Determining Enhanced Inflammatory B cell Function in African Americans with MS

确定患有多发性硬化症的非裔美国人中增强的炎症 B 细胞功能

• 批准号: 9896484
• 负责人: TIMOTHY VARTANIAN
• 金额: $ 25.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-03 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896484
• 关键词: Accounting; Address; Adopted; African; African American; Antibodies; Antigen Presentation; Antigens; Autoimmune Diseases; B cell differentiation; B cell therapy; B-Lymphocyte Subsets; B-Lymphocytes; Biological; CD19 gene; Caucasians; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Central Nervous System Diseases; Clinical; Clinical Data; Clinical Research; Data; Diagnostic; Disease; Ethnic group; Exhibits; Exploratory/Developmental Grant; Frequencies; Future; Genetic Transcription; Health Services Accessibility; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Immune system; Immunoglobulin Class Switching; Immunoglobulin D; Immunoglobulin G; Immunoglobulin M; Immunoglobulin-Secreting Cells; Immunologics; In Vitro; Individual; Inflammatory; Kinetics; Latin American; Leukocytes; Light; Lupus; Malignant Neoplasms; Measures; Mediating; Membrane Proteins; Memory B-Lymphocyte; Multiple Myeloma; Multiple Sclerosis; Nature; Neuraxis; Pathogenesis; Patient Self-Report; Patients; Pattern; Phosphorylation; Plant Roots; Plasma Cells; Plasma Enhancement; Population; Precision Medicine Initiative; Prevalence; Proteins; Publishing; Reporting; Resolution; Risk; STAT3 gene; Severities; Severity of illness; Signal Transduction; Source; Specific qualifier value; Stimulus; Study Subject; Systemic Lupus Erythematosus; T-Lymphocyte; TNFSF5 gene; Testing; Time; Underserved Population; Variant; Work; base; caucasian American; clinically relevant; cohort; comparative; experience; immunopathology; in vitro Assay; innovation; insight; multimodality; multiple sclerosis patient; peripheral blood; plasma cell differentiation; prognostic; response; socioeconomics

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.

为什么非裔美国人和拉丁美洲人患有更严重的多发性硬化症 (MS) 除了回顾性临床图表审查之外，尚未对严重程度进行调查，并且风险 关联研究。 B 细胞通过以下方式为 MS 诊断、严重程度和预后评估提供信息： 他们的免疫生物学活性。由于 B 细胞耗竭疗法的显着疗效，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 中依赖于祖先的功能差异具有临床价值的机制见解。 这种洞察力将支持一种新兴模式，其中祖先介导的 免疫生物学差异是血统不同的临床严重程度、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拥有更大的 T- 相对于白种人血统的炎症 B 细胞功能具有依赖性。我们的 初步结果支持这一假设。在稳态离体（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 ASC 与体外 T 依赖性刺激下的 CAwMS 相比。这些差异不存在 在健康的捐赠者中。我们的初步研究结果表明，潜在的祖先介导的 差异驱动 B 细胞向 ASC 方向分化。我们将指定相关机制 有了这些发现，最终将基于 SNP 的高分辨率祖先分析应用于离体 和体外测定读数。具体来说，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 独立性 ASC 分化、类表达 改变记忆 B 细胞炎症产物并增强 STAT3 信号传导 人口。 该项目 (1) 直接研究炎症 B 细胞功能，比较 BA/LAwMS 和 CAwMS 首次，并且 (2) 最初建立在一个新生范例之上（据我们所知） 在系统性红斑狼疮中以有限的方式得到证实。因此我们的项目符合关键 R21 机制的标准，通过细致入微地阐述 B 细胞驱动的祖先的新兴想法 依赖性疾病差异。至于影响临床研究，我们的项目符合当前 以及未来的精准医学计划，旨在识别和应对生物 以前被纳入或在其他方面代表性不足的族裔群体之间存在差异。