HC) were included in this case-control study. Four single nucleotide polymorphism sites of CTLA-4 gene (rs231775, rs733618, rs16840252 and rs3087243) were selected and analysed. The results showed a significant difference in the rs733618 loci between GC and HC groups. The frequency of the rs733618 polymorphism 'TC' genotype was significantly lower in GC group compared to the HC group [odds ratio (OR), 95% confidence interval (CI): .47 (.35-.63), p<.001]. GC cases with dominant genetic model 'TC+CC' had a 47% reduced risk of GC [OR, 95%CI: .53 (.40-.71), p<.001]. Subgroup analyses revealed that the rs733618 'TC+CC' genotype was associated with a lower risk of GC in male patients [OR, 95%CI: .42 (.31-.58), p<.001], those aged ≤60 years old [OR, 95%CI: .27 (.18-.42), p<.001], non-drinkers [OR, 95%CI: .21 (.13-.33), p<.001], non-smokers [OR, 95%CI: .38 (.25-.57), p<.001] and individuals without Helicobacter pylori infection [OR, 95%CI: .16 (.10-.26), p<.001]. Further multivariated analyses indicated that individuals with the 'TC+CC' rs733618 genotype who were aged ≤60 years old [OR, 95%CI: .42 (.29-.83), p=.032] and had no H. pylori infection [OR, 95%CI: .35 (.28-.76), p=.018] were found to have a protective effect against GC. Additionally, soluble CTLA-4 were significantly lower in GC patients with 'TC' and 'TC+CC' genotypes (all p<.05). Our findings suggest that the rs733618 polymorphism of CTLA-4 gene may play a critical role in the prevention of GC.

Meta-analysis of the rs231775 locus polymorphism in the CTLA-4 gene and the susceptibility to Graves' disease in children.

The aim of this study was to systematically evaluate the correlation between the rs231775 locus polymorphism in the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene and genetic susceptibility to Graves' disease (GD) in children. Some studies found that the CTLA-4 gene polymorphism was associated with GD in children. The data up to February 2022 were retrieved from the databases. Stata 15.0 software was used for meta-analysis. A total of seven studies were included in our research. The results of the meta-analysis showed that the rs231775 locus polymorphism in the CTLA-4 gene in general and Asian populations was correlated with children's susceptibility to GD (A vs G: OR = 0.75, 95% CI (0.660-0.86); GG vs AA: OR = 1.34, 95% CI (1.04-1.73); AG vs AA: OR = 1.32, 95% CI (1.02-1.10); AG + GG vs AA: OR = 3.81, 95% CI (2.17-6.70); GG vs AA + AG: OR = 1.23, 95% CI (1.05-1.45)). In summary, the rs231775 locus polymorphism in the CLTA-4 gene may be a risk factor for GD in Asian children. The G allele may be a susceptibility factor, while the allele A may be a protective factor against GD in Asian children. In the future, more large-scale studies may be needed to verify our results.

