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更严重的多发性硬化症(MS) 除了回顾临床图表审查之外，没有对严重性进行调查，以及风险 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细胞是多发性硬化症临床活动的主要驱动力。我们建议以B细胞为基础， 多发性硬化症的祖先依赖性功能差异具有临床价值的机制洞察力。 这样的洞察力将支持一种新出现的模式，即祖先调停 免疫生物学差异是祖先-不同的临床严重性、异质性和 流行率。 在这项研究中，我们检验了我们的假设，即非洲血统的多发性硬化症患者具有更大的T- 相对于高加索血统的依赖的炎性B细胞功能。我们的 初步发现支持这一假设。处于稳定状态的体外(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细胞更容易分化为ASCs 与体外T依赖刺激下的CAwMS进行比较。这些差异是不存在的 在健康的捐赠者中。我们的初步发现表明，潜在的祖先调节 差异促使B细胞分化为ASC的命运。我们将指定相关的机制 有了这些发现，最终将基于精细分辨率SNP的祖先分析应用于体外 和体外分析读数。具体地说，我们将进行纵向体外评估 ASC以及记忆B细胞上的抗原提呈功能相关蛋白。我们还将 体外诱导T依赖性和非T依赖性ASC分化，表达Class-2 其中交换了记忆B细胞炎症产物和增强的STAT3信号 人口。 本项目(1)直接研究炎性B细胞功能，比较BA/LAwMS和 CAwMS是第一次，以及(2)最初建立在一个新的范式(据我们所知)之上 在系统性红斑狼疮中表现有限。因此，我们的项目符合Key R21机制的标准通过细微差别B细胞驱动祖先的新概念- 依存性疾病差异。至于对临床研究的影响，我们的项目符合当前的情况 以及未来的精准医学倡议，旨在识别和应对生物 在以前被纳入或以其他方式代表不足的种族群体中的差异。

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.