广东人汉族群CTLA-4基因外显子1多态性与Graves病的相关性

目的探讨CTLA-4基因外显子1多态性与广东地区汉族人群Graves病的关系。方法以PCR-RFLP技术观察100名健康人与100例Graves病(GD)患者细胞毒性T淋巴细胞相关抗原4(CTLA-4)基因外显子1的多态性。结果提示GD患者的CTLA-4外显子1的G49等位基因频率较正常对照组显著增高(P<0.01)。结论CTLA-4基因可能是广东地区汉族人群中GD的易感候选基因。     

CTLA-4基因多态性与Graves病

细胞毒性T淋巴细胞相关抗原4（cytotoxie Tlymphocyte associated antigen4，CTLA-4）是激活的T细胞表达的一种膜蛋白，属免疫球蛋白超家族成员，对T细胞增生起负性调节作用。与抗原呈递细胞（APC）表面的B7分子结合，作为协同刺激信号抑制T细胞增生、活化，诱导T细胞耐受。CTLA-4功能和（或）表达缺陷参与了T细胞介导的自身免疫性疾病的发生发展。Graves病（GD）是一种由于抑制性T淋巴细胞（TS）功能缺陷所导致的器官特异性自身免疫病。近年来研究结果认为，CTLA4基因的多态性与GD有关，CTLA4基因作为GD的易感候选基因已成为研究的热点。     

免疫调节基因的多态性与Graves病易感性的相关性研究进展

Graves病(GD)是一种遗传背景强的器官特异性自身免疫性疾病,其核心发病环节是免疫因素,但遗传因素在其发病机制中也起到重要作用。GD的易感基因主要分为免疫调节基因和甲状腺特异性基因,其中免疫调节基因多态性可通过各种机制影响GD的易感性,故可为进一步研究GD的易感基因及发病机制提供新的思路。     

自身免疫性甲状腺病CTLA—4基因外显子1A／G^49多态性研究

目的　探讨细胞毒性T淋巴细胞相关抗原4（CTLA-4）基因外显子1的49位点A／G多态性与自身免疫性甲状腺病（AITDs）的相关性。方法　采用多聚酶链反应限制性片段长度多态性（PCR-RFLP）技术分析122例自身免疫甲状腺病患者,其中Graves’病（GD）87例,桥本甲状腺炎（HT）35例,84例健康对照的CTLA-4基因外显子1的49位点基因型。采用ELISA技术检测AITDs患者甲状腺功能,间接免疫荧光法检测甲状腺球蛋白抗体（TGAb）和甲状腺抗过氧化物酶抗体（TPOAb）。结果　AITDs患者CTLA-4／G     

CTLA-4基因外显子4区AT重复序列多态性及碘摄入量与Graves病的相关性研究

目的 探讨细胞毒性T淋巴细胞相关抗原-4(cytotoxic T lymphocyte associated antigen-4,CTLA-4)基因第4外显子区AT重复序列多态性多态性[CTLA-4(AT)n]及碘摄入状况与粤西汉族人Graves病(Graves disease,GD)发病的相关性.方法 收取2006年...     

Graves病相关的易感基因研究进展

Graves病是一种器官特异性自身免疫病，是一种由多个基因与环境因素参与的多基因病。尽管进行了大量的研究, GD的遗传学机制至今尚未阐明。与GD发病相关的候选基因主要分成两大类：（1）与机体免疫调节有关的基因：（2）与甲状腺生理机能调节有关的基因。本文就与 GD易感性研究最多的基因 HLA 、CTLA-4 、TSH-R 及一些细胞因子作一简要综述。     

Graves病相关易感基因的研究进展

目的:总结Graves病(GD)相关易感基因的研究现状.方法:在PubMed数据库采用关键词检索方法,查阅并分析近10年来与GD易感基因研究相关的文献.结果:已发现人白细胞抗原(HLA)-Ⅱ类基因、细胞毒性T淋巴细胞相关抗原4(CTLA-4)基因、促甲状腺激素受体(TSHR)基因、甲状腺免疫球蛋白(TG)基因、细胞因子及其相关基因、蛋白酪氨酸磷酸酶-22(PTPN-22)基因等多个基因与GD存在一定的关系.结论:有多个基因参与GD的发病,其遗传易感性被认为是几个或多个基因座遗传变异的累积效应.     