Reduced Number of Thymoma CTLA4-Positive Cells Is Associated With a Higher Probability of Developing Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune disease associated with comorbid thymoma in 10%-15% of cases. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) expressed by T cells downregulates T-cell-mediated immune response. Polymorphisms in the CTLA4 gene have been associated with the development of MG. In this context, we aimed to determine whether CTLA4 expression in the thymoma differs between patients with and without MG and whether CTLA4 gene polymorphisms are associated with these differences. This is a retrospective study of all patients, with and without MG, surgically treated at our institution for thymoma between January 2010 and December 2020. Ten samples were obtained from normal thymuses as controls. The number of CTLA4-positive cells in paraffin-embedded thymoma samples was determined by immunohistochemistry. The presence of follicular-center and regulatory T-cell lymphocytes was determined by immunohistochemistry (B-cell lymphoma [BCL]-6 expression) and double immunofluorescence-based staining of CD4-FOXP3, respectively. We evaluated the association between thymic expression of CTLA4 and the development of MG. We also determined the association between CTLA4 expression and various clinical and prognostic characteristics of MG. We sequenced the CTLA4 gene and evaluated possible associations between CTLA4 polymorphisms and thymic CTLA4 expression. Finally, we assessed the potential association between these polymorphisms and the risk of MG. Forty-one patients with thymoma were included. Of them, 23 had comorbid MG (56.1%). On average, patients with MG had fewer CTLA4-positive cells in the thymoma than non-MG patients: 69.3 cells/mm2 (95% CIs: 39.6-99.1) vs 674.4 (276.0-1,024.0) cells/mm2; p = 0.001 and vs controls (200.74 [57.9-343.6] cells/mm2; p = 0.02). No between-group differences (MG vs non-MG) were observed in the number of cells positive for BCL6 or CD4-FOXP3. CTLA4 expression was not associated with differences in MG outcome or treatment refractoriness. Two polymorphisms were detected in the CTLA4 gene, rs231770 (n = 30 patients) and rs231775 (n = 17). MG was present in a similar proportion of patients for all genotypes. However, a nonsignificant trend toward a lower CTLA4-positive cell count was observed among carriers of the rs231775 polymorphism vs noncarriers: 77.9 cells/mm2 (95% CI: -51.5 to 207.5) vs 343.3 cells/mm2 (95% CI: 126.2-560.4). Reduced CTLA4 expression in thymoma may predispose to a higher risk of developing MG.

CTLA4 haploinsufficiency caused by a novel heterozygous splice site mutation

Background: Cytotoxic T lymphocyte-associated antigen-4 (CTLA4) haploinsufficiency is characterized by a variety of phenotypes, ranging from autoimmune disorders, enteropathy, fatal combined immunodeficiency, as well as lymphoproliferation and malignancy. Aim: To broaden the genotypic spectrum and clinical presentations of patients with CTLA4 variants. Methods: We evaluated a female patient with autoimmunity and lymphopenia. Immune workup and whole exome sequencing (WES) were performed. Results: The proband presented at 11 years of age with hypothyroidism and later developed Evans syndrome, alopecia, eczema, and lymphocytic interstitial pneumonia. Immune evaluation revealed T, B, and NK lymphopenia with normal humoral immunity. Following a negative genetic panel for autoimmune lymphoproliferative syndrome (ALPS), WES analysis identified a novel heterozygous intronic variant predicted in-silico to cause skipping of exon 2 of the CTLA4 gene. Conclusion: A novel heterozygous mutation in CTLA4 caused variable presentations of immune dysregulation, one of the hallmarks of CTLA4 haploinsufficiency. Statement of Novelty: We herein report a novel mutation in CTLA4 resulting in various features of autoimmunity.

The Association of CTLA-4 rs231775 and rs3087243 Polymorphisms with Latent Autoimmune Diabetes in Adults: A Meta-Analysis.

Polymorphisms rs231775 and rs3087243 of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene have been associated with risk of latent autoimmune diabetes in adults (LADA). However, the results were inconsistent. The purpose of this study was to quantitatively assess the relationship between polymorphisms rs231775 and rs3087243 of CTLA-4 and LADA in a larger pooled population by performing a meta-analysis. Systematic search for eligible studies was conducted in PubMed, Web of Science, and Embase. Case-control studies containing genotype frequencies of polymorphisms rs231775 or rs3087243 were selected, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the associations between polymorphisms of CTLA-4 and LADA in allelic, dominant and recessive genetic model. A total of eleven studies, in which five studies reported rs231775, two studies reported rs3087342, and four studies reported both rs231775 and rs3087243, were identified. Among them, one study wasn't included in the following meta-analysis because the distribution of genotypes in the control group didn't comply with Hardy-Weinberg equilibrium. Significant associations with susceptibility to LADA were detected for rs231775 (785 cases and 3435 controls) and for rs3087243 (820 cases and 4824 controls) in overall population. Further subgroup analyses for ethnicity (Asian, Caucasian, and African) have also indicated the positive association between rs231775 and LADA. As for rs3087243, subgroup analyses detected the association between polymorphism and LADA in Caucasian population under recessive model. Polymorphisms rs231775 and rs3087243 of CTLA-4 gene are potential risk factors for LADA and may serve as novel genetic biomarkers of LADA.

