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.

为什么非裔美国人和拉丁美洲人出现更多多发性硬化症（MS）疾病在回顾性的临床图审查之外，尚未对严重性进行调查，风险协会研究。 B细胞通过他们的免疫生物学活性。多亏了B细胞耗竭疗法的显着功效，我们现在知道B细胞是MS临床活性的主要驱动因素。我们提出了基于B细胞的祖先依赖于MS的功能差异具有临床上有价值的机械洞察力。这种见解将支持祖先介导的新兴模式免疫生物学差异是祖先育序严重程度，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MS患者具有更大的T- 相对于高加索血统的依赖性炎症B细胞功能。我们的初步发现支持这一假设。在稳态的Ex Vivo（直接来自受试者外周血）循环抗体分泌细胞（ASC）子集频率在与CAWM有关的BA/法律。此外，分离的B细胞更容易区分为ASC 与CAWM相比，体外T依赖性刺激。这些差异不存在在健康的捐助者中。我们的初步发现暗示着基本的祖先介导差异将B细胞分化向ASC命运。我们将指定相关的机制通过这些发现，最终将基于SNP的精细SNP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以及抗原在记忆B细胞上呈现功能相关的蛋白质。我们也会描绘体外T依赖性和T依赖性的ASC分化，类表达切换内存B细胞炎症产品和增强的STAT3信号传导人口。该项目（1）直接研究了比较BA/Lawms和首次CAWM，（2）最初是基于新生范式建立的（据我们所知）在系统性的红斑红斑中以有限的方式展示。因此，我们的项目适合密钥 R21机制的标准通过滋养B细胞驱动的血统的新兴思想 - 依赖性疾病差异。至于影响临床研究，我们的项目与当前以及未来的精密医学计划，旨在识别和应对生物学以前属于或以其他代表性不足的种族群体之间的变化。