Immunology of advancing disease among minorities with Multiple Sclerosis

少数族裔多发性硬化症进展性疾病的免疫学

• 批准号: 10277054
• 负责人: Lilyana Amezcua
• 金额: $ 56.91万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10277054
• 关键词: Address; African American; Antibodies; Antigen Targeting; Atrophic; B-Lymphocytes; Binding; Biological; Caring; Cells; Clinical; Data; Diagnostic; Disease; Disease Progression; Event; Face; Flow Cytometry; Frequencies; Future; Genes; Genetic; Goals; Health; Hispanics; Immune; Immune response; Immunoglobulin G; Immunologics; Immunology; Incidence; Inflammation; Inflammatory; Knowledge; Latinx; Mediating; Minority; Minority Groups; Molecular Genetics; Multiple Sclerosis; Neurologic Deficit; Neurons; Oligoclonal Bands; Outcome; Patients; Plasmablast; Population; Positioning Attribute; Predisposition; Prevalence; Prevention; Production; Recovery; Refractory; Relapse; Reporting; Risk; Role; Severity of illness; Technology; Testing; advanced disease; base; clinical investigation; cognitive disability; cohort; disability; experience; gray matter; in vivo Model; indexing; insight; minority subjects; mouse model; multiple sclerosis patient; neuroimmunology; neurotoxicity; next generation sequencing; novel; patient response; physically handicapped; predictive tools; tool; treatment response

PROJECT SUMMARY Greater disease severity and a more rapid disease progression is observed among US minority populations such as African Americans (AA) and Hispanics (Latinx) with Multiple Sclerosis (MS) compared to whites with MS. Despite these observations, very little data is available regarding the biological underpinnings resulting in this increased risk of unequivocal advancing disease among minorities with MS even though the incidence of MS disease is growing among minority populations. Further, there are concerns that AA and Latinx with MS are refractory to first-line therapies, which increases the concern that the poor outcomes reported reflect substandard care and treatment. Our long term goal is to facilitate prevention of neurological deficits in minority patients with MS by identifying the mechanism(s) of CNS inflammation contributing to intensified progression and severity of disease. Others have shown that minorities with MS display higher IgG index and synthesis rate, oligoclonal band positivity and an inverse correlation of IgG index with gray matter atrophy. These data support a pronounced role for B cells and their antibody products in the pathobiology of MS in minority populations. Our central hypothesis is that the underlying mechanism of unequivocal advancing disease among minorities with MS involves expansion of plasmablasts producing antibodies and/or inflammatory products that cause neuronal toxicity independent of genetic (i.e. ancestral) predispositions. These studies will provide novel mechanistic insights into the role of neuron-reactive plasmablasts in CNS inflammatory events associated with intensified progression and severity of disease in minorities with MS. Our findings will also support future studies to develop diagnostic and predictive tools that inform patient response to treatment and inform clinical course such as relapse of MS or progression to MS in minority populations.

项目总结 在美国少数民族人群中观察到更严重的疾病和更快的疾病进展 例如患有多发性硬化症(MS)的非裔美国人(AA)和拉美裔(Latinx)与患有 尽管有这些观察，可获得的关于导致 这增加了患有多发性硬化症的少数民族中明确进展的疾病的风险，尽管 多发性硬化症在少数族裔人群中呈上升趋势。此外，还有人担心，AA和Latinx与MS 对一线治疗无效，这增加了人们的担忧，即报告的不良结果反映了 护理和治疗不达标。 我们的长期目标是促进少数族裔MS患者神经功能障碍的预防 中枢神经系统炎症导致疾病进展和严重程度加剧的机制(S)。其他 结果表明，少数MS患者表现出较高的免疫球蛋白G指数和合成率、寡克隆带阳性率和 免疫球蛋白指数与灰质萎缩呈负相关。这些数据支持B细胞的显著作用 以及他们的抗体产物在少数民族人群MS的病理生物学中的作用。 我们的中心假设是，在少数民族中明确推进疾病的潜在机制 多发性硬化症涉及血浆母细胞的扩张，产生抗体和/或炎症产物，从而导致 与遗传(即祖先)倾向无关的神经元毒性。这些研究将为我们提供新的 神经元反应性浆母细胞在中枢神经系统炎症事件中作用的机制洞察 在患有多发性硬化症的少数民族中，疾病的进展和严重程度加剧。我们的发现也将支持未来 研究开发诊断和预测工具，告知患者对治疗的反应并告知临床 少数民族人群中的MS复发或进展为MS等病程。