细胞毒T淋巴细胞相关抗原4基因C-658T多态性与溃疡性结肠炎相关性研究

,与UC患者的病变范围有显著相关(P=0.037;P=0.0067);UC组C61T基因型频率与对照组相比,差异无统计学意义(P=0.192).结论 CTLA-4基因启动子区C-658T位点T等位基因与中国汉族UC存在显著相关性.     

Graves病候选基因多态性研究进展

Graves病是一种器官特异性自身免疫性疾病，它的病因学十分复杂，是遗传和环境因素相互作用的结果。近几年，人类基因组序列和SNP的研究使这类多基因疾病易感基因的鉴定取得很大进展。目前，Graves病候选基因研究多选择与该病病理过程有关的基因以及甲状腺固有基因，如：HLA系统基因、CTLA-4基因、TSH-R基因、TG基因等，并取得一定进展。本文就这些基因多态性与Graves病关系研究现状进行综述。     

华东地区汉族人群IL12B基因多态性与Graves病相关性研究

目的 研究华东地区汉族人群IL12B基因3’UTR多态性与Graves病的相关性。方法 用直接测序法对华东地区93例Graves病患者及94例正常对照者的IL12B基因的3’UTR 的多态位点进行检测，分析华东地区汉族人群IL12B基因与Graves病的相关性。结果 在IL12B的3’UTR区检测到2个SNPs：1188A/C和1358-/G，基因型分布在GD患者和正常对照中无统计学差异；单倍型分析显示A-频率在GD患者中显著低于正常对照：P=0.046。结论 IL12B可能与GD的易感性有关。     

TNFβ基因微卫星多态性与Graves病的相关性研究

目的 研究Graves病患者TNF(tumor necrosis factor)β基因第一内含子的微卫星多态性(TNFc)，分析TNFc与Graves病发病的关联，进一步探讨Graves病的发病机制。方法 选取Graves病实验组和正常对照组患者各36例，应用聚合酶链反应(PCR)技术，扩增具有微卫星多态性的TNFβ基因第一内合于，通过聚丙烯酰胺凝胶电泳，分析两组的基因频率和基因型频率。结果 TNFc微卫星多态性合有两个等位基因(TNFcl和TNFc2)及三种基因型(纯合于TNFclcl和TNFc2c2，亲合于TNFclc2)；Graves病实验组的TNFc2基因频率高于正常对照组，有显著性差异(x^2=4，02，P＜0．05)，TNFclcl基因型频率在Graves病实验组与正常对照组无显著性差异(X^2=2．72，P＞0．05)。结论 TNFc2等位基因与Graves病发病的易感性有关联，TNFclcl基因型在Graves病发病的遗传基础中不起重要作用。     

CTLA4 gene polymorphisms and soluble CTLA4 protein in Behcet's disease

Cytotoxic T lymphocyte antigen 4 (CTLA4; CD152) is a costimulatory molecule expressed on activated T cells that plays a key inhibitory role during T lymphocyte activation. The gene encoding for CTLA4 has been suggested as a candidate for conferring susceptibility to autoinflammatory diseases. We investigated the polymorphisms of the CTLA4 gene [promoter region (−1722 T/C, −1661 A/G and −318 C/T) and exon 1 (+49 G/A)] and the differences of serum soluble sCTLA4 levels in 285 patients with Behcet's disease (BD) and 287 controls. The frequency of the CTLA4 −1661 GG genotype was significantly higher in BD patients than in controls [ P  = 0.019, odds ratio (OR) = 5.2, 95% confidence interval (CI) = 1.13–23.86]. Also, the genotype frequency for CTLA4 −1722 TC was significantly higher ( P  = 0.014, OR = 1.8, 95% CI = 1.13–2.99), while CTLA4 −1722 CC was significantly lower ( P  = 0.018, OR = 0.4, 95% CI = 0.20–0.87) in BD patients with ocular lesions compared with patients without this symptom. Serum sCTLA4 levels in BD patients were significantly lower, especially in BD patients with the CTLA4 +49 G allele, than those in healthy controls ( P  < 0.05). Although our understanding of the role of the CTLA4 gene and its protein product in BD is incomplete, these results suggest that single nucleotide polymorphisms of the promoter and exon regions in the CTLA4 gene are candidates that predispose to BD and that sCTLA4 may be related to the immunological abnormalities and disease expressions associated with BD.     

