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

了解 I 型干扰素和 TH17 在视神经脊髓炎和其他自身免疫性疾病中的作用。

• 批准号: 10215451
• 负责人: Robert C Axtell
• 金额: $ 70.08万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215451
• 关键词: Address; Adverse effects; Affect; Animal Experiments; Animal Model; Antibodies; Antigen-Presenting Cells; Applications Grants; Autoantigens; Autoimmune Diseases; Automobile Driving; B-Cell Activation; Biological Assay; Blood; CD4 Positive T Lymphocytes; CNS autoimmunity; Cell Differentiation process; Cells; Central Nervous System Diseases; Coculture Techniques; Data; Development; Disease; Experimental Autoimmune Encephalomyelitis; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Helper-Inducer T-Lymphocyte; Human; IFNAR1 gene; Immune; In Vitro; Individual; Inflammation; Inflammatory; Interferon Type I; Interferon-beta; Interferons; Interleukin-17; Interleukin-6; Knowledge; Lupus; Mediating; Mediator of activation protein; Memory B-Lymphocyte; Modeling; Multiple Sclerosis; Mus; Myelin; Myelogenous; Neuraxis; Neuromyelitis Optica; Optic Nerve; Optic Neuritis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Patients; Phenotype; Play; Production; Psoriasis; Recombinants; Research; Role; Sampling; Site; Solid; Spinal; Spinal Cord; T cell differentiation; T-Lymphocyte; Th1 Cells; Therapeutic; Transcript; Ulcerative Colitis; aquaporin 4; autoreactivity; cell type; chemokine receptor; cytokine; experimental study; genetic signature; human disease; human subject; in vivo; in vivo evaluation; inhibitor/antagonist; insight; nervous system disorder; neuroinflammation; neutrophil; new therapeutic target; novel; orphan nuclear receptor ROR-gamma; peripheral blood; receptor; transcriptome sequencing; transcriptomics

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.

总结： 视神经肌萎缩症（NMO）是一种罕见但破坏性的中枢神经系统炎症性疾病 (CNS)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。研究表明，I型干扰素 IFN-1和辅助性T细胞17（Th 17）在NMO的病理学中起关键作用，然而，目前尚不清楚IFN-1是如何影响NMO的病理学的。 和TH 17合作驱动疾病病理学。我们的初步数据现在显示，IFN-I基因签名是 在血液中从NMO升高，并与TH 17签名高度相关。此外，我们的研究使用 患有TH 17诱导的实验性自身免疫性脑脊髓炎（TH 17-EAE）的小鼠支持以下假设， IFN-I通过刺激抗原呈递细胞产生IL-6而刺激TH 17介导的疾病， GM-CSF和其他炎性细胞因子的产生。对于此拨款申请，我们建议使用NMO 患者样本和TH 17-EAE，以研究TH 17和IFN-I如何协同驱动人类神经炎症 疾病和体内动物模型。在AIM 1中，我们将使用RNA测序来识别离散的细胞类型。 在NMO患者中携带IFN-I特征，并发现了可以调节IFN-I和TH 17的新基因 途径。目的二：通过体外培养实验，研究IFN-Ⅰ对T辅助细胞的影响 与健康对照相比，NMO患者的分化。在目标3中，我们将使用TH 17-EAE模型来 了解IFN-I加剧TH 17诱导的神经自身免疫性疾病的机制。的 结合对人体的研究和本提案中概述的机械动物实验 有潜力深入了解病理过程的基础NMO和其他自身免疫性疾病， IFN-I和TH 17签名的疾病。