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

类风湿关节炎(RA)的发病机制尚不清楚。然而， 累积的研究表明，类风湿性关节炎是一种多因素疾病， 受遗传和环境因素的影响。例如，DR4， Dw4和Dw14以及免疫球蛋白基因座上的某些多态标记 一直与类风湿关节炎有关。有趣的是，DR4和RA之间的联系是 主要在有类风湿因子(RF)的RA患者中具有显著意义，这些患者 与慢性组织损伤的产生有牵连 关节。最近，我们的初步数据表明，疾病与 1例RA患者滑膜免疫球蛋白RF为单克隆性，另1例为双克隆性 另一例类风湿关节炎患者，类似于发现的单克隆性和寡克隆性 自身免疫小鼠体内的免疫球蛋白RFS。这些观察结果意味着 一种或几种免疫球蛋白RF B细胞显性克隆的出现 抗原选择。除免疫球蛋白外，类风湿T细胞 滑液被发现对分枝杆菌抗原有强烈的反应， 诱导大鼠关节炎；这种T细胞主要是Gammadelta T细胞 细胞。综上所述，这些发现表明Gammadelta T细胞可能在 在联合销毁中发挥了重要作用。 因此，为了检验类风湿性关节炎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 疾病相关的免疫球蛋白受体和滑膜T细胞受体 早期类风湿性关节炎患者的(TCR)VGamma基因及其特征良好的类风湿双生子 不同的人类白细胞抗原单倍型，并破译潜在的遗传和 影响RFS和TCR表达的环境因素 VGamma基因。具体地说，我们将：i)为RAPID开发方法 类风湿关节炎中编码免疫球蛋白RFS的H链V(VH)基因表达分析 患者；ii)分析10对同卵双胞胎中的IgGRF VH基因 符合类风湿性关节炎，10对同卵双胞胎 与RA不一致；III)确定选定的Ig V基因的基因类型 在所有被分析个体中；IV)表达的TCR VGamma的特征 早期RA患者炎症关节和血液中的基因；V)比较 上述20例单合子患者中与疾病相关的TCR VGamma基因 双胞胎；VI)确定报告的多态TCR VGamma的基因类型 所有被分析个体的基因。总而言之，这些研究将揭示 类风湿关节炎相关遗传因素对疾病表达的影响 相关的Ig V基因和TCR VGamma基因，这类信息可能会进展 我们对类风湿关节炎发病机制的认识。

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.