Association of CTLA4 polymorphism with regulatory T cell frequency

A common single nucleotide polymorphism in CTLA4 has been linked with susceptibility and outcome in autoimmune and infectious diseases, respectively. Here, we show that this polymorphism is associated with the frequency of CD4(+)CD25(+) regulatory T cells in healthy human volunteers. We further show that, on a per cell basis, such regulatory T cells appear to be functionally indistinguishable across CTLA4 genotypes. These data implicate CTLA4 in regulatory T cell development, and provide a mechanism to account for the link between polymorphisms at this locus and the biological outcome of adaptive immune responses to self and to pathogens.     

Association of CTLA4 gene polymorphisms with lymphatic filariasis in an East Malaysian population

Lymphatic filariasis (LF) is a parasitic disease caused by threadlike worms of the Brugia and Wuchereria species that live in the human lymphatic system. Regulatory T cells (Tregs) may play a key role in the pathogenesis of LF, and cytotoxic T-lymphocyte antigen-4 (CTLA4) expressed by Tregs is a potential candidate gene because it modulates T-cell activation. A case-control study was performed to establish a potential association of 5 CTLA4 gene promoter single nucleotide polymorphisms (SNPs; rs733618, rs11571316, rs5742909, rs231775, and rs16840252) with the occurrence of LF in an East Malaysian population (320 LF-infected individuals and 150 healthy controls). Polymorphisms were evaluated using TaqMan real-time polymerase chain reaction followed by direct sequencing. LF carriers of the rs733618 AG genotypes (p = 0.02) and those with combined minor allele G carriers (AG + GG; p = 0.01) exhibited a significantly decreased risk for LF. Among the asymptomatic amicrofilaremic cases, positive associations were reported for all genotypes and variants of rs733618 with odds ratios (ORs) ranging from 0.27 to 0.45. In the asymptomatic microfilaremic cases, marker rs231775 exhibited a significant decreased risk, with ORs ranging from 0.50 to 0.57. The study has identified SNPs in the CTLA4 promoter gene that may be functionally linked with susceptibility to LF.     

转录因子FOXP3基因多态性与广西壮族系统性红斑狼疮的遗传易感性

目的 探讨转录因子FOXP3基因单核苷酸多态性与广西壮族系统性红斑狼疮(systematic lupus erythematosus,SLE)易感性之间的关系.方法 以120例SLE患者和160名健康对照者为研究对象,应用聚合酶链反应-限制性片段长度多态性和DNA测序的方法对FOXP3基因-2383 C/T、-3281 C/A单核苷酸多态性进行基因分型.结果 FOXP3基因-3281 C/A多态性在SLE组和正常人群中的分布差异无统计学意义(P＞0.05),而FOXP3基因-2383 C/T多态性在两组人群中的分布差异有统计学意义(P＜0.05),等位基因频率的相对风险分析发现,-2383 T等位基因携带者患系统性红斑狼疮的风险是-2383 C等位基因的1.715倍(OR=1.715,95%CI:1.165～2.525).联合基因型分析发现,FOXP3的-2383 T/-3281 A等位基因频率在SLE组中显著高于对照组(P＜0.05),-2383 T/-3281 A等位基因携带者显著增加了SLE的发病风险(OR=2.196,95%CI:1.165～4.142).结论 FOXP3基因-2383 C/T多态性与SLE的发病具有相关性,其中-2383 T等位基因可能是SLE的遗传易感基因.     

CTLA4 codon 17 dimorphism in patients with rheumatoid arthritis

Abstract: The genetic susceptibility to rheumatoid arthritis is conferred by genes in the human leukocyte antigen (HLA) region on chromosome 6, but additional genes may be involved to determine disease susceptibility. We have studied the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in rheumatoid arthritis. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, SSCP and RFLP in 258 Caucasian rheumatoid arthritis patients and 456 controls. Rheumatoid arthritis patients were characterized by a decreased frequency of homozygotes for the Thr-17 substitution (32% versus 39%) and an overrepresentation of patients heterozygous for the Thr/Ala substitution (54% versus 46%). Gene frequencies for the Ala/Thr substitution differed only marginally from controls. In contrast, analyses of the CTLA4 exon 1 polymorphism with respect to HLA-DRB1*04 revealed significantly more patients with Ala in the homozygous (19% versus 15% controls) or heterozygous state (54% versus 39% controls) and less homozygous for Thr (27% versus 46% controls), with a particular increase of Ala/Ala genotypes among rheumatoid arthritis patients carrying the HLA-DRB1*0401 subtype. Among HLA-DRB1*04 negative rheumatoid arthritis patients, we observed no difference between the allele frequencies of the Ala-17 or Thr-17 substitution.     

