TCR V GENE REPERTOIRE IN MS AND SELECTIVE IMMUNOTHERAPY

多发性硬化症（MS）的易感性与以下基因有关： 免疫球蛋白超基因家族，包括HLA II类基因、基因 编码免疫球蛋白的基因和编码T细胞受体的基因 （TCR）。 我们和其他人以前描述了生殖系多态性 与MS易感性相关的Ig和TCR V基因 技术，我们扩增了重排的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， 和脱髓鞘区域的Vbeta基因重排。 测序 进一步揭示了有限的连接多样性。 最后，在一个特定的 分子表型HLA-DRB 1 *1501，DQA 1 *0102，DQB 1 *0602，DPB 1 *0401， 与MS连锁的HLA-DR 2Dw 2单倍型相关， V β 5.2和V β 6的优先重排。 基于动物 模型此类观察结果可能具有临床相关性。 我们已经证明 TCR V基因产物的抗体，以及II类 组织相容性分子，与对 实验性自身免疫性脑脊髓炎已经成功地用于 治疗小鼠的临床瘫痪。 HLA II类和TCR的鉴定 参与MS发病机制的V基因可能使我们能够设计 人类的治疗方法，类似于我们在人类中成功使用的方法， 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.