Analysis of CTLA-4 -318C/T Polymorphism in Thalassemia Patients Transfused at the Casablanca Children's Hospital (Morocco)

Red blood cells (RBC) alloimmunization is a delayed adverse transfusion reaction in thalassemia patients. The mechanisms behind the inhibition or tolerance of red blood cells are still poorly understood. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) molecule is expressed on Treg -lymphocyte membrane and is an inhibitory molecule which plays the mediator role of peripheral tolerance and maintains tolerance to self-antigens. Recent studies have reported that defect in the CTLA-4 gene expression could affect its function and be involved in the development of various pathologies as autoimmune diseases and the outcome after Allogenic hematopoietic stem cell transplantation; indeed, the objective of our study is the search for the association of the CTLA-4 polymorphism with the susceptibility to red blood cells alloimmunizations. In this study we looked for the polymorphism of the CTLA-4 gene at the -318 C/T position in 35 β-thalassemic patients (15alloimmunized and 20 non alloimunized) followed at the children's hospital in Casablanca, and 20 healthy controls, by PCR-RFLP and Sanger sequencing. In our cohort, none of the group cases revealed the mutation carried out by PCR RFLP. Indeed, this result was confirmed by Sanger sequencing. This study does not find an association of -318C/T SNPs in CTLA-4 gene and RBC alloimmunization among our cohort. Following these preliminary results, an investigation of the other exons of the CTLA-4 gene on a large cohort is necessary to complete this study.

Otoimmün tiroid hastalıklarında CTLA-4 geninin in silico analizinin değerlendirilmesi

Giriş: CTLA-4 (sitotoksik T-lenfosit ilişkili antijen 4) geni, immünoglobulin gen süper ailesinin bir üyesidir ve T hücrelerine inhibe edici bir sinyal ileten proteini kodlamaktadır. Son günlerde immün kontrol noktası olan CTLA-4 geni araştırılan genler arasındadır. Bu çalışmada amaç; CTLA-4 geninde oluşan çeşitli polimorfizmlerin, CTLA-4 geni ile benzer genlerin Otoimmün Tiroid Hastalığı (OTH) patogenezine katkıda bulunabileceğini in silico olarak değerlendirmektir. Gereç ve Yöntem: Çalışmamızda CTLA-4 geni ile benzer genleri bulmak için GeneMania ve STRING veri tabanları, tek nükleotid polimorfizmlerini (SNP’leri) bulmak için Polyphen2, Exome Variant Server ve SIFT veritabanları, mikro RNA’ları tespit etmek için; miRDB ve miRWalk veritabanları kullanıldı. Bulgular: Çalışmamızdan elde ettiğimiz verilere göre; FYN geninin OTH’nın patogenezine katkıda bulunabileceğini, CTLA-4 geniyle ilişkili (rs201778935, rs138279736, rs369567630 ve rs376038796) şüpheli SNP’lerin olduğunu tespit ettik. Sonuç: Çalışmamızda 31 miRNA’nın mesajcı RNA’ların protein üretmesini düzenleyici rol üstlendiğinden, terapötik açıdan önemli olduğunu düşünmekteyiz. Biyoinformatik yöntemlerle değerlendirdiğimiz bu çalışma, ilerde laboratuvar ortamında uygulanarak, birçok hastalığın patogenezinin aydınlatılmasına katkıda bulunabileceğini düşünmekteyiz.

CTLA-4 rs5742909 polymorphism and cervical cancer risk: A meta-analysis.

