Ethnicity-associated, differential CNS demyelinating autoimmune disease severity: reconciling identity, ancestry and neurotoxic antibody response

种族相关的、不同的中枢神经系统脱髓鞘自身免疫性疾病严重程度：协调身份、血统和神经毒性抗体反应

• 批准号: 10283790
• 负责人: Kiel Telesford
• 金额: $ 12.62万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283790
• 关键词: Address; African; Antibodies; Antibody Repertoire; Antibody Response; Atrophic; Axon; B cell therapy; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Biological Assay; Blood; CNS Demyelinating Autoimmune Diseases; CNS autoimmunity; CNS degeneration; Caucasians; Cell Culture Techniques; Cells; Cellular Immunology; Central Nervous System Diseases; Chronic; Clinical; Competence; Data; Data Set; Demyelinations; Disease; Ethnic Origin; Exhibits; Faculty; Foundations; Frequencies; Generations; Genetic; Health Status; Human; Immune; Immunoglobulin D; Immunoglobulin G; Immunoglobulin-Secreting Cells; Individual; Inequality; Investigation; Knowledge; Latin American; Lymphocyte; Measures; Mediating; Mediator of activation protein; Mentors; Methodology; Methods; Molecular; Molecular Genetics; Molecular Immunology; Multiple Sclerosis; Nerve Degeneration; Neuraxis; Neurons; Participant; Patient Self-Report; Patients; Phase; Phenotype; Population; Positioning Attribute; Prevalence; Production; Publishing; Recombinants; Reporting; Research; Secure; Severities; Severity of illness; Shapes; Socioeconomic Factors; Source; Supervision; Symptoms; Techniques; Testing; Therapeutic; Tissues; Ursidae Family; Work; autoreactivity; base; burden of illness; career; cohort; disease disparity; disparity reduction; effective therapy; efficacious treatment; ethnic identity; ethnic minority population; experience; genetic approach; gray matter; improved; meetings; member; multiple sclerosis patient; multiple sclerosis treatment; neurotoxic; neurotoxicity; novel; personalized diagnostics; prognostic; programs; socioeconomics; tissue culture

Black African multiple sclerosis (BA-MS) patients exhibit double the neurodegeneration rates of Caucasian patients (CA-MS). Socioeconomic factors do not completely account for this disparity, pointing to biological mediators. Antibody-secreting cells (ASC)s are associated with MS disease activity and production of neurotoxic demyelinating and axopathic antibodies. Intrathecal antibody levels strongly correlate with neurodegeneration among Black African but not Caucasian MS patients. This suggests that ethnicity-associated differences in neurotoxic antibody function may promote the heightened clinical severity reported for BA-MS patients. However, no study has examined whether the prevalence or quality of neurotoxic antibodies differs according to ethnicity. Determining how neurotoxic antibody responses in MS vary by ethnicity will improve our understanding of antibody-mediated CNS degeneration. This will better position us to address inordinate CNS disease burden faced by MS patients from underserved backgrounds. The mentored phase (Aim 1) includes: generating recombinant human antibodies (rhAb) derived from individually sorted ASCs; culturing these rhAbs with myelinating central nervous system tissue; and, measuring rhAb-mediated demyelination and axon loss through immunohistochemical analysis. Sequencing data collected as a byproduct of single cell rhAb generation will provide the candidate opportunity to gain high-level knowledge of antibody genetic repertoire analysis. During the independent phase, the above approaches will be applied to other B cell subsets that feature in MS disease activity; double negative 2 (DN2) B cells in Aim2, and repopulating B cells after depletion therapy in Aim3. Each of the three aims employs subject cohorts that correspond to different stages of MS: early MS patients experiencing their first symptoms (Aim1); established clinically- managed MS patients (Aim2); and established clinically-managed MS patients after B cell depletion therapy (Aim3). For each cohort we will determine the quality, quantity and cellular sources of neurotoxic antibodies in relation to self-identified ethnicity and genetic ancestry. Employing similar technical approaches across all aims establishes complementary phenotypic, functional and genetic antibody repertoire datasets for different B cell subsets and stages of MS. This facilitates future research avenues for the candidate. The proposed work will provide competencies for an independent research career. The mentoring team: Drs Vartanian, Monson, Elemento, & Pascual, will supervise the candidate in experimental methodology. Through regular meetings, they will advise the candidate in securing a faculty position and developing a research program. Advisor team members: Drs. Bennett, Nussenzweig, Davis, Kittles, Sanz & Kister will provide additional technical & professional guidance through their extensive experience with methods & approaches outlined in the Research Strategy; such as, neuroimmunologic assays, molecular genetic approaches, as well as with studying differential ethnicity or ancestry-associated clinical disparities.

非洲黑人多发性硬化症（BA-MS）患者的神经变性率是白人的两倍。 患者（CA-MS）。社会经济因素并不能完全解释这种差异，指出生物学 调解员抗体分泌细胞（ASC）与MS疾病活动和神经毒素的产生有关。 脱髓鞘和轴突病抗体。鞘内抗体水平与神经退行性变密切相关 在非洲黑人而非高加索人的多发性硬化症患者中。这表明，种族相关的差异， 神经毒性抗体功能可能促进BA-MS患者报告的临床严重性升高。然而，在这方面， 没有研究检查神经毒性抗体的流行率或质量是否因种族而异。 确定MS中神经毒性抗体反应如何因种族而异将提高我们对MS的理解。 抗体介导的CNS变性。这将使我们更好地解决过度的CNS疾病负担 来自医疗服务不足背景的多发性硬化症患者面临的问题。 指导阶段（目标1）包括：产生重组人抗体（rhAb）， 单独分选的ASC;将这些rhAb与髓鞘形成中枢神经系统组织一起培养;以及，测量 通过免疫组织化学分析的rhAb介导的脱髓鞘和轴突损失。收集的测序数据 作为单细胞rhAb生产的副产品，将为候选人提供获得高级知识的机会 抗体基因库分析在独立阶段，上述方法将适用于 在MS疾病活动中具有特征的其他B细胞亚群; Aim 2中的双阴性2（DN 2）B细胞，并重新增殖 Aim 3中耗竭治疗后的B细胞。这三个目标中的每一个都采用了与以下目标相对应的受试者群体： MS的不同阶段：出现首次症状的早期MS患者（Aim 1）;临床确定- 管理的MS患者（Aim 2）;和B细胞耗竭治疗后确定的临床管理的MS患者 （目标3）。对于每个队列，我们将确定神经毒性抗体的质量、数量和细胞来源， 与自我认定的种族和遗传祖先的关系。在所有目标中采用类似的技术方法 建立不同B细胞的互补表型、功能和遗传抗体库数据集 这有利于候选人未来的研究途径。 拟议的工作将提供独立研究生涯的能力。指导团队： 博士Vartanian，蒙森，元素，和帕斯夸尔，将监督候选人在实验方法。 通过定期会议，他们将建议候选人在确保教师职位和发展研究 程序.顾问团队成员：班尼特博士、Nussenzweig博士、Davis博士、Kittles博士、Sanz博士和Kister博士将提供额外的 通过他们在方法和方法方面的丰富经验提供技术和专业指导， 研究策略;例如，神经免疫测定，分子遗传学方法，以及与研究 不同种族或祖先相关的临床差异。