TCR V GENE REPERTOIRE IN MS AND SELECTIVE IMMUNOTHERAPY

多发性硬化症(MS)的易感性与 免疫球蛋白超基因家族，包括人类白细胞抗原II类基因、基因 编码免疫球蛋白和编码T细胞受体的基因 (TCR)。我们和其他人之前已经描述了生殖系的多态 用聚合酶链式反应检测与MS易感性相关的LG和TCRV基因 我们已经扩增了重排的TCR Valpha和Vbeta基因 直接从多发性硬化症脑斑块中提取。TCR Valpha的多样性有限 脱髓鞘区域的Vbeta基因重排。定序 进一步揭示了有限的交界处多样性。最后，在一个特殊的情况下 分子表型：HLA-DRB1*1501，DQA1*0102，DQB1*0602，DPB1*0401， 与多发性硬化症相关的HLA-DR2Dw2单倍型 Vbeta5.2和Vbeta6的优先重排。以动物为基础 这样的观察模型可能具有临床意义。我们已经证明了 针对TCR V基因产物的抗体以及针对II类的抗体 组织相容性分子，与易感性相关 实验性自身免疫性脑脊髓炎已成功用于 治疗小鼠临床麻痹。人类白细胞抗原II类和TCR的鉴定 参与多发性硬化症发病机制的V基因可能允许我们设计 人类的治疗方法，类似于我们在 实验动物。

Susceptibility to multiple sclerosis (MS) is linked to genes of the immunoglobulin supergene family, including the HLA class II genes, genes encoding the immunoglobulins, and genes encoding the T cell receptor (TCR). We and others have previously described germline polymorphisms in lg and TCR V genes associated with susceptibility to MS. Using PCR technology we have amplified rearranged TCR Valpha and Vbeta genes directly from MS brain plaque. There is limited diversity of TCR Valpha and Vbeta gene rearrangements in areas of demyelination. Sequencing further reveals limited junctional diversity. Finally, in a particular molecular phenotype HLA-DRB1 *1501, DQA1*0102, DQB1*0602, DPB1*0401, associated with the HLA-DR2Dw2 haplotype linked to MS, there is preferential rearrangement of Vbeta5.2 and Vbeta6. Based on animal models such observations may have clinical relevance. We have shown that antibodies to TCR V gene products, as well as to class II histocompatibility molecules, associated with susceptibility to experimental autoimmune encephalomyelitis have been used successfully to treat clinical paralysis in mice. Identification of HLA class II and TCR V genes involved in the pathogenesis of MS may allow us to design therapies in man, similar to that which we have used successfully in experimental animals.