Autoimmunity to Axoglial Apparatus Proteins in Multiple Sclerosis

多发性硬化症中轴神经胶质装置蛋白的自身免疫

• 批准号: 9925282
• 负责人: Kristina Rae Patterson
• 金额: $ 19.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925282
• 关键词: Age; Aggressive course; Antibodies; Antigen Targeting; Antigens; Area; Atrophic; Autoantibodies; Autoantigens; Autoimmune encephalitis; Autoimmunity; Avidity; Axon; Benchmarking; Biological Assay; Biometry; Brain imaging; CD4 Positive T Lymphocytes; CNS autoimmunity; Cell Proliferation; Cells; Cellular Immunity; Cellular Immunology; Cerebrospinal Fluid; Child; Chronic Inflammatory Demyelinating Polyradiculoneuropathy; Clinical; Collaborations; Databases; Demyelinating Diseases; Deterioration; Development; Environment; Ethics; Flow Cytometry; Frequencies; Future; Goals; Grant; Heterogeneity; Humoral Immunities; Immune; Immune Targeting; Immunity; Immunodominant Epitopes; Inflammation; Inflammatory; Injury; K-Series Research Career Programs; Knowledge; Lesion; MHC Class II Genes; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mentors; Methodology; Mimosa; Molecular; Molecular Immunology; Monitor; Multiple Sclerosis; Myelin; Myelin Sheath; Outcome; Pathogenesis; Pathology; Patients; Peptide Library; Peptides; Phenotype; Play; Prevalence; Proteins; Proteomics; Recombinants; Regulation; Reporting; Research; Research Personnel; Role; Scientist; Serum; Severity of illness; Structure; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Tissues; Training; Translational Research; Work; antigen-specific T cells; autoreactivity; axon injury; base; career; career development; cerebral atrophy; contactin; cytokine; disability; experience; human subject; memory CD4 T lymphocyte; multiple sclerosis patient; nervous system disorder; neurofascin; neuroimaging; novel; pediatric multiple sclerosis; personalized strategies; programs; relating to nervous system; research and development; response; skills; tool

PROJECT SUMMARY This K08 career development award will facilitate the development of the PI into a clinician-scientist with an independent research program focused on humoral and cellular immunity of MS and other neurological disorders. The PI and her coworkers have recently reported on the prevalence and mechanisms antibodies to axoglial antigens in neurological diseases, e.g. CIDP and autoimmune encephalitis (Patterson et al. 2018, Burnor et al., 2018). This work demonstrates functional and structural consequences of autoimmunity to the axoglial apparatus in the pathogenesis of neurological diseases. The scientific program in this grant expands on this prior work, focusing axoglial autoimmunity in MS, an exciting new avenue of research with the potential to explain the dual pathology of both myelin and underlying axons in MS, as well as the substantial heterogeneity in the clinical course and outcomes that exists across patients. The modulating more study are to: (1) test matched frequencies as MRI trajectories central hypothesis of this proposal is that autoimmunity to the axoglial apparatus plays a role in MS pathogenesis and that patients with autoimmunity to the axoglial apparatus will experience severe axonal loss and consequently higher r ate s of brain atrophy . whether MS patients are more likely to have axoglial autoantibodies compared to age- healthy controls and controls with other inflammatory neurological diseases, (2) enumerate the and proinf lammatory potential of axoglial- reactive T cells in MS patients versus controls, and (3) a proof of principle, axoglial autoimmunity will be measured in subsets of MS patients defined based on measures of differing rates of atrophy to test the hypothesis that axoglial autoimmunity correlates with of brain atrophy. The objectives of the proposed These studies will lead to not only a better understanding of the pathogenesis and heterogeneity that exists in the spectrum of MS but also develop specific for tools to better monitor relevant antigen- responses and potentially to better prognosticate and possibly revisit more individualized strategies antigen-specific therapies. The PI will be guided by three mentors with distinct areas of expertise that are necessary to complete this project. Dr. Bar-Or is a world regulation expert in molecular and cellular immunology studying the principles of immune and immune neural interactions in MS;Dr. Scherer is an expert on the molecular organization of myelinated axons; and Dr. Lancaster is a leading expert in the field CNS autoimmunity, and particularly of antibody-mediated neurological diseases with extensive experience in the discovery of novel autoantigens, including axoglial apparatus molecules. A training plan to assist the PI in developing new research skills is an integral part of this application. In addition to completing the proposed research, the applicant will engage in a rigorous program of didactic courses and mentoring by experts in cellular and molecular immunology, brain imaging, and biostatistics. She will gain expertise in identification of immunodominant epitopes using overlapping peptide libraries, immunospot assays, cell proliferation assays, multiparametric flow cytometry, and statistical methodologies relevant to translational research as well as gain a working knowledge of development of recombinant MHC receptors and advanced MRI analytic techniques (MIMoSA and SuBLIME). Since this project involves both human subjects, specific training in the ethical concerns involved is integrated into the training plan. The applicant's progress and attainment of specific benchmarks in research and career development will be regularly reviewed by her mentors who have extensive experience in training junior investigators and facilitating their transition to independent research careers. Completion of the proposed study will be facilitated by an institutional environment that prioritizes collaboration and provides exemplary research and career support. Through the proposed study, the applicant will make significant contributions to the understanding of axoglial autoimmunity in neurological diseases and novel tools necessary for future projects examining T-cell mediated axoglial immunity in not only MS but also other neurological diseases such as autoimmune encephalitis and CIDP.

