TARGETING INTERFERON LAMBDA SIGNALING DURING CENTRAL NERVOUS SYSTEM AUTOIMMUNITY

项目摘要/摘要 本研究的目的是阐明干扰素λ在中枢神经系统中的作用。 自身免疫力。人类中枢神经系统自身免疫最常见的形式是多发性硬化症(MS)，这是一种疾病 多发性硬化症是一种脱髓鞘的自身免疫性疾病，可导致 各种神经系统症状，包括四肢无力、视神经炎和共济失调1；它是 年轻人的残疾。由于发病年龄较小和疾病的持续进展性，MS 这不仅是个人负担，也是重大的社会经济负担。目前，大约有 十几种治疗多发性硬化症的选择；尽管它们在减少复发频率和严重程度方面有效，但它们 有许多副作用，实际上没有一种能阻止疾病进展或促进康复19。这表明有必要 为了更好地理解导致慢性病的机制，并将这些信息转化为新的 多发性硬化的治疗策略 干扰素λ(干扰素或III型干扰素)是一类与I型干扰素密切相关的细胞因子；这两类干扰素都是由 诱导抗病毒基因表达的类似JAK STAT信号通路8-10。I型干扰素已经被 在中枢神经系统自身免疫性疾病中得到高度研究，并发挥保护作用，这与其作为 治疗MS12，13，31。然而，对干扰素λ在多发性硬化症中的作用知之甚少。 干扰素λ可阻止中枢神经系统小鼠模型的恢复并导致持续性炎症 自身免疫，实验性自身免疫性脑脊髓炎(EAE)。干扰素λ信号缺陷动物 在恢复过程中表现出临床评分的改善，炎症减轻，轴突损伤减轻 来自EAE的。这表明干扰素λ可能在疾病发生后的疾病维持中发挥关键作用。 已启动。因此，本项目的目标是了解干扰素λ是如何调节免疫介导的。 中枢神经系统自身免疫过程中的炎症和神经元损伤。这项建议中概述的研究包括 分析干扰素λ及其受体的时空表达，条件性删除干扰素λ受体的实验 以细胞特异性的方式，分析体外培养的抗原提呈细胞(APC)和T细胞，以检查 干扰素λ的S对脱髓鞘的影响，并检测MS患者标本中干扰素λ的水平。本项目竣工 将提供对中枢神经系统自身免疫性疾病潜在的细胞机制的见解。

Project Summary/Abstract The goal of this proposal is to elucidate the role of interferon lambda (IFNλ) during central nervous system (CNS) autoimmunity. The most common form of CNS autoimmunity among humans is multiple sclerosis (MS), a disease that affects over 2.5 million people worldwide2,16. MS is a demyelinating autoimmune disease that can cause a variety of neurologic symptoms including extremity weakness, optic neuritis, and ataxia1; it is a major cause of disability in young adults. Due to the young age of onset and continuously progressive nature of the disease, MS is not only a personal burden but also a substantial socioeconomic burden16. Currently, there are approximately one dozen therapeutic options for MS; although effective in reducing relapse frequency and severity, they have numerous side effects and none actually halt disease progression or promote recovery19. This suggests the need for an improved understanding of mechanisms driving chronic disease and to translate this information into new therapeutic strategies for MS. IFNλ (interferon lambda or type III IFN) is a class of cytokines closely related to type I IFN; both classes initiate analogous JAK STAT signaling pathways that induce expression of antiviral genes8-10. Type I IFN have been highly studied in CNS autoimmune diseases and play a protective role that is consistent with its use as a therapeutic for MS12,13,31. Very little, however, is known about the role of IFNλ in MS. Preliminary data has demonstrated that IFNλ may prevent recovery and lead to sustained inflammation in the murine model of CNS autoimmunity, experimental autoimmune encephalomyelitis (EAE). Animals deficient in IFNλ signaling demonstrated improved clinical scores, decreased inflammation, and decreased axonal damage during recovery from EAE. This suggests that IFNλ may play a critical role in disease maintenance after disease is already initiated. Therefore, the goal of this project is to understand how IFNλ modulates immune mediated inflammation and neuronal damage during CNS autoimmunity. The studies outlined in this proposal include experiments to analyze spatiotemporal expression of IFNλ and its receptor, to conditionally delete IFNλ receptor in a cell specific manner, to analyze in vitro cultures of antigen presenting cells (APCs) and T cells, to examine IFNλ’s effects on demyelination, and to measure IFNλ levels in MS patient samples. Completion of this project will provide insights into the cellular mechanisms underlying CNS autoimmune diseases.