ANALYSIS OF HLA, IGG, AND TCR GENES IN RHEUMATOID ARTHRITIS

类风湿关节炎中 HLA、IGG 和 TCR 基因分析

• 批准号: 6235768
• 负责人: POJEN P CHEN
• 金额: $ 16.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6235768
• 关键词: B lymphocyte; T cell receptor; behavioral /social science research tag; blood chemistry; dizygotic twins; family genetics; gene expression; gene interaction; genetic polymorphism; genotype; histocompatibility antigens; histocompatibility gene; histocompatibility typing; human ecology; human subject; immunoglobulin G; monozygotic twins; nucleic acid hybridization; pathologic process; polymerase chain reaction; rapid diagnosis; rheumatoid arthritis

The pathogenesis of rheumatoid arthritis (RA) remains unclear. However, accumulated studies indicate that RA is a multifactorial disease, influenced by both genetic and environmental factors. For example, DR4, Dw4 and Dw14 as well as certain polymorphic markers in Ig gene loci have been associated with RA. Interestingly, the linkage between DR4 and RA is significant mainly in RA patients with rheumatoid factors (RF), which have been implicated in the production of chronic tissue damage in the inflamed joints. Recently, our preliminary data suggest that disease relevant synovial IgG RFs are monoclonal in one RA patient and are bi-clonal in another RA patient, analogous to the finding of monoclonal and oligoclonal IgG RFs in individual autoimmune mice. These observations imply the occurrence of one or a few dominant clones of IgG RF B cells due to antigen selection. In addition to IgG RFs, T cells from rheumatoid synovia were found to respond vigorously to mycobacterial antigens, which induce arthritis in rats; the majority of such T cells were gammadelta T cells. Combined, these findings suggest gammadelta T cells may play a major role in joint destruction. Thus, to examine the hypothesis that RA is a multifactorial disease, affected by both genetic and environmental factors, we intend to analyze globally the disease-relevant IgG RFs and the synovial T cell receptor (TCR) Vgamma gene in early RA patients and well characterized RA twins of different HLA haplotypes, and to decipher the underlying genetic and environmental factors which influence the expression of such RFs and TCR Vgamma gene. Specifically, we will: I) develop methodologies for rapid analyses of the expressed H chain V (Vh) genes that encode IgG RFs in RA patients; II) analyze IgG RF Vh genes in 10 pairs of monozygotic twins who are concordant for RA, and 10 pairs of monozygotic twins who are discordant for RA; III) determine the genotypes of the selected Ig V genes in all analyzed individuals; IV) characterize the expressed TCR Vgamma genes in the inflamed joints and blood of early RA patients; V) compare the disease-relevant TCR Vgamma genes in the 20 aforementioned monozygotic twins; VI) determine the genotypes of the reported polymorphic TCR Vgamma genes in all analyzed individuals. Together, these studies will reveal the effects of RA-related genetic factors on the expression of the disease related Ig V genes and TCR Vgamma genes, and such information may advance our understanding of the pathogenesis of RA.

类风湿性关节炎（RA）的发病机制尚不清楚。 然而，在这方面， 累积的研究表明RA是一种多因素疾病， 受遗传和环境因素的影响。 例如，DR 4， Dw 4和Dw 14以及IG基因座上的某些多态性标记， 与RA有关。 有趣的是，DR 4和RA之间的联系是 主要在伴有类风湿因子（RF）的RA患者中有意义， 在发炎的组织中， 接头. 最近，我们的初步数据表明， 滑膜IgG RF在一个RA患者中是单克隆的，在另一个RA患者中是双克隆的。 另一个RA患者，类似于单克隆和寡克隆的发现， 个体自身免疫小鼠中的IgG RF。 这些观察结果意味着 IgG RF B细胞的一个或几个优势克隆的出现， 抗原选择 除了IgG RF，来自类风湿性关节炎的T细胞 发现滑膜对分枝杆菌抗原有强烈反应， 诱导大鼠关节炎;大多数这样的T细胞是γ δ T细胞 细胞 综合起来，这些发现表明γ δ T细胞可能在免疫系统中起作用。 联合破坏的主要作用。 因此，为了检验RA是一种多因素疾病的假设， 受遗传和环境因素的影响，我们打算分析 在全球范围内，疾病相关IgG RF和滑膜T细胞受体 (TCR)在早期RA患者和具有良好特征的RA双胞胎中的Vgamma基因 不同的HLA单倍型，并破译潜在的遗传和 影响这些RF和TCR表达的环境因素 Vgamma基因。 具体而言，我们将：I）制定快速的方法， RA中编码IgG RF的表达H链V（Vh）基因的分析 II）分析10对单卵双胞胎中的IgG RF Vh基因， 是一致的RA，和10对单卵双胞胎谁是 III）确定所选IG V基因的基因型 IV）表征表达的TCR V γ 早期类风湿关节炎患者发炎关节和血液中的基因; V）比较 上述20个单合子中的疾病相关TCR V γ基因 VI）确定所报道的多态性TCR V γ的基因型 所有被分析的个体中的基因。 这些研究将揭示 RA相关遗传因素对疾病表达的影响 相关的IG V基因和TCR V γ基因，这些信息可能会促进 我们对RA发病机制的理解。