Viruses and Autoimmunity ot the Central Nervous System

描述(申请人提供)：大多数证据表明多发性硬化症(MS)是一种中枢神经系统(CNS)的自身免疫性疾病。这是人类最常见的脱髓鞘疾病。免疫介导的事件参与了疾病的病因和发病机制。因此，髓鞘特异性自身反应性T细胞被认为介导了炎性脱髓鞘。在这种疾病中，病毒感染与发病和/或恶化有关。流行病学研究表明，一个人生活在哪里，他们头15年的生活有助于确定一个人是获得了多发性硬化症的高风险表型还是低风险表型。这些数据表明，生命早期的感染使个人有可能患上源于晚年的自身免疫性疾病。报告显示，大约30%的多发性硬化症恶化(发作)之前有病毒感染。虽然没有一种感染源被证明是多发性硬化症的病原体，但有大量证据表明，病毒感染参与了疾病的起始和后来的触发。我们已经为多发性硬化症建立了一个动物模型，在生命早期的病毒感染可以使他们在以后的生活中病情恶化。病情恶化是由与第一次不同的病毒感染引起的。在我们的模型中，第一个感染与中枢神经系统蛋白有分子模仿(S)。我们制备了编码髓鞘蛋白脂蛋白(PLP)的重组痘苗病毒(VV)。这种初始感染(VV-PLP)本身似乎不会引发中枢神经系统疾病。然而，当我们用小鼠巨细胞病毒(MCMV)挑战VV-PLP免疫的动物时，动物会出现炎性中枢神经系统损害。第二次或挑战感染可能通过两种不相互排斥的机制诱发疾病：1)第二次感染通过旁观者激活激活已经启动的自身反应性T细胞，如果数量足够多，这些T细胞将迁移到中枢神经系统并引发疾病；2)MCMV可能与激活的树突状细胞呈递的PLP具有交叉反应表位，从而启动炎症性CNS疾病。我们建议探讨炎症性中枢神经系统疾病启动或启动阶段以及后期挑战阶段的免疫学基础。我们的模型可以解释为什么没有单一的微生物被确定为多发性硬化症的病原体，但很可能是多种感染事件的组合。

DESCRIPTION (provided by applicant): Most evidence suggests that multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). It is the most common human demyelinating disease. Immune mediated events are involved in the etiology and pathogenesis. Therefore, myelin specific autoreactive T cells are believed to mediate the inflammatory demyelination. In this disease viral infections are associated with initiation and/or exacerbations. Epidemiologic studies indicate that where one lives their first 15 years of life help determines whether one acquires a high or low MS risk phenotype. These data suggest that infections early in life confer a risk or primes individuals for autoimmune disease that originates later in life. Reports show approximately 30% of MS exacerbations (attacks) is preceded by viral infections. While no one infectious agent has been demonstrated to be etiologic agent for MS, there is ample evidence pointing towards viral infections being involved in the initiation and later triggering attacks of disease. We have established an animal model for MS where a viral infection early in life can prime them for exacerbations later in life. The exacerbation is induced by a different viral infection than the first. In our model the first infection has molecular mimicry with a CNS protein(s). We have made a recombinant vaccinia virus (VV) that encodes myelin proteolipid protein (PLP). This initial infection (VV-PLP) does not appear to incite CNS disease by itself. However, when we challenge VV-PLP primed animals with murine cytomegalovirus (MCMV), animals develop inflammatory CNS lesions. The second or challenge infection could induce disease by two mechanisms that are not mutually exclusive: 1) The second infection activates already primed autoreactive T cells by bystander activation, and in sufficient numbers, these T cells would migrate into the CNS and initiate disease; and 2) MCMV could have a cross-reactive epitope with PLP presented by activated dendritic cells to primed autoreactive T cells leading to inflammatory CNS disease. We propose to investigate the immunological basis for the initiation or priming phase and the later challenge phase of inflammatory CNS disease. Our model could provide an explanation why no single microbe has been identified as the MS agent but is likely to be a combination of infectious events.