Pathogenic B cell and T helper cell interactions in Neuromyelitis Optica

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。目前，还没有FDA批准的治疗方法 为国家气象组织。事实上，许多多发性硬化症的治疗方法，尤其是干扰素-β(干扰素-β)，会加重近视眼的病情。有限的治疗方法 因为NMO证明了这种疾病在神经学上有明显的未得到满足的需求。这个项目的目标是 了解在NMO中导致疾病活动的免疫途径。这项提案的目的将是 解决三个相互关联但不同的问题，这三个问题将对NMO患者产生影响。目标1将如何决定 干扰素-β信号如何影响神经母细胞瘤患者的B细胞。这将通过细胞功能和转录切割来实现 患者外周血中B细胞分析。目标2将评估B细胞亚群和T辅助细胞之间的直接相互作用 来自NMO和健康志愿者的细胞利用细胞培养技术。目标3将利用 实验性自身免疫性脑脊髓炎模型研究B细胞细胞因子对TH17的影响 诱发神经自身免疫性疾病。这项提议的前两个目标将是高度的翻译合作 埃克斯泰尔博士、莱萨德博士(自身免疫遗传学家)和帕尔多博士(OMRF多发性硬化症中心主任)之间 卓越)，以及加速治愈项目(ACP)。该病的临床专长和庞大的患者群体 OMRF MS Center和ACP将为该项目提供支持，使这些目标得以实现。第三 Aim利用我们在神经自身免疫动物模型中的优势，将深入了解 NMO背后的机制。人的主体研究与机械动物的结合 这项提案中概述的实验有可能深入了解病理过程 Underlie和NMO。

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. Currently, there are no FDA approved therapies for NMO. In fact, many MS therapies, most notably interferon-beta (IFN-β), worsens NMO. The limited therapies for NMO demonstrates that this disease has clear unmet needs in neurology. The goal of this project is to understand the immune pathways that contribute to disease activity in NMO. The aims of this proposal will address three connected but distinct issues that will have an impact NMO patients. Aim 1 will how determine how IFN-β signaling effects B-cells from patients with NMO. This will be achieved by CyTOF and transcriptomic analysis of B-cells from patients. Aim 2 will assess the direct interaction between B-cell subsets and T helper cells from NMO and healthy volunteers by utilizing cell culturing techniques. Aim 3 will utilize variations of experimental autoimmune encephalomyelitis model to understand how the B-cells cytokines effect TH17- induced neuro-autoimmune disease. The first two aims of this proposal will be a highly translation collaboration between Drs. Axtell, Lessard (autoimmune geneticist) and Pardo (the director of OMRF's MS Center of Excellence), and the Accelerated Cure Project (ACP). The clinical expertise and large patient population of the OMRF MS Center and the ACP will provide to this project will enable these aims to be accomplished. The third aim utilizes our strength in animal models of neuro-autoimmunity that will give insight into the biological mechanisms behind NMO. 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 and NMO.