IMMUNOGENETICS OF SUSCEPTIBILITY TO TMEV-INDUCED DEMYELINATION

该项目旨在识别和分析 影响不同菌株差异感受性的基因 小鼠对泰勒氏小鼠脑脊髓炎病毒(TMEV)的毒株- 诱导性脱髓鞘疾病。TMEV诱导的脱髓鞘病 为人类多发性硬化症(MS)提供了一个极好的模型，两者 在临床症状和组织病理学水平上。这种病 是活跃的细胞免疫反应的结果， 可能是迟发性超敏反应，对这种病毒 导致“无辜的旁观者”破坏髓鞘。像人类一样 MS，疾病发展有明显的遗传影响，而且 对相关基因的鉴定/分析可能会提供线索 关于机制(包括预防或缓解)和遗传 风险因素。在以下情况下，这些将特别相关 相同的人类基因是已知的，它们与哪些相关 在这些研究中定义的。 分析将沿着三条调查路线进行。第一 是使用经典的遗传分析方法，涉及 杂种F_1、F_2及其回交后代的产生与研究 以确定敏感和耐药菌株之间的关系 易感性是显性的还是隐性的，并使 对涉及的基因数量的最低估计。后续使用 合适的同源、重组、突变体和重组近交系 菌株将允许识别和绘制特定的 精神错乱。 第二阶段是分析是否发生了抗病。 (被动地，因为抵抗的动物缺乏免疫力 进行破坏性免疫反应的“机械”或(B) 因为他们有积极的机制来防止破坏性的 回应。这些将通过涉及细胞的实验进行分析 易感和耐药动物之间的转移，以及通过使用 影响抑制机制的试剂，如抑制物 T淋巴细胞。 第三个阶段是免疫反应的分析。 不同抗性和易感小鼠品系的遗传学研究 病毒衣壳蛋白。我们希望确定是否有 差异识别的特定蛋白质或表位 通过敏感和耐药菌株，并鉴定基因 参与了这种不同的免疫反应。

This project is directed toward the identification and analysis of the genes affecting the differential susceptibility of different mouse strains to Theiler's murine encephalomyelitis virus (TMEV)- induced demyelinating disease. TMEV-induced demyelinating disease provides an excellent model for human multiple sclerosis (MS), both at a level of clinical symptoms and of histopathology. The disease occurs as the result of an active cell-mediated immune response, probably delayed type hypersensitivity, against the virus which results in "innocent bystander" destruction of myelin. Like human MS, there is a clear genetic influence of disease development, and the identification/analysis of the involved genes may provide clues as to mechanisms (including prevention or alleviation) and genetic risk factors. These will be especially relevant where the equivalent human genes are known which correlate which those defined in these studies. The analysis will proceed along three lines of inquiry. The first is the use of classical methods of genetic analysis, involving the generation and study of Fl and F2 hybirds and backcross progeny between susceptible and resistant strains in order to determine whether susceptibility is a dominant or recessive trait and to make a minimal estimate of the number of genes involved. Subsequent use of appropriate congenic, recombinant, mutant and recombinant-inbred strains will permit the identification and mapping of specific loci. The second phase is to analyse whether resistance to disease occurs (at passively, because the resistant animals lack the immunological "machinery" to carry out the destructive immune response or (b) because they have active mechanisms for preventing the destructive response. These will be analyzed by experiments involving cell transfers between susceptible and resistant animals, and by the use of reagents which affect inhibitory mechanisms such as suppressor T lymphocytes. The third phase will be the analysis of the immune response genetics of resistant and susceptible mouse strains against various viral capsid proteins. We hope to determine if there are particular proteins or epitopes which are differentially recognized by susceptible and resistant strains, and to identify the genes involved in such differential immune responsiveness.