Virus Infection Leads to Autoreactive T Cells Having Multiple TCRs

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的炎性脱髓鞘疾病。多发性硬化症通常被称为一种免疫介导的疾病，即人体的免疫系统被欺骗而攻击中枢神经系统内的髓磷脂。多发性硬化症的病因尚不清楚。然而，病毒感染通常与这种疾病的发生和恶化有关。目前尚不清楚不同的病毒如何引发多发性硬化症的攻击，但至少已经提出了两种假设来解释这种情况是如何发生的。第一个假设涉及病毒直接感染大脑。这种病毒感染导致 产生髓磷脂的细胞发生炎症和损伤。这种损伤会释放髓鞘质碎片，这些碎片会被自身反应性 T 细胞识别，然后在炎症环境中被激活。这些识别髓磷脂蛋白表位的 T 细胞随后会触发一系列事件，导致中枢神经系统出现更多炎症并破坏髓磷脂。第二个假设涉及中枢神经系统外部发生的病毒感染，其中对病毒的免疫反应与中枢神经系统髓磷脂或“自身”发生交叉反应。因此，T 细胞具有识别病毒和髓磷脂的能力。这些被病毒感染激活的细胞也识别髓磷脂，现在进入中枢神经系统并引起炎症和脱髓鞘。我们建议测试第二个假设的变体。我们有证据表明，某些病毒感染后被激活的 T 细胞可以识别病毒和髓磷脂。我们提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身的 T 细胞表面有不止一种受体。 T 细胞通常有一种 T 细胞受体 (TCR)，只能识别病毒或自身，但不能同时识别两者；但是，通过拥有不止一种受体，T 细胞可以被识别病毒的 TCR 和其他针对髓磷脂或自身的 TCR 激活。相关性：我们怀疑有多种途径导致我们称之为多发性硬化症的疾病。我们的提案研究了其中一种途径。我们正在测试以下假设：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调节并扩张，它们可能会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多发性硬化症的病原体。

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.