Virus Infection Leads to Autoreactive T Cells Having Multiple TCRs

描述（由申请人提供）：多发性硬化（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病。MS通常被称为免疫介导的疾病，其中身体的免疫系统被愚弄以攻击CNS内的髓鞘。MS的病因尚不清楚。然而，病毒感染通常与这种疾病的开始和恶化有关。不同的病毒如何触发MS的攻击仍然不清楚，但至少有两种假设已经提出来解释这是如何发生的。第一种假设涉及病毒直接感染大脑。这种病毒感染会导致 炎症和损伤产生髓鞘的细胞。这种损伤释放出髓鞘的片段，这些片段被自身反应性T细胞识别，然后在炎症环境中被激活。这些识别髓鞘蛋白表位的T细胞随后触发一系列事件，导致CNS中更多的炎症和髓鞘破坏。第二种假设是病毒感染发生在中枢神经系统外，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细胞具有识别病毒和髓鞘的能力。这些被病毒感染激活的细胞也识别髓鞘，现在进入CNS并引起炎症和脱髓鞘。我们打算检验第二个假设的一个变体。我们有证据表明，在某些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细胞如何识别两种不同的实体。在我们的初步研究中，我们发现识别病毒和自身的T细胞在其表面上有不止一个受体。T细胞通常具有一个T细胞受体（TCR），其仅识别病毒或自身，但不能识别两者;但是，通过具有多于一个受体，T细胞可以被识别病毒的TCR激活，而另一个TCR靶向髓鞘或自身。相关性：我们怀疑有多种途径导致我们称之为MS的疾病，我们的提案调查了其中一种途径。我们正在验证外周感染可以产生对病毒和自身都具有特异性的T细胞的假设。如果这些细胞能够绕过调节并扩增，它们可能引发自身免疫性炎症疾病。这些研究将深入了解病毒感染如何诱导T细胞识别病毒和自身，并帮助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.