Autoimmune CNSnDisease Induced by Virus Infection

病毒感染引起的自身免疫性中枢神经系统疾病

• 批准号: 6746548
• 负责人: Robert S Fujinami
• 金额: $ 35.17万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746548
• 关键词: autoimmune disorder; cytokine; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; experimental allergic encephalomyelitis; genetically modified animals; helper T lymphocyte; host organism interaction; laboratory mouse; multiple sclerosis; myelin; myelin basic proteins; virus infection mechanism

Numerous reports indicate the important role infections play in multiple sclerosis (MS) and other autoimmune diseases of humans such as diabetes. Viral infections appear to be associated with attacks and/or exacerbations of MS and are thought to be involved at the initial priming stage by expanding autoreactive T cells in certain individuals with a susceptible genetic phenotype. More than a dozen viruses have been isolated from MS patients in the past 50 years, but no single virus has been identified as the causative agent. We propose that infections having molecular mimicry with self central nervous system (CNS) proteins can prime genetically susceptible individuals; once priming has occurred, an immunologic challenge could result in disease, through bystander activation and/or molecular mimicry. It is hypothesized that myelin specific Th1 CD4 + T cells mediate MS. In the experimental animal model for MS, experimental allergic encephalomyelitis (EAE), myelin specific CD4 + and more recently CD8 + T cells can adoptively transfer disease to naive animals. In conventional forms of EAE, mice are sensitized to myelin antigens by injection of myelin proteins or encephalitogenic peptides in powerful adjuvants eliciting these myelin specific Th1 CD4 + T cells. This results in an inflammatory demyelinating disease of the CNS. Lesions seen in EAE are very similar to early lesions present in MS patients. Mice with EAE also will develop a relapsing-remitting clinical course seen in about 80% of MS patients. In this proposal we will test the hypothesis that viral infections having molecular mimicry with self-CNS proteins can prime animals for EAE. Once this "fertile field" is sown an infection favoring proinflammatory cytokines such as IL-12 will initiate an exacerbation. Preliminary data shows that cDNAs or recombinant viruses encoding self-CNS proteins when used to inoculate or infect mice can prime for EAE creating the fertile field. These primed mice do not show any clinical or pathological changes indicative of EAE. However, at a later time when these mice are challenged by a viral infection, mice develop an acute attack of EAE. This application proposes to understand the immunological basis for the initiation of disease and investigate the mechanisms involved in the priming and challenge phases. This proposal will provide insight into how infectious agents cause autoimmune disease.

许多报告表明，感染在多发性硬化症（MS）和其他疾病中起着重要作用。 人类自身免疫性疾病，如糖尿病。病毒感染似乎与MS的发作和/或加重相关，并且被认为在初始引发阶段通过扩增具有易感遗传表型的某些个体中的自身反应性T细胞而参与。在过去的50年里，已经从MS患者中分离出了十几种病毒，但没有一种病毒被确定为病原体。我们提出，感染具有与自身中枢神经系统（CNS）蛋白质的分子模拟可以引发遗传易感个体;一旦引发发生，免疫挑战可能导致疾病，通过旁观者激活和/或分子模拟。假设髓磷脂特异性Th 1 CD 4 + T细胞介导MS。在MS的实验动物模型中，实验性过敏性脑脊髓炎（EAE）、髓磷脂特异性CD 4+和最近的CD 8 + T细胞可以过继性地将疾病转移到幼稚动物。在EAE的常规形式中，通过注射在强效佐剂中的髓鞘蛋白或致脑炎肽来使小鼠对髓鞘抗原致敏，从而引发这些髓鞘特异性Th 1 CD 4 + T细胞。这导致CNS的炎性脱髓鞘疾病。在EAE中观察到的病变与MS患者中存在的早期病变非常相似。患有EAE的小鼠也 在大约80%的MS患者中会出现复发缓解的临床过程。在这个建议中，我们将测试病毒感染与自身CNS具有分子模拟的假设。 蛋白质可以引发动物EAE。一旦这片“肥沃的土地”被播种，有利于促炎细胞因子如IL-12的感染将开始恶化。初步数据显示，编码自身CNS蛋白的cDNA或重组病毒在用于接种或感染小鼠时可引发EAE，从而产生可育区域。这些致敏小鼠未显示出任何指示EAE的临床或病理学变化。然而，在稍后的时间，当这些小鼠受到病毒感染的攻击时，小鼠发展为EAE的急性发作。本申请旨在了解疾病发生的免疫学基础，并研究引发和激发阶段所涉及的机制。这一提议将为传染性病原体如何引起自身免疫性疾病提供深入了解。