4p14区段和CTLA-4基因多态性与Graves病相关

目的探讨中国安徽蚌埠地区汉族人群4p14区段位点rs6832151和CTLA-4基因4个SNPs(单核苷酸多态性)位点基因多态性与Graves病相关性,和基因-基因交互作用对Graves病的影响。方法提取611例诊断明确的GD患者和644名健康对照者的全基因组DNA,用Taq Man探针技术进行基因分型,使用Plink和Haploview等统计软件分析这些位点与蚌埠地区汉族人群Graves病的相关性。结果 4p14区段位点rs6832151的等位基因、基因型频率在GD组和对照组之间有差异(P0.05),CTLA-4基因区域内rs231804和rs231726两个SNP位点基因型在显性模型下差异显著(P0.05);GMDR模型显示CTLA-4基因内rs10197319、rs231726、rs231804、rs1024161位点和4p14区段内rs6832151位点组成的五阶模型(P=0.001)为最佳模型,CTLA-4基因内rs1024161和rs10197319位点之间上位效应分析结果有差异(P0.05)结论 4p14区段rs6832151,CTLA-4基因区域内rs231804和rs231726位点基因多态性与蚌埠地区汉族人群Graves病的遗传易感性相关;rs6832151(4p14区段)和rs10197319、rs231726、rs231804、rs1024161(CTLA-4基因)5个SNP位点间的基因-基因交互作用与Graves病相关,CTLA-4基因内rs1024161和rs10197319位点之间存在上位效应。     

FcRL3基因三个单核苷酸多态性与重庆汉族人群Graves病关联研究

目的 了解中国重庆地区汉族人群Fc受体样因子(Fc receptor-like proteins,FcRL3)基因启动子A/G,第2外显子C/G,第4外显子C/T多态性与Graves病(Graves disease,GD)的相关性.方法 采用聚合酶链反应限制性片段长度多态性分析方法结合直接测序技术,对重庆地区无亲缘关系的120名正常人和128例GD患者进行多态性研究,同时进行甲状腺功能和自身抗体的检测,应用Unphased1122和LDA1.0软件进行连锁不平衡和单倍型分析,用卡方检验分析基因型、等位基因和单倍型频率在GD组和对照组之间的差异.结果 GD组FcRL3基因3个多态性位点基因型和等位基因的频率与对照组相比,其差异均有统计学意义(P＜0.05).连锁不平衡分析显示启动子和第2外显子存在连锁不平衡,在构建的3个主要单倍型中,仅H2(G-G)单倍型频率GD组明显高于对照组(50.8%vs 35.8%,P＜0.05).除甲状腺疾病家族史与启动子多态性有关联(P%0.05),余临床特征与FcRL3多态性均无相关.结论 多个位点及单倍型分析提示FcRL3基因启动子A/G,第2外显子C/G,第4外显子C/T多态性可能是中国重庆地区汉族人群GD关联的危险因素.     

Lentiviral gene transfer of CTLA4 generates B cells with reduced costimulatory properties

Peripheral T-cell (TC) tolerance can be induced by tolerogenic antigen-presenting cell (APC). A prerequisite is the reduction or blockade of B7 of APC. Besides dendritic cell, B cells can be used as APC. Here, we show the generation B cells with reduced B7 expression by lentiviral transduction of endoplasmic reticulum (ER)-directed CTLA4. Vectors coding for the human CTL4-Ig were used for the human B-cell line Raji. Transduction efficiency was over 90% (MOI = 3). For the murine B-cell line A20 and for primary mouse B cells, murine CTLA4 was used. We show that B cells with reduced B7 expression reduce the antigen (Ag) specific TC proliferation in vitro. B cells expressing an ER-directed CTLA4 may reduce Ag-specific immune responses.