T CELL RECEPTORS/SUSCEPTIBILITY TO RHEUMATOID ARTHRITIS

类风湿性关节炎(RA)的易感性与 人类白细胞抗原II类，称为DR4。根据DNA序列分析，DR4可以 可细分为几个子类型(例如，Dw4、Dw10、Dwl3、Dwl4、Dwl5) 它们之间只有1-4个氨基酸的差异。然而，只有一些 这些亚型中与类风湿关节炎(即Dw4、Dw14、Dw15)。基于 最近在小鼠身上的研究表明，II类抗原可以 对T细胞受体(TCR)谱系的影响，可以认为 DR4亚型与RA易感性的不同关联是由于 他们对TCR曲目的不同影响。这个项目的总体目标是 该项目旨在深入了解人类白细胞抗原II类抗原在人类免疫缺陷中的作用 确定TCR曲目。特别是，这些研究将侧重于 DR4的各种亚集以及DR1和DR6等位基因也表现出 与类风湿关节炎易感性的关系。这些研究将包括 成人外周血淋巴细胞TCR谱系分析 已知的人类白细胞抗原类型的选定个体。TCR曲目将是 用Vbeta特异性单抗进行免疫荧光分析 并使用Valpha和Vbeta特异性引物进行定量聚合酶链式反应。在……里面 此外，将进行研究以确定不同的TCR是否 用于识别DR4的不同亚型并定义 区别它们的特征。这将通过以下方式实现 分析同种异体反应中单个个体的TCR谱 不同DR4亚型等位基因对人B细胞的免疫应答。 此外，人类白细胞抗原II类基因对TCR选择的影响 将通过以下方式评估对DR4亚型的应答曲目 这些曲目如何随应答者的人类白细胞抗原类型而变化。

Susceptibility to rheumatoid arthritis (RA) is genetically linked to the HLA class II antigen known as DR4. Based on DNA sequence analysis, DR4 can be subdivided into several subtypes (eg. Dw4, Dw10, Dwl3, Dwl4, Dwl5) which differ from each other by only 1-4 amino acids. However, only some of these subtypes are associated with RA (ie. Dw4, Dw14, Dw15). Based on recent studies in mice which demonstrate that class II antigens can influence the T cell receptor (TCR) repertoire, it may be proposed that the differing association of DR4 subtypes with susceptibility to RA is due to their differing effects on the TCR repertoire. The overall goal of this project is to gain insight into the role of HLA class II antigens in determining the TCR repertoire. In particular, these studies will focus on the various subsets of DR4 and those DR1 and DR6 alleles which also display association with susceptibility to RA. The studies will include an analysis of the TCR repertoire of peripheral blood lymphocytes from selected individuals of known HLA type. The TCR repertoire will be analyzed by immunofluorescence using Vbeta-specific monoclonal antibodies and, quantitative PCR using Valpha and Vbeta-specific primers. In addition, studies will be performed to determine whether distinct TCR are used to recognize the different subtypes of DR4 and to define the characteristics that distinguish them. This will be accomplished by analyzing the TCR repertoire of a single individual in an alloreactive response to human B cells transfected with the various DR4 subtype alleles. Furthermore, the influence of HLA class II genes on selection of the TCR repertoire in responses to the DR4 subtypes will be assessed by determining how these repertoires vary with the HLA type of the responder.