Investigation of Novel Roles For IRF7 in EAE

项目摘要/摘要 内源性和外源性干扰素-β联合抑制实验性自身免疫性脑脊髓炎 小鼠(EAE)和人类多发性硬化症(MS)的发病机制尚未明确。尽管如此，干扰素-β非 在这两种疾病中都可以找到应答者。转录因子，干扰素调节因子-7(IRF7)是一个关键 体内产生I型干扰素的调节因子。遗传数据已将IRF基因多态性与多发性硬化症联系起来， 包括一个病例，其中疾病相关变异与未能诱导多种已知干扰素相关 干扰素-β治疗开始后的反应基因。我们发现IRF7基因缺陷的小鼠发育更快 与野生型对照相比，重度EAE和趋化因子C-X-C基序趋化因子配体13水平 (CXCL13)，在基础水平和EAE期间，IRF7缺陷小鼠的脊髓中都异常高。 先前的研究表明，CXCL13维持髓鞘特异性的CD4+T细胞反应和临床症状 在疾病期间。综上所述，这些数据使我们假设IRF7/I型干扰素抑制 CXCL13的淋巴样细胞产生(或防止产生CXCL13的淋巴样细胞的出现)作为一种 在EAE期间限制致病性中枢神经系统炎症的适应性机制。我们将通过两个例子来检验我们的假设 具体目的：1)阐明IRF7如何抑制脑源性Th17细胞和抑制过继转移 通过在受体宿主中的作用，以及2)确认IRF7缺陷小鼠对 EAE与CXCL13表达改变有因果关系，并研究CXCL13是如何维持EAE的 严肃性。我们的主要目标是进一步研究IRF7在中枢神经系统自身免疫性脱髓鞘过程中的作用 并更直接地将IRF7和I型干扰素的作用与淋巴趋化因子的产生联系起来。我们的 长期目标是更好地了解干扰素-β是如何在EAE和MS中有效的，并开发方法来 快速识别干扰素-β无应答的多发性硬化症患者，以便启动替代治疗 毫不迟疑。干扰素-β仍然是RRMS最常用的处方治疗方法，并将继续使用 因此，了解它在这一疾病中的行动仍然是义不容辞的。

Project Summary/Abstract Both endogenous and exogenous interferon (IFN)-β suppress experimental autoimmune encephalomyelitis (EAE) in mice and multiple sclerosis (MS) in humans through poorly defined mechanisms. Still, IFN-β non- responders can be identified in both diseases. The transcription factor, IFN regulatory factor-7 (IRF7), is a key regulator of type-I IFN production in vivo. Genetic data have linked IRF gene polymorphisms with MS, including one case where the disease-associated variant correlated with a failure to induce multiple known IFN response genes following the initiation of IFN-β therapy. We find that IRF7-deficient mice develop more severe EAE than wild-type controls, and that levels of the chemokine, C-X-C motif chemokine ligand 13 (CXCL13), are abnormally high in IRF7-deficient mice both at baseline and in the spinal cord during EAE. Prior studies demonstrate that CXCL13 sustains myelin-specific CD4+ T cell responses and clinical symptoms during disease. Taken together, these data lead us to hypothesize that IRF7/type-I IFN acts to suppress lymphoid cell production of CXCL13 (or to prevent the emergence of CXCL13-producing lymphoid cells) as an adaptive mechanism to limit pathogenic CNS inflammation during EAE. We will test our hypothesis via two specific aims: 1) To clarify how IRF7 constrains encephalitogenic Th17 cells and suppresses adoptive transfer EAE via actions in the recipient host, and 2) To confirm the heightened susceptibility of IRF7-deficient mice to EAE is causally related to altered expression of CXCL13, and to investigate how CXCL13 acts to sustain EAE severity. Our main objective is to further characterize the role of IRF7 during CNS autoimmune demyelinating disease and to more directly link the actions of IRF7 and type-I IFN with lymphoid chemokine production. Our long-term goal is to better understand how IFN-β is efficacious in EAE and MS, and to develop methods to quickly identify MS patients who will be IFN-β non-responders so that alternative treatments can be initiated without delay. IFN-β remains the most commonly prescribed therapy for RRMS and will continue to be used for many years to come, so it remains incumbent to understand its actions in this disease.