The Role of B cells in the Origin and Progression of Multiple Sclerosis

多发性硬化症(MS)是一种慢性中枢神经系统自身免疫性疾病，影响近1 在美国有一百万人。这种疾病的特点是急性和慢性炎症，髓鞘 丧失；少突胶质细胞、神经元和轴突病理；进行性神经功能障碍。一批 突破性的翻译发现，特别是B细胞耗竭药物的高度有益作用，已经 为不断增长但仍不完善的治疗渠道铺平道路。研究将达不到其潜力 改善患者预后，直到确定疾病发生的触发因素(S)和进展的修饰因素。 这个项目的核心是假设存在于脑脊液(CSF)和外周的B细胞 多发性硬化症早期的血液在引发多发性硬化症和调节正在进行的疾病活动中起着关键作用。我们 建议审问独特的患者队列，包括事件队列，使用新的使能技术来 确定多发性硬化症的诱因和临床病程的修饰者。特征明确的临床人群，高场 序列磁共振成像(MRI)，组织为功能操作网络的遗传信息，以及 对B细胞生物学的关注是这一倡议的核心要素。一个主要目标将是描述 B细胞及其受体在疾病不同阶段的分子多样性识别致病人群 以及它们的抗原性靶标。 多层次的实验策略包括单细胞B细胞转录，以及全面的 噬菌体展示的合成人、病毒和微生物多肽用于抗体指纹的筛选 针对血清、脑脊液和重组抗体库中的外部驱动因素。综合分析将 使用临床、核磁共振和遗传决定因素将数据与背景联系起来，努力应用严格的统计学 原则，包括独立复制。

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system affecting nearly one million individuals in the United States. The disease is characterized by acute and chronic inflammation, myelin loss; oligodendrocyte, neuronal and axonal pathology; and progressive neurological dysfunction. A number of breakthrough translational discoveries, and especially the highly beneficial effects of B cell depleting drugs, have set the stage for a growing, yet still imperfect, therapeutic pipeline. Research will fall short of its potential to improve patient outcomes until the trigger(s) of disease onset and modifiers of progression are identified. Central to this project is the hypothesis that B cells presenting in the cerebrospinal fluid (CSF) and peripheral blood during early MS play key roles in triggering MS and in mediating ongoing progressive disease activity. We propose to interrogate unique patient cohorts, including an incident cohort, with novel enabling technologies to identify triggers of MS and modifiers of the clinical course. Well characterized clinical populations, high-field serial magnetic resonance imaging (MRI), genetic information organized as functional operational networks, and a focus on B cell biology are the central elements of this initiative. A primary goal will be to characterize the molecular diversity of B cells and their receptors at various stages of disease to identify pathogenic populations and their antigenic targets. A multi-layered experimental strategy includes single cell B cell transcriptomics, together with comprehensive phage-displayed synthetic human, viral and microbial peptidomes for the screening of antibody fingerprints against external drivers in the serum, CSF, and recombinant antibody libraries. The integrative analysis will contextualize the data using clinical, MRI and genetic determinants, striving to apply rigorous statistical principles, including independent replication.