Ethnicity-Associated, Differential CNS Demyelinating Autoimmune Disease Severity: Reconciling Identity, Ancestry and Neurotoxic Antibody Response

种族相关、差异化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: 10439899
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439899
• 关键词: Address; African; Antibodies; Antibody Repertoire; Antibody Response; Atrophic; Axon; B cell therapy; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Biological Assay; Black race; Blood; CNS Demyelinating Autoimmune Diseases; CNS autoimmunity; CNS degeneration; Caucasians; 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; 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; experience; genetic approach; gray matter; improved; meetings; member; minority patient; multiple sclerosis patient; multiple sclerosis treatment; neurotoxic; neurotoxicity; novel; personalized diagnostics; prognostic; programs; socioeconomic disparity; 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)患者的神经退行性变发生率是高加索人的两倍 患者(CA-MS)。社会经济因素并不能完全解释这种差异，而是生物因素。 调解人。抗体分泌细胞S与MS疾病活动性及神经毒物的产生 脱髓鞘抗体和轴突抗体。鞘内抗体水平与神经退行性变密切相关 在非洲黑人多发性硬化症患者中，但不包括高加索多发性硬化症患者。这表明与种族相关的差异 神经毒性抗体功能可能促进报道的BA-MS患者较高的临床严重度。然而， 还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。 确定多发性硬化症的神经毒性抗体反应如何因种族而异将有助于我们对 抗体介导的中枢神经系统变性。这将使我们更好地应对过度的中枢神经系统疾病负担 面对来自不充分服务背景的多发性硬化症患者。 指导阶段(目标1)包括：产生源于以下来源的重组人抗体 单独分离的ASCs；将这些重组人抗体与髓鞘中枢神经系统组织一起培养；以及，测量 重组人抗体介导的脱髓鞘和轴突丢失的免疫组织化学分析。收集的测序数据 作为单细胞的副产品，重组人抗体的产生将为候选人提供获得高水平知识的机会 抗体基因谱系分析。在独立阶段，上述方法将应用于 其他表现为MS疾病活动性的B细胞亚群；AIM2中的双阴性2(DN2)B细胞，并重新繁殖 Aim3耗竭治疗后的B细胞。这三个目标中的每一个都使用与以下各项相对应的受试者队列 MS的不同阶段：早期MS患者出现首发症状(AIM1)；临床确诊- 管理多发性硬化症患者(AIM2)；并在B细胞耗尽治疗后建立临床管理的多发性硬化症患者 (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 与自我认同的种族和遗传血统的关系。在所有目标中采用类似的技术方法 为不同的B细胞建立互补的表型、功能和遗传抗体库数据集 MS的子集和阶段这有利于候选人未来的研究途径。 拟议的工作将为独立研究事业提供能力。指导团队： Vartanian、Monson、Elemento和Pascual博士将在实验方法论方面指导候选人。 通过定期会议，他们将建议候选人获得教员职位并开展研究。 程序。顾问团队成员：贝内特、努森茨韦格、戴维斯、基特尔斯、桑兹和基斯特博士将提供额外的 通过他们在方法和途径方面的丰富经验提供技术和专业指导 研究策略；如神经免疫学分析、分子遗传学方法以及与研究 不同的种族或血统相关的临床差异。

项目成果

Neuron-binding antibody responses are associated with Black ethnicity in multiple sclerosis during natalizumab treatment.

• DOI: 10.1093/braincomms/fcad218
• 发表时间: 2023
• 期刊: Brain communications
• 影响因子: 4.8