MOLECULAR MIMICRY AND VIRUS-INDUCED AUTOIMMUNITY

分子拟态和病毒引起的自身免疫

• 批准号: 3406391
• 负责人: Robert S Fujinami
• 金额: $ 23.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3406391
• 关键词: autoantibody; autoimmune disorder; autoimmunity; cellular immunity; central nervous system; cerebrosides; disease /disorder model; electron microscopy; encephalitis virus; enzyme linked immunosorbent assay; experimental allergic encephalomyelitis; gel electrophoresis; host organism interaction; hybridomas; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rabbit; leukocyte activation /transformation; monoclonal antibody; myelin; myelinopathy; tissue /cell culture; vaccinia virus; virus infection mechanism; virus protein

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.

多发性硬化的病因、发病机制及治疗后 感染性脑病是未知的。 处理通常 无效。 病毒感染和/或产生异常免疫 反应被怀疑在病因学中起主要作用， 这些实体。 该建议旨在研究 病毒与抗病毒免疫反应安装的主机。 此类事件 可能导致自身免疫现象，通过产生和/或 中枢神经系统（CNS）内的自身反应细胞的扩增。 此外，直接的病毒相互作用可导致CNS病理学。 通过理解病毒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CNS疾病的信息， 希望他们最终的治疗和预防。 在这个提议中，实验计划扩展我们最初的 检查同源性和交叉反应免疫应答的观察结果 病毒决定因子和自身成分之间的联系 在许多情况下 这些交叉反应是有趣的，然而， 不清楚 因此，研究的目的是调查模型， 检查交叉免疫反应的生物相关性 在实际的疾病诱导中。 将深入研究两种模式。 第一 与病毒和自身成分交叉反应抗体的作用 在引发或增强CNS疾病中的作用将被研究。 第二、 使用具有来自 髓鞘碱性蛋白、蛋白脂质蛋白和髓鞘相关蛋白 糖蛋白，小鼠将被感染，以确定是否有自身免疫性 疾病可由携带已知的“疾病”诱导因子的病毒引发。 地区此外，对疾病诱导的要求以及是否 构建体可以保护或改变现有的自身免疫性疾病， 追求。 此外，病毒对中枢神经系统疾病以及免疫系统的直接影响 将检查介导的脱髓鞘作用。 模型 Theiler氏鼠脑脊髓炎病毒感染小鼠后， 利用。 这是一种鼠小核糖核酸病毒， 疾病在适当的小鼠品系。 这里的实验定义了 病毒对免疫介导的疾病的作用被提出， 免疫受损的小鼠。 重构实验被描述为 确定每一个在发起和维持 CNS损伤。 计划进行更多的实验，以确定是否 免疫应答可以介导模型系统中的病毒清除。