Background:Number of studies have been performed to evaluate the relationship between the cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) gene variant rs5742909 polymorphism and cervical cancer risk, but the sample size was small and the results were conflicting. This meta-analysis was conducted to comprehensively evaluate the overall association.Methods:PubMed, Web of Science, Embase, China Biology Medical Literature database, China National Knowledge Infrastructure, WanFang, and Weipu databases were searched before July 31, 2018. The strength of associations was assessed using odds ratios (ORs) and 95% confidence intervals (CIs). All of the statistical analyses were conducted using Review Manager 5.3 and Stata 14.0.Results:Eleven studies involved 3899 cases and 4608 controls. Overall, significant association was observed between the CTLA-4 gene variant rs5742909 polymorphism and cervical cancer (T vs C: OR = 1.40, 95% CI = 1.12–1.76; TT vs CC: OR = 2.22, 95% CI = 1.13–4.37; TT vs CT+CC: OR = 1.96, 95% CI = 1.03–3.74; TT+CT vs CC: OR = 1.47, 95% CI = 1.14–1.90). In subgroup analysis by ethnic group, a statistically significant association was observed in Asians (T vs C: OR = 1.56, 95% CI = 1.22–1.99), but not in Caucasians (T vs C: OR = 1.19, 95% CI = 0.87–1.62). The sensitivity analysis confirmed the reliability and stability of the meta-analysis.Conclusion:our meta-analysis supports that the CTLA-4 gene variant rs5742909 polymorphism might contribute to individual susceptibility to cervical cancer in Asians.

Associations between cytotoxic T-lymphocyte-associated antigen 4 gene polymorphisms and diabetes mellitus: a meta-analysis of 76 case-control studies.

Background: Several genetic association studies already investigated potential roles of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms in diabetes mellitus (DM), with inconsistent results. Therefore, we performed this meta-analysis to better assess the relationship between CTLA-4 gene polymorphisms and DM in a larger pooled population.Methods: PubMed, Embase, Web of Science, and CNKI were systematically searched for eligible studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of associations between CTLA-4 gene polymorphisms and DM in all possible genetic models.Results: A total of 76 studies were finally included in our analyses. Significant associations with susceptibility to type 1 diabetes mellitus (T1DM) were detected for rs231775 (dominant model: P=0.008, OR = 0.83, 95%CI 0.73–0.95; recessive model: P=0.003, OR = 1.27, 95%CI 1.09–1.50; allele model: P=0.004, OR = 0.85, 95%CI 0.77–0.95) and rs5742909 (recessive model: P=0.02, OR = 1.50, 95%CI 1.05–2.13) polymorphisms in overall population. Further subgroup analyses revealed that rs231775 polymorphism was significantly associated with susceptibility to T1DM in Caucasians and South Asians, and rs5742909 polymorphism was significantly associated with susceptibility to T1DM in South Asians. Moreover, rs231775 polymorphism was also found to be significantly associated with susceptibility to type 2 diabetes mellitus (T2DM) in East Asians and South Asians.Conclusions: Our findings indicated that rs231775 and rs5742909 polymorphisms may serve as genetic biomarkers of T1DM, and rs231775 polymorphism may also serve as a genetic biomarker of T2DM.

Identification of porcine CTLA4 gene polymorphism and their association with piglet diarrhea and performance traits.

The objective of this study was to evaluate the association between the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) gene and piglet diarrhea. In this study, the mRNA expression of the CTLA4 gene increased significantly in IPEC-J2 cells after Escherichia coli K88 infection. Single nucleotide polymorphisms (SNPs) located in the 5' flanking region (SNPs g.107281989C>T) and 3'-untranslated region (3'-UTR; SNPs g.107288753C>A) were identified, and they were in linkage disequilibrium in both Min pigs and the Landrace population. Association analysis showed that Landrace piglets with a TT or AA genotype had a lower diarrhea index, and AA animals had higher average daily gain when compared to CC pigs, respectively (p < 0.05). However, the relationship between SNPs and diarrhea and performance traits in the Min population was not significant. Haplotype analysis indicated that the TC haplotype had the lowest diarrhea index. The 5' flanking deletion assay suggested that SNP g.107281989C>T was a molecular marker instead of the functional marker. This research demonstrated that genetic variances in the CTLA4 gene had significant effects on Landrace piglet diarrhea resistance.

