Understanding the roles type I Interferon and TH17 play in Neuromyelitis Optica and other autoimmune diseases.

摘要： 视神经脊髓炎(NMO)是一种罕见但具有破坏性的中枢神经系统炎症性疾病。 (中枢神经系统)，主要影响视神经和脊髓。NMO最初被描述为 多发性硬化症(MS)，但现在被认为是一种独特的疾病。已有研究表明，两种I型干扰素 干扰素-I和辅助性T细胞17(TH17)在NMO的病理过程中起关键作用，但目前尚不清楚干扰素-I是如何发生的 和TH17共同推动疾病病理。我们的初步数据现在显示，干扰素-I基因签名是 在NMO的血液中升高，并与TH17签名高度相关。此外，我们的研究使用了 TH17诱导的实验性自身免疫性脑脊髓炎(TH17-EAE)小鼠支持以下假设 干扰素-I通过刺激抗原提呈细胞产生IL-6来刺激TH17介导的疾病，进而推动 GM-CSF和其他炎性细胞因子的产生。对于这项赠款申请，我们建议使用NMO 患者样本和TH17-EAE研究TH17和干扰素-I在人类神经炎症中的协同作用 疾病和在活体动物模型中。在目标1中，我们将使用RNA测序来鉴定离散细胞类型 在NMO患者中含有干扰素-I信号，并发现了可以调节干扰素-I和TH17的新基因 小路。在目标2中，我们将进行体外培养实验，以确定干扰素-I如何影响T辅助细胞 NMO患者与健康对照组的差异。在目标3中，我们将使用TH17-EAE模型来 了解干扰素-I加重TH17诱导的神经自身免疫性疾病的机制。这个 将人体研究与本方案中概述的机械动物实验相结合 有可能深入了解NMO和其他自身免疫的病理过程 有干扰素-I和TH17标志的疾病。

Summary: Neuromyelitis optica (NMO) is a rare but devastating inflammatory disorder of the central nervous system (CNS) that primarily affects the optic nerves and spinal cord. NMO was initially characterized as a subset of multiple sclerosis (MS), but is now considered a distinct disease. It has been shown that both type I interferon (IFN-I) and T helper 17 (TH17) cells play a critical role in the pathology of NMO, however it is unclear how IFN-I and TH17 cooperate to drive disease pathology. Our preliminary data now show that IFN-I gene signatures are elevated in blood from NMO and are highly correlated with TH17 signatures. Furthermore, our studies using mice with TH17-induced experimental autoimmune encephalomyelitis (TH17-EAE) supports the hypothesis that IFN-I fuels TH17-mediated disease by stimulating antigen presenting cells to produce IL-6 which in turn drives the production of GM-CSF and other inflammatory cytokines. For this grant application, we propose to use NMO patient samples and TH17-EAE to study how TH17 and IFN-I cooperate in driving neuro-inflammation in human disease and in an in vivo animal model. In AIM 1, we will use RNA-sequencing to identify the discrete cell types that harbor the IFN-I signature in NMO patients and discover novel genes that could regulate IFN-I and TH17 pathways. In Aim 2, we will perform in vitro culture experiments to determine how IFN-I affects T helper cell differentiation in NMO patients compared to healthy controls. In Aim 3, we will use the TH17-EAE model to understand the mechanisms by which IFN-I exacerbates TH17-induced neuro-autoimmune disease. The combination of research on human subject and the mechanistic animal experiments outlined in this proposal have the potential to give deep insight into pathological processes that underlie NMO and other autoimmune diseases with IFN-I and TH17 signatures.