Contribution of plasmablasts in the conversion of transverse myelitis to multiple sclerosis

项目总结 临床隔离综合征(CIS)患者首次出现与中枢相关的神经临床发作 神经系统(CNS)炎症是研究早期免疫学事件的独特机会 在治疗开始前与中枢神经系统炎症有关。我们实验室获得了世界上最大的人类 独联体患者经历他们的第一次临床发作的样本库。我们的初步数据使用状态- -ART细胞和遗传表型显示未经治疗的CIS中存在广泛的B细胞失调 与包括一种称为CD27高浆母细胞的B细胞亚型扩大群体的对照组进行比较 在他们第一次有记录的临床发作时，他们在脑脊液(CSF)和外周血液中发现了病毒。事实上, 那些在首次临床发作时有CD27高水平浆母细胞扩张的患者是唯一 世卫组织记录了接下来的两年里病情恶化的情况。此外，循环中的CD27高水平浆母细胞 利用特定的抗体基因往往会产生与神经元抗原结合的抗体。这些发现有 促使我们质疑CD27高水平的浆母细胞是否参与了与此相关的自身反应 在首次有记录的临床发作时，有高风险转为多发性硬化症的独联体患者亚组。我们是 还调查了表现为中枢神经系统炎症的放射隔离综合征(RIS)患者 与CIS相似但没有临床症状的患者也表现出CD27高浆母细胞的扩张 产生抗神经元抗体。本项目的重点将有助于从新的机械角度深入了解 CD27高表达的浆母细胞在早期中枢神经系统炎症中的作用

PROJECT SUMMARY Clinically Isolated Syndrome (CIS) patients experiencing their first neurological clinical episode related to Central Nervous System (CNS) inflammation represent a unique opportunity to study the earliest immunological events associated with CNS inflammation prior to treatment initiation. Our laboratory has acquired the largest human sample repository of CIS patients experiencing their first clinical episode. Our preliminary data using state-of- the-art cellular and genetic phenotyping demonstrate extensive B cell dysregulation within our untreated, CIS cohort compared to controls including an expanded population of a B cell subtype called CD27high plasmablasts in the cerebrospinal fluid (CSF) and peripheral blood at the time of their first documented clinical attack. In fact, those patients with CD27high plasmablast expansion at the time of their first clinical attack were the only ones who had documented exacerbations over the next two years. In addition, circulating CD27high plasmablasts utilizing particular antibody genes tend to produce antibodies that bind neuronal antigens. These findings have prompted us to question whether CD27high plasmablasts are involved in the autoreactivity associated with this subset of CIS patients at high risk to convert to MS at the time of their first documented clinical attack. We are also investigating whether Radiologically Isolated Syndrome (RIS) patients, who display CNS inflammation similar to CIS patients but without clinical symptoms also exhibit expansion of CD27high plasmablasts that produce anti-neuronal antibodies. The focus of this project will facilitate new mechanistic insights into the contribution of CD27high plasmablasts in early CNS inflammation.