CONSEQUENCES OF A T CELL RECEPTOR B CHAIN GENE DELETION

我们已经确定了T细胞受体β链的一个不寻常的等位基因 新西兰白色（NZW）小鼠中的基因座。 该等位基因的特征在于 缺失8.8 kb的含有C β 1、D β 2和整个J β 2的DNA 集群 因此，所有的NZW T细胞受体β链都来源于一种 单组β链基因片段（DBeta 1、JBeta 1和CBeta 2）。 有趣的是，这种T细胞受体β基因片段的缺失， 存在于已知导致狼疮样自身免疫性疾病的菌株中。 这项资助计划充分描述这种不寻常的β链等位基因 并检查其表达的后果。 首先计划将 从NZW小鼠克隆和测序生殖系β链基因复合物。 这可能阐明该等位基因产生的机制。 与NZW β链基因同源的小鼠将在C57 BL/6上繁殖， BALB/c背景。 一旦这些同类菌株可用，实验 在这些小鼠中检查T细胞特异性的库将是 执行。 对同种异体抗原（突变H-2Kb基因产物）的反应，以及 将研究常规抗原（卵清蛋白的肽）。 这些 研究应该使我们能够检查DBeta 2和JBeta 2的贡献 基因片段的T细胞库。 由于NZW小鼠有助于狼疮样自身免疫的发展， NZB x NZW F1动物，简单的遗传分析[（NZB x NZW）F1 x NZB回交]将进行，以确定是否NZW Beta 链基因参与F1自身免疫性疾病的发病机制。 如果NZW β链基因与狼疮样 疾病，实验计划阐明NZW β链的作用 疾病过程中的基因 还计划进行测绘实验， 检查其他NZW基因座对NZB/NZW疾病的贡献。 最后，我们将检查系统性狼疮患者的DNA， 确定T细胞受体基因多态性 存在于这些个体中。

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.