Determining Enhanced Inflammatory B cell Function in African Americans with MS

为什么非洲裔美国人和拉丁美洲人患有多发性硬化症（MS）疾病 除了回顾性临床病历审查外，尚未对严重程度进行研究， 协会研究。B细胞通过以下途径为MS诊断、严重程度和预后评估提供信息： 它们的免疫生物学活性。由于B细胞耗竭疗法的显著疗效，我们 现在知道B细胞是MS临床活动的主要驱动力。我们建议基于B细胞， MS中的祖先依赖性功能差异具有临床上有价值的机制见解。 这样的洞察力将支持一种涌现模式，即祖先介导的 免疫生物学差异是祖先的基础-不同的临床严重程度，异质性和 普遍性。 在这项研究中，我们测试了我们的假设，即非洲血统的MS患者具有更大的T- 依赖性炎症B细胞功能。我们 初步研究结果支持这一假设。离体稳态（直接来自受试者 外周血）循环抗体分泌细胞（ASC）亚群频率增加， BA/LAwMS相对于CAwMS此外，分离的B细胞更容易分化成ASC 与体外T依赖性刺激时的CAwMS相比。这些差异是不存在的 健康的捐赠者。我们的初步研究结果表明，潜在的祖先介导 差异驱使B细胞向ASC命运分化。我们将详细说明相关机制 有了这些发现，最终将基于SNP的精细分辨率祖先分析应用于离体 和体外测定读数。具体而言，我们将进行纵向离体评估， ASC以及记忆B细胞上的抗原呈递功能相关蛋白。我们还将 描述体外T依赖性和T非依赖性ASC分化， 转换记忆B细胞炎症产物并增强STAT 3信号传导， 人口 本项目（1）直接研究炎症B细胞功能，比较BA/LAwMS和 CAWMS的第一次，（2）建立在一个新生的范式（据我们所知）最初 在系统性红斑狼疮中表现出有限的形式。因此，我们的项目符合关键 R21机制的标准，通过细微差别的出现的想法，B细胞驱动的祖先- 依赖性疾病差异。至于影响临床研究，我们的项目符合当前的 和未来的精准医学倡议，旨在识别和应对生物 以前被归入或以其他方式代表性不足的族裔群体之间的差异。

Why African American and Latin Americans present with greater multiple sclerosis (MS) disease severity has not been investigated beyond retrospective clinical chart review, and risk association studies. B cells inform MS diagnostic, severity and prognostic assessments through their immunobiological activity. Thanks to the dramatic efficacy of B cell depletion therapy, we now know that B cells are principal drivers of MS clinical activity. We propose that B cell-based, ancestry-dependent functional difference in MS holds clinically valuable mechanistic insight. Such insight would be supportive of an emergent pattern where ancestry-mediated immunobiological differences underlie ancestry-disparate clinical severity, heterogeneity and prevalence. In this study, we test our hypothesis that MS patients of African ancestry possess greater T- dependent inflammatory B cell function relative to those of Caucasian ancestry. Our preliminary findings support this hypothesis. At steady-state ex vivo (directly from subject peripheral blood) circulating antibody secreting cell (ASC) subset frequencies are increased in BA/LAwMS relative to CAwMS. Further, isolated B cells more readily differentiate into ASCs compared to CAwMS upon in vitro T-dependent stimulation. These differences are absent amongst healthy donors. Our preliminary findings imply that underlying ancestry-mediated differences drive B cell differentiation toward ASC fate. We will specify mechanisms associated with these findings, ultimately applying fine-resolution SNP-based ancestral analysis to ex vivo and in vitro assay readouts. Specifically, we will conduct longitudinal ex vivo assessment of ASC as well as antigen presenting function-associated proteins on memory B cells. We will also delineate in vitro T-dependent and T-independent ASC differentiation, expression of class- switched memory B cell inflammatory products and enhanced STAT3 signaling amongst this population. This project (1) directly investigates inflammatory B-cell function comparing BA/LAwMS and CAwMS for the first time, and (2) builds upon a nascent paradigm (to our knowledge) initially demonstrated in limited fashion within systemic lupus erythematosus. Our project thus fits key criteria of the R21 mechanism by nuancing the emergent idea of B cell-driven ancestry- dependent disease disparity. As for impacting clinical research, our project is in-line with current and future precision medicine initiatives geared towards identifying and responding to biological variation across formerly subsumed or otherwise underrepresented ethnic groups.