TARGETING INTERFERON LAMBDA SIGNALING DURING CENTRAL NERVOUS SYSTEM AUTOIMMUNITY

项目总结/摘要 本研究旨在阐明干扰素λ（IFNλ）在中枢神经系统（CNS） 自身免疫人类CNS自身免疫最常见的形式是多发性硬化症（MS）， 影响全球超过250万人2，16。MS是一种脱髓鞘自身免疫性疾病， 多种神经系统症状，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小和疾病的持续进行性，MS 不仅是个人负担，也是巨大的社会经济负担。目前，大约有 MS的十几种治疗选择;虽然有效降低复发频率和严重程度，但它们具有 许多副作用，但没有一个真正阻止疾病进展或促进康复19。这表明需要 为了更好地了解慢性疾病的驱动机制，并将这些信息转化为新的 MS的治疗策略 IFNλ（干扰素λ或III型IFN）是一类与I型IFN密切相关的细胞因子;两类细胞因子均引发IFN-γ。 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 治疗多发性硬化症12，13，31.然而，关于IFNλ在MS中的作用知之甚少。 表明IFNλ可能阻止恢复，并导致持续的炎症在中枢神经系统的小鼠模型 实验性自身免疫性脑脊髓炎（EAE）。IFNλ信号传导缺陷的动物 在恢复过程中表现出改善的临床评分，减少炎症和减少轴突损伤 从EAE。这表明，IFNλ可能在疾病已经发生后的疾病维持中发挥关键作用。 启动。因此，本项目的目标是了解IFNλ如何调节免疫介导的 炎症和CNS自身免疫过程中的神经元损伤。本提案中概述的研究包括 分析IFNλ及其受体时空表达的实验， 以细胞特异性方式，分析抗原呈递细胞（APC）和T细胞的体外培养物， IFNλ对脱髓鞘的作用，并测量MS患者样品中的IFNλ水平。完成本项目 将提供深入了解中枢神经系统自身免疫性疾病的细胞机制。

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.