Defining the role of B cells in modulating CNS inflammation in multiple sclerosis

定义 B 细胞在调节多发性硬化症中枢神经系统炎症中的作用

• 批准号: 10203891
• 负责人: Julie J Ahn
• 金额: $ 3.96万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203891
• 关键词: Ablation; Address; Affect; Animal Model; Animals; Apoptosis; Ataxia; Autoimmune Diseases of the Nervous System; Autopsy; Axon; B cell therapy; B-Lymphocytes; Brain; CASP9 gene; CD19 gene; Caspase; Cell Line; Cell physiology; Cells; Central Nervous System Diseases; Chronic; Complex; Cytokine Signaling; Data; Demyelinations; Development; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Experimental Autoimmune Encephalomyelitis; Factor Analysis; Fellowship; Flow Cytometry; Foundations; Genes; Genetic Transcription; Goals; Health Sciences; Human; Immune; Immune system; Immunocompromised Host; Immunohistochemistry; Immunology; Immunomodulators; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune System; Knowledge; Lead; Lesion; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Manuscripts; Mediating; Mentors; Microglia; Molecular; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Neuraxis; Neurodegenerative Disorders; Neurosciences; Oral; Pain; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral; Phosphorylation; Plasma; Population; Production; Property; Relapse; Research; Role; Scientist; Severities; Severity of illness; Signal Pathway; Signaling Protein; Spinal Cord; Symptoms; Tamoxifen; Technical Expertise; Techniques; Testing; Training; Transgenic Animals; Transgenic Organisms; Transmission Electron Microscopy; Universities; Washington; axon injury; brain tissue; burden of illness; career; central nervous system demyelinating disorder; cytokine; differential expression; experimental study; functional disability; immunopathology; inflammatory marker; insight; medical schools; mouse model; multiple sclerosis patient; multiple sclerosis treatment; neuroimmunology; neuroinflammation; new therapeutic target; novel; novel therapeutics; peripheral blood; prevent; protein expression; remyelination; repaired; response; responsible research conduct; targeted treatment; tool; transcriptome sequencing; transcriptomics

Summary The debilitating central nervous system (CNS) disease multiple sclerosis (MS), is characterized by an influx of peripheral immune cells that coincides with axonal demyelination and damage, resulting in pain and impaired coordination. The role of B cells in MS pathogenesis has emerged as studies showed that B cell directed therapies substantially reduce the formation of new inflammatory demyelinating lesions. Further, the majority of lesions from patients with established MS harbor B cells as well as reactive microglia. While these findings corroborate a pathogenic role for B cells, it is unclear which B cell function contributes to demyelination within the inflamed CNS. In addition, systemic B cell elimination can severely immunocompromise patients, establishing the need to develop more targeted therapies. Emerging evidence suggests that B cells of MS patients are potent regulators of pro-inflammatory cytokines, and these abnormal B cells can regulate the CNS innate immune system when they enter the CNS. Studies in this application will selectively and locally ablate B cells in the CNS using a novel caspase 9-mediated apoptosis transgenic tool in the well-studied experimental autoimmune encephalomyelitis (EAE) animal model of MS. Preliminary data indicate that targeting CNS B cells after the onset of symptoms in EAE reduces microglial reactivity and is accompanied by decreased myelin damage and functional impairment. Inflammatory signaling pathways in microglia from CNS B cell depleted EAE animals will be evaluated using advanced phospho-flow cytometry techniques. Demyelination and remyelination in the brain and spinal cord will be further studied in this powerful, novel animal model to test if CNS B cell ablation prevents further myelin injury and promotes myelin repair. The role of MS B cells in neuroinflammation will be determined by stimulating human microglia with MS patient-derived B cell secreted factors and analyzing transcriptional and translational inflammatory activity of microglial cells. B cell induced microglial activation will be confirmed in human MS brain lesions. Together, the proposed studies will provide novel insights into the complex immunopathology of MS that involves the interaction of CNS B cells and microglia. Completion of these studies will lead to novel immunomodulatory therapeutic avenues that reduce the disease burden of multiple sclerosis without immunocompromising the patient. The proposed training plan is sponsored by Dr. Robert H. Miller at the George Washington University School of Medicine and Health Sciences. The overall goal is to build a strong foundation for the PI, Julie J Ahn, to prepare her for a successful career as an independent scientist in the fields of neuroimmunology and neuroinflammation. The fellowship training plan includes the following goals: 1) enhance scientific knowledge and technical skills that integrate neuroscience and immunology, 2) present research findings through oral presentations and manuscripts, 3) mentor and lead young scientists, and 4) conduct research responsibly.

概括 衰弱的中枢神经系统（CNS）疾病多发性硬化症（MS）的特征是涌入 外围免疫细胞与轴突脱髓鞘和损伤一致，导致疼痛和受损 协调。 B细胞在MS发病机理中的作用已经出现，因为研究表明B细胞定向 疗法大大减少了新的炎症性脱髓鞘病变的形成。此外，大多数 已建立MS Harbor B细胞和反应性小胶质细胞的患者的病变。而这些发现 证实了B细胞的致病作用，目前尚不清楚哪种B细胞功能有助于脱髓鞘 发炎的中枢神经系统。此外，全身性B细胞消除可以严重免疫功能低下的患者， 确定需要开发更多针对性疗法的需求。新兴证据表明MS的B细胞 患者是促炎细胞因子的有效调节剂，这些异常B细胞可以调节中枢神经系统 先天免疫系统进入中枢神经系统。该应用中的研究将有选择地和局部消融B 中枢神经系统中的细胞使用新型caspase 9介导的细胞凋亡转基因工具在良好的实验中 MS的自身免疫性脑脊髓炎（EAE）动物模型。初步数据表明针对CNS B细胞 EAE症状发作后，降低了小胶质细胞的反应性，并伴有髓磷脂降低 损害和功能障碍。 CNS B细胞中小胶质细胞中的炎症信号通路耗尽 将使用晚期磷酸流动细胞仪技术评估EAE动物。脱髓鞘和 在这个强大的新型动物模型中，将进一步研究大脑和脊髓中的再髓呈 CNS B细胞消融可防止进一步的髓磷脂损伤并促进髓磷脂修复。 MS B细胞在 神经炎症将通过用MS患者衍生的B细胞刺激人类小胶质细胞来确定 因素并分析小胶质细胞的转录和翻译炎症活性。 B细胞诱导 小胶质细胞激活将在人类MS脑病变中得到证实。拟议的研究将共同​​提供 对CNS B细胞相互作用和 小胶质细胞。这些研究的完成将导致新型的免疫调节治疗途径，以减少 多发性硬化症的疾病负担，而没有免疫妥协患者。 拟议的培训计划由乔治华盛顿大学学校的Robert H. Miller博士赞助 医学与健康科学。总体目标是为PI朱莉·J·艾恩（Julie J Ahn）建立坚实的基础 为她在神经免疫学领域的独立科学家和独立科学家的职业生涯做好准备 神经炎症。奖学金培训计划包括以下目标：1）增强科学知识 以及整合神经科学和免疫学的技术技能，2）通过口头介绍研究结果 演讲和手稿，3）指导和领导年轻科学家，以及4）负责任地进行研究。