项目概要 该 K08 职业发展奖将促进 PI 发展成为一名临床医生兼科学家 专注于多发性硬化症和其他神经系统疾病的体液和细胞免疫的独立研究项目 失调。 PI 和她的同事最近报告了抗体的流行率和机制 神经系统疾病中的轴胶质抗原，例如CIDP 和自身免疫性脑炎（Patterson 等人，2018 年， 伯纳等人，2018）。这项工作展示了自身免疫对机体的功能和结构影响 轴神经胶质细胞在神经系统疾病发病机制中的作用。这笔赠款的科学计划扩大了 在这项先前的工作中，重点关注多发性硬化症中的轴神经胶质自身免疫，这是一个令人兴奋的新研究途径，具有潜在的潜力 解释多发性硬化症中髓磷脂和底层轴突的双重病理学，以及实质性的 患者之间存在的临床病程和结果的异质性。 这 调制的 更多的 研究目的： (1) 测试 匹配的 频率 作为 核磁共振成像 轨迹 该提议的中心假设是轴胶质细胞的自身免疫在 MS 发病机制以及对轴神经胶质细胞具有自身免疫性的患者将会经历的情况 严重的轴突损失，导致脑萎缩的发生率更高。 与年龄相比，多发性硬化症患者是否更有可能产生轴突胶质细胞自身抗体？ 健康对照和其他炎症性神经系统疾病的对照，(2) 列举 与对照组相比，多发性硬化症患者中轴胶质反应性 T 细胞的促炎症潜能，以及 (3) 作为原理证明，轴胶质细胞自身免疫将在基于以下定义的多发性硬化症患者子集中进行测量 测量不同萎缩率来检验轴突胶质细胞自身免疫与相关的假设 脑萎缩。 拟议的目标 这些研究不仅有助于更好地了解发病机制 和 MS 谱中存在的异质性，但也在发展 具体的 为了 更好地监测相关抗原的工具 反应并可能更好地预测并可能重新审视更个性化的策略 抗原特异性疗法。 PI 将由三位具有完成此任务所需的不同专业领域的导师指导 项目。巴-奥尔博士是一个世界 规定 研究免疫原理的分子和细胞免疫学专家 和 MS 中的免疫神经相互作用；博士。 Scherer 是分子组织方面的专家 有髓轴突；兰卡斯特博士是中枢神经系统自身免疫领域的领先专家，特别是 抗体介导的神经系统疾病，在发现新型自身抗原方面拥有丰富的经验， 包括轴胶质细胞分子。 协助 PI 发展新研究技能的培训计划是本申请不可或缺的一部分。在 除了完成拟议的研究之外，申请人还将参与严格的教学计划 由细胞和分子免疫学、脑成像和生物统计学专家提供的课程和指导。她 将获得使用重叠肽库鉴定免疫显性表位的专业知识， 免疫斑点测定、细胞增殖测定、多参数流式细胞术和统计方法 与转化研究相关并获得重组 MHC 开发的工作知识 受体和先进的 MRI 分析技术（MIMoSA 和 SuBLIME）。由于本项目涉及两方面 人类受试者，涉及道德问题的具体培训已纳入培训计划。这 申请人在研究和职业发展方面的进展和具体基准的实现情况将 她的导师定期进行审查，他们在培训初级调查员方面拥有丰富的经验， 促进他们向独立研究职业的过渡。将有助于完成拟议的研究 通过优先考虑合作并提供模范研究和职业的制度环境 支持。通过拟议的研究，申请人将为理解 神经系统疾病中的轴胶质自身免疫以及未来检查 T 细胞项目所需的新工具 轴突胶质细胞免疫不仅在多发性硬化症中介导，而且在其他神经系统疾病（例如自身免疫性疾病）中也有介导 脑炎和 CIDP。