Determination of mir-155 and mir-146a expression rates and its association with expression level of TNF-α and CTLA4 genes in patients with Behcet’s disease

IntroductionMicroRNAs (miRNAs) are involved in the pathogenesis of inflammatory diseases. MiR-146 and miR-155 emerged as key regulators of the immune response. This study designed to analyze the miR-146a and miR-155 expression in patients with Behcet’s disease (BD) and investigated their association with the expression of tumor necrosis factor-alpha (TNF-α) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) genes. MethodologyIn a case-control study, 47 Iranian Azeri BD patients and 61 age- and sex matched healthy controls recruited to the study. Peripheral blood mononuclear cells (PBMCs) were isolated from EDTA blood tubes by Ficoll density-gradient centrifugation. Genomic DNA samples of BD and healthy controls were extracted using the rapid genomic DNA extraction method from the peripheral blood collected in tubes containing EDTA. Total RNA was extracted from the PBMCs according to the TRIzol protocol. MiR-146a, miR-155, TNF-α and CTLA-4 expression were studied using real-time PCR. ResultsMiR-155 and TNF-α expression was significantly increased, whilst CTLA-4 expression was significantly decreased in the PBMCs of BD patients. There was no significant difference in the miR-146a expression rate between BD patients and controls. A positive correlation between miR-155 and TNF-α expression and negative correlation between miR-155 and CTLA-4 expression were observed. No significant association was observed between the expression of miR-155, miR-146a, TNF-α and CTLA-4 genes with BD activity. MiR-155 and miR-146a expression rate were significantly higher in patients with uveitis and phlebitis, respectively. Discussion and conclusionThe expression of miR-155 increased in BD and associated with upregulation of TNF-α and downregulation of CTLA-4 genes.

Association of cytotoxic T-lymphocyte antigen 4 gene with immune thrombocytopenia in Chinese Han children

ABSTRACTObjectives: To investigate the association of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) with immune thrombocytopenia (ITP).Methods: A case–control association analysis of 277 Chinese Han children was performed. The tagging variants rs11571315 and rs3087243 in the CTLA4 gene were detected using polymerase chain reaction-restriction fragment length polymorphism method. The expression quantitative trait loci (eQTL) analysis and quantitative real-time polymerase chain reaction were performed to determine the relationship of CTLA4 with ITP.Results: Neither SNP was significantly different between case and control groups in either the genotypic or allelic distribution. The eQTL analysis results indicated that in the spleen, the rs3087243 was significant with the expression of CTLA4. The rs11571315 has similar results. Interestingly, the transcript level of CTLA4 was found to significantly decrease in patients with ITP.Discussion: The autoimmune and gene etiology is implicated in the pathogen of ITP. The CTLA4 is important for negative regulation of T-cell activation, and CTLA-4 gene has been identified as a risk factor for some autoimmune diseases. However, association studies of ITP and CTLA4 gene have obtained conflicting results. This is the first study to systematically investigate the association of CTLA4 with ITP in Chinese Han children.Conclusions: The CTLA4 gene is suggested to correlate with ITP through its abnormal expression level instead of gene site mutation.

Genetic association of CTLA4 gene with polycystic ovary syndrome in the Chinese Han population.

The autoimmune and gene etiology are implicated in the pathogenesis of polycystic ovary syndrome (PCOS). The cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is important for negative regulation of T-cell activation, and CTLA4 gene has been identified as a risk factor for some autoimmune diseases. However, none studies have been performed about the association between PCOS and the CTLA4 gene before. Here, we aimed to investigate the association of CTLA4 with PCOS in the Chinese Han population though a case-control association analysis of 606 individuals. The tagging variants rs733618 and rs231775 in the CTLA4 gene were detected using polymerase chain reaction-denaturing gradient gel electrophoresis method. Further analysis found the rs733618 was significantly different between case and control groups in either genotypic or allelic distribution (P = .01 and .009, respectively) while rs231775 not. Moreover, rs733618 was significantly associated with higher body mass index in the dominant model (P = .003) and with higher waist/hip ratio in the recessive model (P = .02). Interestingly, rs733618 was only found to have significant association with homeostatic model assessment for insulin resistance (HOMA-IR) in both dominant and recessive model (P = .009 and .0065, respectively). This is the first study to investigate the association of CTLA4 gene with PCOS. The CTLA4 gene is suggested to correlated with PCOS, and influence PCOS through regulating obesity and the HOMA-IR in a novel way.

