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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

基本信息

批准号：
10088395
负责人：
TIMOTHY VARTANIAN
金额：
$ 21.19万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
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/10088395
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 black patient caucasian American clinically relevant cohort comparative disease disparity experience immunopathology in vitro Assay innovation insight multimodality multiple sclerosis patient peripheral blood plasma cell differentiation prognostic response socioeconomics

项目摘要

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细胞更容易分化为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。