Viruses and Autoimmunity ot the Central Nervous System

描述（由申请人提供）：大多数证据表明多发性硬化症（MS）是中枢神经系统（CNS）的自身免疫性疾病。是人类最常见的脱髓鞘疾病。免疫介导的事件参与了病因和发病机制。因此，髓鞘特异性自身反应性T细胞被认为介导炎性脱髓鞘。在这种疾病中，病毒感染与发病和/或加重有关。流行病学研究表明，一个人在生命的前15年生活的地方有助于确定一个人是否获得高或低MS风险表型。这些数据表明，生命早期的感染赋予个体在生命后期起源的自身免疫性疾病的风险或引发个体。报告显示，大约30%的MS恶化（发作）之前是病毒感染。虽然没有一种感染因子被证明是MS的病原体，但有充分的证据表明病毒感染参与了疾病的起始和随后的触发攻击。我们已经建立了MS的动物模型，其中生命早期的病毒感染可以使它们在生命后期恶化。急性加重是由与第一次不同的病毒感染引起的。在我们的模型中，第一次感染具有CNS蛋白的分子模拟。我们已经制作了编码髓鞘蛋白脂质蛋白（PLP）的重组痘苗病毒（VV）。这种初始感染（VV-PLP）本身似乎不会引起CNS疾病。然而，当我们用鼠巨细胞病毒（MCMV）攻击VV-PLP致敏的动物时，动物出现炎性CNS病变。第二次感染或攻击感染可以通过两种不相互排斥的机制诱导疾病：1）第二次感染通过旁观者激活激活已经引发的自身反应性T细胞，并且足够数量的这些T细胞将迁移到CNS中并引发疾病; 2）MCMV可能具有一个交叉-与PLP的反应性表位由活化的树突状细胞呈递给致敏的自身反应性T细胞，导致炎性CNS疾病。我们建议调查的免疫学基础的启动或启动阶段和后来的挑战阶段的炎性中枢神经系统疾病。我们的模型可以解释为什么没有单一的微生物被确定为MS代理，但很可能是一个传染性事件的组合。

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.