Association of the gene polymorphism of cytotoxic T lymphocyte-associated antigen-4with Graves ophthalmopathy in Qinghai Tibetans

To investigate the association of the gene polymorphism of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)with Graves′ ophthalmopathy(GO)in Qinghai Tibetans. 130 case of Graves′ disease(GD)were selected from June 2013 to November 2016 in The People′s Hospital of Qinghai Province. These patients were assigned into 2 groups, GO(n=71)and GD without GO(n=59). The genotypes and alleles of CTLA-4 gene were detected by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). Distribution of CTLA-4 exon 1(+ 49A/G)genotype frequencies(AA, AG, and GG)was different between 2 groups. (Chin J Endocrinol Metab, 2017, 33: 962-964) Key words: Graves′ disease; Polymorphism, restriction fragment length

-318C/T polymorphism of the CTLA-4 gene is an independent risk factor for RBC alloimmunization among sickle cell disease patients.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) molecule is expressed on T-lymphocyte membrane and negatively influences the antigen-presenting process. Reduced expression of CTLA-4 due to gene polymorphisms is associated with increased risk of autoimmune disorders, whose physiopathology is similar to that of post-transfusion red blood cell (RBC) alloimmunization. Our goal was to evaluate if polymorphisms of CTLA-4 gene that affect protein expression are associated with RBC alloimmunization. This was a case-control study in which 134 sickle cell disease (SCD) patients and 253 non-SCD patients were included. All patients were genotyped for the polymorphisms 49A/G and -318C/T of CTLA-4 gene. The genotype frequency of -318C/T differed significantly between alloimmunized and nonalloimmunized SCD patients, irrespective of clinical confounders (p=.016). SCD patients heterozygous for -318T allele presented higher risk of alloantibody development (OR: 5.4, CI: 1.15-25.6). In conclusion, the polymorphism -318C/T of CTLA-4 gene is associated with RBC alloimmunization among SCD patients. This highlights the role played by CTLA-4 on post-transfusion alloantibody development.

Enhance the anti-renca carcinoma effect of a DNA vaccine targeting G250 gene by co-expression with cytotoxic T-lymphocyte associated antigen-4(CTLA-4).

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T cell activation, which competes with CD28 for B7.1/B7.2 binding with a greater affinity. Co-expression specific antigens and extracellular domain of CTLA4 represents a promising approach to increase the immunogenicity of DNA vaccines. In this study, we evaluated this interesting approach for its enhancement on G250/MN/CA IX (G250)-specific immune responses and its anti-tumor effects in renal carcinoma mice model. Consequently, we constructed a DNA vaccine containing the G250 and the CTLA-4 gene. Vaccination with the co-expression DNA not only induced much higher level of anti-CTLA4 and anti-G250 antibody, but also increased G250-specific T cell response in mice. To evaluate the anti-tumor efficacy of the plasmids, murine models with G250-expressing tumors were generated. After injection into the tumor-bearing mouse model, the plasmid carrying the co-expression gene of CTLA4 and G250 showed stronger inhibition of tumor growth than the plasmid expressing CTLA4 or G250 alone. These observations emphasize the potential of the CTLA4 and G250 co-expression DNA vaccine, which could represent a promising approach for tumor immunotherapy.

A novel approach to investigation of the pathogenesis of pterygium based on assessment of promoter hyper-methylation and expression profile of CTLA4 gene: A credible report of CTLA4 gene expression in human eye tissue

