Virus Infection Leads to Autoreactive T Cells Having Multiple TCRs

病毒感染导致自身反应性 T 细胞产生多个 TCR

• 批准号: 8594567
• 负责人: Robert S Fujinami
• 金额: $ 32.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594567
• 关键词: Address; Autoimmune Diseases; Autoimmune Process; Biology; Blood Circulation; Brain; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Line; Cell surface; Cells; Central Nervous System Diseases; Central Nervous System Viral Diseases; Cerebrospinal Fluid; Chromosomes; Cytolysis; Cytotoxic T-Lymphocytes; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Environment; Epitopes; Event; Experimental Animal Model; Family Picornaviridae; HLA-A2 Antigen; HLA-A3 Antigen; Human; Immune; Immune response; Immune system; Individual; Infection; Inflammation; Inflammatory; Interferons; Lead; MHC Class I Genes; Maintenance; Mediating; Microbe; Molecular Mimicry; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Myelin Associated Glycoprotein; Myelin Basic Proteins; Myelin Proteins; Myelin Proteolipid Protein; Neuraxis; Pathway interactions; Patients; Peptides; Peripheral; Picornaviridae Infections; Population; Process; Proteins; Proteolipids; Regulation; Reporting; Risk; Role; Saccharomyces cerevisiae; Series; Specificity; Surface; T-Cell Receptor; T-Lymphocyte; TMEV; Testing; Tumor Necrosis Factor-alpha; Variant; Virus; Virus Diseases; autoreactive T cell; central nervous system demyelinating disorder; insight; public health relevance; receptor; self help

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.

描述（由申请人提供）：多发性硬化症（MS）是中枢神经系统（CNS）的炎症性脱髓鞘疾病。 MS通常被称为免疫介导的疾病，在该疾病中，人体的免疫系统被愚弄了中枢神经系统内的髓磷脂。 MS的原因尚不清楚。但是，病毒感染通常与该疾病的起始和加剧有关。不同的病毒如何触发MS的攻击仍不清楚，但是至少提出了两个假设来解释如何发生这种情况。第一个假设涉及通过病毒直接感染大脑。这种病毒感染引起 炎症和对产生髓磷脂的细胞的损害。这种损害释放出髓磷脂的碎片，这些碎片被自动反应性T细胞识别，然后在炎症环境中激活。这些识别髓磷脂蛋白表位的T细胞随后触发了一系列事件，导致CNS和髓磷脂破坏更多的炎症。第二个假设涉及在中枢神经系统之外发生的病毒感染，其中免疫反应与CNS髓磷脂或“自我”交叉反应。因此，T细胞具有识别病毒和髓磷脂的能力。这些细胞被病毒感染激活，这些细胞也识别出髓磷脂现在进入中枢神经系统并引起炎症和脱髓鞘。我们提议检验第二个假设的变化。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磷脂。我们建议探索如何生成这些细胞，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细胞表面上有多个受体。 T细胞通常具有一个T细胞受体（TCR），该受体仅识别病毒或自我，但两者兼而有之。但是，通过具有多个受体，可以通过识别病毒和其他TCR靶标的髓磷脂或自我的TCR激活T细胞。相关性：我们怀疑有多种途径导致我们称为MS的疾病。我们的建议调查了这些途径之一。我们正在检验以下假设：外周感染可以产生对病毒和自我具有特异性的T细胞。如果这些细胞能够规避调节和扩展，它们可以启动自身免疫性炎症性疾病。这些研究将洞悉病毒感染如何诱导识别病毒和自我的T细胞，并有助于解释为什么没有将单一病毒鉴定为MS的病因。