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

项目摘要 临床孤立综合征（CIS）患者首次发生与中枢神经系统相关的神经系统临床发作 神经系统（CNS）炎症是研究最早期免疫学事件的独特机会 治疗开始前与CNS炎症相关。我们的实验室获得了世界上最大的 CIS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的状态- 最先进的细胞和遗传表型分析表明，在我们的未经治疗的CIS患者中， 与对照组相比的队列，包括称为CD 27高浆母细胞的B细胞亚型的扩增群体 在他们第一次记录的临床发作时，脑脊液（CSF）和外周血中的事实上， 在首次临床发作时具有CD 27高水平浆母细胞扩增的患者是唯一的 他们在接下来的两年里记录了病情的恶化。此外，循环中的CD 27高浆母细胞 利用特定的抗体基因倾向于产生结合神经元抗原的抗体。这些发现 提示我们质疑CD 27高浆母细胞是否参与与此相关的自身反应性。 CIS患者在首次记录临床发作时转化为MS的高风险子集。我们 还调查了放射性孤立综合征（RIS）患者， 与CIS患者相似但没有临床症状的患者也表现出CD 27高浆母细胞的扩增， 产生抗神经元抗体。该项目的重点将促进新的机械见解， CD 27高浆母细胞在早期CNS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.