GENETICS OF AUTOIMMUNITY

我们发现了T细胞受体Beta链的一种不寻常的等位基因 新西兰白鼠(NZW)的基因座。此等位基因的区别在于 含有CBeta1、DBeta2和整个JBeta2的8.8 kb DNA的缺失 集群。因此，所有NZW T细胞受体Beta链都来自于 单组Beta链基因片段(DBeta1、JBeta1和CBeta2)。 有趣的是，这种T细胞受体Beta基因片段的缺失 存在于一种已知会导致狼疮样自身免疫性疾病的菌株中。 这项资助建议完全描述这种不寻常的Beta链等位基因 并考察其表达的后果。它最初的计划是 克隆和测序NZW小鼠胚系Beta链基因复合体。 这可能解释该等位基因产生的机制。 NZW Beta链基因同源小鼠将在C57BL/6和 BALB/C背景。一旦这些同源菌株可用，就可以进行实验 检查这些小鼠的T细胞特异性的谱系将是 已执行。对同种异体抗原(突变的H-2kb基因产物)的反应，以及 将对常规抗原(卵清蛋白多肽)进行研究。这些 研究应该允许我们检查DBeta2和JBeta2的贡献 T细胞库中的基因片段。 由于NZW小鼠在狼疮样自身免疫的形成中起重要作用 NZB x NZW F1动物，简单的遗传分析[(NZB X NZW)F1 x NZB回交]将用于确定NZW Beta 链基因参与了F1自身免疫性疾病的发病机制。 如果NZW Beta链基因与狼疮样的发生有关 疾病，计划进行实验以阐明NZW Beta链的作用 疾病过程中的基因。测绘实验也计划进行到 研究其他NZW基因座对NZB/NZW病的影响。 最后，我们将检测系统性红斑狼疮患者的DNA。 红斑狼疮(SLE)是否存在T细胞受体基因多态性 都存在于这些个体身上。

We have identified an unusual allele of the T cell receptor Beta chain locus in New Zealand White (NZW) mice. This allele is distinguished by the deletion of 8.8 kb of DNA containing CBeta1, DBeta2, and the entire JBeta2 cluster. Thus, all NZW T cell receptor Beta chains are derived from a single set of Beta chain gene segments (DBeta1, JBeta1 and CBeta2). Interestingly, this deletion of T cell receptor Beta gene segments is present in a strain known to contribute to lupus-like autoimmune diseases. This grant proposes to fully characterize this unusual Beta chain allele and to examine the consequences of its expression. It is first planned to clone and sequence the germline Beta chain gene complex from NZW mice. This may elucidate the mechanism by which this allele was generated. Mice congenic for the NZW Beta chain genes will be bred on the C57BL/6 and BALB/c backgrounds. Once these congenic strains are available, experiments examining the repertoire of T cell specificities in these mice will be performed. The response to alloantigens (mutant H-2Kb gene products), and conventional antigens (peptides of ovalbumin) will be investigated. These studies should allow us to examine the contribution of DBeta2 and JBeta2 gene segments to the T cell repertoire. Since NZW mice contribute to the development of lupus-like autoimmunity in NZB x NZW F1 animals, a straightforward genetic analysis [(NZB x NZW) F1 x NZB backcross] will be undertaken to determine whether or not the NZW Beta chain genes are involved in the pathogenesis of the F1 autoimmune disease. If the NZW Beta chain genes are linked to development of lupus-like disease, experiments are planned to elucidate the role of NZW Beta chain genes in the disease process. Mapping experiments are also planned to examine the contribution of other NZW loci to NZB/NZW disease. Finally, we will examine the DNA from patients with systemic lupus erythematosus (SLE) to determine whether T cell receptor gene polymorphisms are present in these individuals.