MOLECULAR MIMICRY AND VIRUS-INDUCED AUTOIMMUNITY

多发性硬化症的病因、发病机制及治疗后 感染性脑病尚不清楚。治疗一般是 效果不佳。病毒感染和/或产生异常免疫 反应被怀疑在致病因素中起主要作用。 这些实体。这项建议旨在研究 宿主具有抗病毒免疫反应的病毒。这样的事件 可能导致自体免疫现象通过世代和/或 中枢神经系统(CNS)内自我反应细胞的扩张。 此外，病毒的直接相互作用也有助于中枢神经系统的病理。 通过了解病毒如何与免疫系统相互作用的机制 系统和靶组织产生疾病将提供有价值的 适用于了解人类中枢神经系统疾病的信息 希望他们最终的治疗和预防。 在这项提议中，计划进行实验以延长我们最初的 检测同源性和交叉反应免疫反应的观察 病毒决定因素和自身成分之间的关系。在许多情况下 这些交叉反应是有趣的，然而在疾病中的作用是 不清楚。因此，研究的目的是调查模型以 检查交叉反应免疫反应的生物学相关性 在实际的疾病诱导中。将对两个模型进行深入研究。第一 与病毒和自身成分发生交叉反应的抗体的作用 在引发或加强中枢神经系统疾病方面将进行调查。第二, 使用具有来自以下各项的编码区的痘苗病毒构建体 髓鞘碱性蛋白、蛋白脂蛋白和髓鞘相关 糖蛋白，小鼠是否会被感染来确定是否有自身免疫 疾病可由携带已知的“疾病”诱因的病毒引起 区域。此外，诱发疾病的要求以及是否如此 构建物可以保护或修改现有的自身免疫性疾病 被追捕。 此外，病毒对中枢神经系统疾病以及免疫的直接作用 我们将研究其对脱髓鞘的调节作用。的模型。 泰勒氏小鼠脑脊髓炎病毒感染的小鼠 被利用了。这是一种小鼠小核糖核酸病毒，可以产生脱髓鞘 疾病在适当的小鼠品系中。这里的实验定义了 病毒对免疫介导性疾病的作用在 免疫功能低下的小鼠。重建实验被描绘成 确定每个组件在启动和维护过程中可能扮演的相对角色 中枢神经系统损伤。计划进行更多的实验，以确定 免疫反应可以调节模型系统中病毒的清除。

The etiology and pathogenesis of multiple sclerosis and the post- infectious encephalopathies are not known. Treatment is generally ineffective. Virus infection and/or the generation of aberrant immune responses have been suspected to play a major role in the etiology of these entities. This proposal is directed at studying the interaction of virus with antiviral immune responses mounted by the host. Such events could lead to autoimmune phenomenon through the generation and/or expansion of self reactive cells within the central nervous system (CNS). In addition, direct viral interactions can contribute to CNS pathology. By comprehending the mechanisms how viruses interact with the immune system and target tissues to produce disease will provide valuable information applicable toward understanding CNS diseases in man and hopefully their eventual treatment and prevention. In this proposal experiments are planned to extend our initial observations examining homologies and cross-reacting immune responses between viral determinants and self constituents. In many instances these cross-reactions are interesting however the role in disease is unclear. Therefore, studies are purposed to investigate models to examine the biological relevance of the cross-reacting immune responses in actual disease induction. Two models will be studied in depth. First the role of antibodies which cross-react with virus and self components in initiating or enhancing CNS disease will be investigated. Second, employing vaccinia virus constructs having cDNA coding regions from myelin basic protein, proteolipid protein and myelin associated glycoprotein, mice will be infected to determine whether an autoimmune disease can be initiated by a virus carrying a known "disease" inducing region. Further, the requirements for disease induction and whether such constructs can protect or modify an existing autoimmune disease will be pursued. In addition the direct viral effects on CNS disease as well as immune mediated contributions to demyelination will be examined. The model of Theiler's murine encephalomyelitis virus infection of mice will be utilized. This is a murine picornavirus that can produce a demyelinating disease in the appropriate mouse strains. Here experiments defining the role of virus versus immune mediated disease are proposed in immunocompromised mice. Reconstitution experiments are delineated to determine the relative role each may play in initiating and maintaining CNS injury. Additional experiments are planned to define whether immunologic responses can mediate viral clearance in the model system.