Virus Infection Leads to Autoreactive T Cells Having Multiple TCRs

描述(申请人提供)：多发性硬化症(MS)是一种中枢神经系统(CNS)的炎症性脱髓鞘疾病。MS通常被称为一种免疫介导性疾病，即人体的免疫系统被愚弄而攻击中枢神经系统内的髓鞘。多发性硬化症的病因尚不清楚。然而，病毒感染往往与这种疾病的开始和恶化有关。目前尚不清楚不同的病毒如何触发多发性硬化症的攻击，但至少提出了两种假设来解释这种情况是如何发生的。第一种假设涉及病毒直接感染大脑。这种病毒感染会导致 炎症和对产生髓鞘的细胞的破坏。这种损伤会释放被自身反应性T细胞识别的髓鞘片段，然后在炎症环境中被激活。这些识别髓鞘蛋白表位的T细胞然后触发一系列事件，导致中枢神经系统更多的炎症和髓鞘的破坏。第二种假设认为病毒感染发生在中枢神经系统之外，对病毒的免疫反应与中枢神经系统髓鞘或“自身”发生交叉反应。因此，T细胞既能识别病毒，又能识别髓鞘。这些被病毒感染激活的细胞也识别髓鞘，现在进入中枢神经系统，导致炎症和脱髓鞘。我们建议测试第二个假设的一个变种。我们有证据表明，在某些类型的病毒感染后被激活的T细胞可以识别病毒和髓鞘。我们建议探索这些细胞是如何产生的，并了解这些T细胞如何识别两个不同的实体。在我们的初步研究中，我们发现识别病毒和自我的T细胞表面有不止一个受体。T细胞通常有一个T细胞受体(TCR)，它只识别病毒或自身，但不能同时识别两者；但是，如果有多个受体，T细胞可以被识别病毒的TCR激活，另一个TCR针对髓鞘或自身。相关性：我们怀疑有多条途径导致了我们称之为MS的疾病，我们的提案调查了其中一条途径。我们正在验证这样一个假设，即外周感染可以产生对病毒和自身都具有特异性的T细胞。如果这些细胞能够绕过监管并扩张，它们可能会引发自身免疫性炎症性疾病。这些研究将深入了解病毒感染如何诱导同时识别病毒和自身的T细胞，并有助于解释为什么没有单一病毒被确定为MS的病原体。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). MS is often referred to as an immune mediated disease, where the body's immune system is fooled into attacking myelin within the CNS. The cause of MS is not known. However, viral infections are often associated with the initiation and exacerbations of this disease. How different viruses trigger attacks of MS is still unclear, but at least two hypotheses have been put forth to explain how this could occur. The first hypothesis involves direct infection of the brain by a virus. This viral infection causes inflammation and damage to cells that produce myelin. This damage releases fragments of myelin that are recognized by autoreactive T cells which then are activated within the inflammatory milieu. These T cells that recognize epitopes of myelin proteins then trigger a series of events that result in more inflammation in the CNS and myelin destruction. A second hypothesis involves a virus infection taking place outside of the CNS where the immune response to the virus cross-reacts with CNS myelin or "self." Therefore, T cells have the ability to recognize both the virus as well as myelin. These cells activated by the virus infection that also recognize myelin now ingress into the CNS and cause inflammation and demyelination. We are proposing to test a variation of this second hypothesis. We have evidence that the T cells that are activated following certain kinds of virus infections can recognize virus and myelin. We are proposing to explore how these cells are generated and understand how these T cells can recognize two disparate entities. In our preliminary studies, we find that the T cells that recognize both virus and self have more than one receptor on their surface. T cells normally have one T cell receptor (TCR) that recognizes just virus or self but not both; but, by having more than one receptor, the T cell can be activated by the TCR that recognizes virus and the other TCR targets myelin or self. Relevance: We suspect that there are multiple pathways that lead to the disease we call MS. Our proposal investigates one of these pathways. We are testing the hypothesis that peripheral infections can generate T cells which have specificity to both virus and self. If such cells are able to circumvent regulation and expand, they could initiat autoimmune inflammatory disease. These studies will provide insight into how viral infections could induce T cells that recognize both virus and self and help explain why no single virus has been identified as the causative agent of MS.