Autoimmune CNSnDisease Induced by Virus Infection

大量报告表明，感染在多发性硬化症(MS)和其他疾病中发挥着重要作用 人类的自身免疫性疾病，如糖尿病。病毒感染似乎与MS的发作和/或恶化有关，并被认为在初始启动阶段通过在某些具有易感遗传表型的个体中扩大自身反应性T细胞而参与。在过去的50年里，从多发性硬化症患者身上分离出了十几种病毒，但没有一种病毒被确定为病原体。我们认为，与自身中枢神经系统(CNS)蛋白发生分子模仿的感染可以启动遗传易感个体；一旦启动，免疫挑战可能通过旁观者激活和/或分子模仿而导致疾病。在MS的实验动物模型中，假设髓鞘特异的Th1CD4+T细胞介导MS，实验性变态反应性脑脊髓炎(EAE)、髓鞘特异的CD4+T细胞以及最近的CD8+T细胞可以过继地将疾病传递给幼稚动物。在传统形式的EAE中，通过在强大的佐剂中注射髓鞘蛋白或脑源性多肽来诱导这些髓鞘特异的Th1 CD4+T细胞，使小鼠对髓鞘抗原敏感。这会导致中枢神经系统的炎性脱髓鞘疾病。EAE中的病变与MS患者的早期病变非常相似。患有EAE的小鼠也 会出现复发缓解的临床病程，见于大约80%的多发性硬化症患者。在这项提议中，我们将检验病毒感染与自身中枢神经系统具有分子模仿性的假设 蛋白质可以为动物的EAE做好准备。一旦这片“沃土”被播种，一种有利于IL-12等促炎细胞因子的感染将引发病情恶化。初步数据显示，编码自身中枢神经系统蛋白的cDNA或重组病毒用于接种或感染小鼠时，可以为EAE创造肥沃的田地做好准备。这些免疫的小鼠没有表现出任何表明EAE的临床或病理变化。然而，稍后当这些小鼠受到病毒感染的挑战时，小鼠就会患上急性EAE。这项应用旨在了解疾病发生的免疫学基础，并研究启动和挑战阶段所涉及的机制。这项提议将提供对感染性病原体如何导致自身免疫性疾病的洞察。

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.