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

多发性硬化症（MS）是一种中枢神经系统的慢性自身免疫性疾病， 在美国的百万人。该病的特点是急性和慢性炎症，髓鞘 损失;少突胶质细胞、神经元和轴突病理学;和进行性神经功能障碍。一些 突破性的转化发现，特别是B细胞耗竭药物的高度有益作用， 为一个不断发展但仍不完善的治疗管道奠定了基础。研究将达不到其潜力， 改善患者结局，直至确定疾病发作的触发因素和进展的调节因素。 该项目的核心是假设B细胞存在于脑脊液（CSF）和外周血中， 在早期MS期间，血液在触发MS和介导进行性疾病活动中起关键作用。我们 建议使用新的使能技术询问独特的患者队列，包括事件队列， 识别MS的触发器和临床过程的修饰符。充分表征的临床人群，高场 序列磁共振成像（MRI），组织为功能操作网络的遗传信息， 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 疾病不同阶段B细胞及其受体的分子多样性，以鉴定致病群体 和它们的抗原靶点。 多层次的实验策略包括单细胞B细胞转录组学，以及全面的 噬菌体展示的合成人、病毒和微生物肽段用于抗体指纹的筛选 针对血清、CSF和重组抗体文库中的外部驱动因子。综合分析将 使用临床、MRI和遗传决定因素对数据进行背景分析，努力应用严格的统计学方法， 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.