BackgroundPterygium is the human eye lesion whose prevalence in the general population is estimated about 2%. The disease, in extreme phase, can lead to visual disturbance and eventually causes complete loss of vision due to the lesion growth over the papillary axis. Pterygium invasive tissue is a tumor-like tissue that is initially identified and then is attacked by cytotoxic T cells. Cytotoxic T lymphocyte associated antigen 4 (CTLA4), as a modulator molecule of the adaptive immune system, plays a critical role in maintaining peripheral T cell tolerance by diminishing its responsiveness and increasing its activation threshold. The aim of this study is to investigate the association between some epigenetic changes of the CTLA4 gene, such as promoter methylation and gene expression, and pathogenesis of pterygia. Materials and methodsGenomic DNA was extracted from 75 formalin-fixed, paraffin-embedded tissues of pterygia and 70 specimens of normal conjunctiva from eyes without pterygium as the control group, collected from Sistan and Baluchestan population. CTLA4 gene promoter methylation was carried out by methylation-specific PCR technique. The gene expression analysis was done on extracted total RNA from 20 healthy and 23 pterygium tissue samples using Real-Time PCR technique. ResultsPromoter methylation changes of CTLA4 gene were not statistically different in patients with pterygium in comparison with healthy controls (OR=1.614; 95% CI=0.57–4.75; P value=0.37). However, gene expression level of CTLA4 was remarkably different in patients and healthy controls (Mean±SD: 1.343±0.133 and 2.027±0.219, respectively; P value=0.009). ConclusionThis is a credible evidence of CTLA4 gene expression in human eye tissue. This first hand attempt of investigating the association of epigenetic changes of the CTLA4 gene and pathogenesis of pterygia, indicated a significant intensification of the gene expression of CTLA4 in patients with pterygia. We suggest that increasing CTLA4 gene expression can be a trigger which promotes pterygium enlargement. However, further studies on more populations with larger sample sizes need to be done to verify this hypothesis in the future.

Construction of a fusion plasmid containing the PSCA gene and cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and its anti-tumor effect in an animal model of prostate cancer.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T cell activation, which competes with CD28 for B7.1/B7.2 binding, and which has a greater affinity. Fusion of specific antigens to extracellular domain of CTLA4 represents a promising approach to increase the immunogenicity of DNA vaccines. In this study, we evaluated this interesting approach for CTLA4 enhancement on prostate stem cell antigen (PSCA)-specific immune responses and its anti-tumor effects in a prostate cancer mouse model. Consequently, we constructed a DNA vaccine containing the PSCA and the CTLA-4 gene. Vaccination with the CTLA4-fused DNA not only induced a much higher level of anti-PSCA antibody, but also increased PSCA-specific T cell response in mice. To evaluate the anti-tumor efficacy of the plasmids, murine models with PSCA-expressing tumors were generated. After injection of the tumor-bearing mouse model, the plasmid carrying the CTLA4 and PSCA fusion gene showed stronger inhibition of tumor growth than the plasmid expressing PSCA alone. These observations emphasize the potential of the CTLA4-fused DNA vaccine, which could represent a promising approach for tumor immunotherapy.

&amp;lt;i&amp;gt;CTLA-4&amp;lt;/i&amp;gt; Gene Polymorphism in Women with Idiopathic Recurrent Pregnancy Loss

Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is considered as a negative regulator of T cell activation and its role in maintaining immune tolerance is well established. The present case-control study aimed to investigate the CTLA-4 +49 A/G, -1661 A/G, -318 C/T and -1722 T/C single nucleotide polymorphisms (SNPs) and predisposition to recurrent pregnancy loss (RPL) in Gaza Strip - Palestine. The study was performed on 200 women with a history of two or more pregnancy losses (case group) and 200 control women with at least two live births and without any previous history of abortion. PCR-based restriction fragment length polymorphism (RFLP-PCR) method was used for genotyping CTLA-4 polymorphisms. Study results revealed that there is no significant association between the allele/genotype frequencies of the four investigated CTLA-4 SNPs and RPL. This trend remained true under dominant, co-dominant and recessive models. The A\G genotype of -1661 A\G polymorphism was higher in patients (45%) as compared to controls (39.5%) but without statistical significance. The minor allele frequencies (MAFs) of the CTLA-4 gene polymorphisms in the patient/control group were as follows: +49A>G: 0.22/0.22, -318 C>T: 0.15/0.11, -1661 A>G: 0.30/0.26 and -1722 T>C: 0.08/0.08. The four investigated CTLA-4 polymorphisms do not contribute to the risk of RPL in the study population. Testing other CTLA-4 gene polymorphisms and the level of CTLA-4 expression in RPL patients is recommended.