Pathological Mechanisms of Immune-Mediated Cerebellar Ataxia with Associated Sez6L2 Autoantibodies

免疫介导的小脑共济失调与相关 Sez6L2 自身抗体的病理机制

• 批准号: 10740682
• 负责人: JENNETTA W HAMMOND
• 金额: $ 8.88万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10740682
• 关键词: Abnormal coordination; Administrative Supplement; Animals; Antibodies; Ataxia; Autoantibodies; Autoimmune; Autoimmunity; B-Lymphocytes; Behavior assessment; Biological Markers; Bradykinesia; Brain; Brain region; Case Study; Cells; Cerebellar Ataxia; Cerebellum; Cognitive deficits; Complement; Coupled; Cytotoxic T-Lymphocytes; Disease; Flow Cytometry; Gait Ataxia; Health; Human; Immune; Immune response; Immune system; Immunization; Immunize; Immunohistochemistry; Immunosuppression; Immunotherapy; In Vitro; Integral Membrane Protein; Limb Ataxia; Link; Mediating; Mentors; Minority Graduate Student; Mouse Strains; Movement; Mus; Neurons; Parkinsonian Disorders; Pathologic; Pathology; Patients; Phenotype; Physicians; Population; Positioning Attribute; Postdoctoral Fellow; Predisposition; Proteins; Purkinje Cells; Reporting; Research Project Grants; Research Support; Risk; Speech; Symptoms; Testing; Underrepresented Minority; Viral Vector; autoimmune pathogenesis; career development; falls; granule cell; immune cell infiltrate; motor symptom; mouse model; neuroimmunology; novel therapeutics; oculomotor; parent grant; research and development; routine screening; vaccination strategy

Project Summary/Abstract Parent Grant Project: Sez6L2 autoantibodies have been reported in patients with subacute cerebellar ataxia. Patients present with gait ataxia, slurred speech, and ocular motor symptoms. Some patients also develop limb ataxia, cognitive deficits, bradykinesia, and/or Parkinsonism. These case studies have led to the hypothesis that autoimmunity against Sez6L2 can directly cause cerebellar damage leading to ataxia. Sez6L2 is a transmembrane protein expressed by most neurons in the brain including Purkinje cells and granule cells of the cerebellum. Currently, no animal studies have been performed to help understand if Sez6L2 autoantibodies are directly pathologic, whether they are a biomarker of cell-based autoimmunity to Sez6L2, or whether are simply superfluous to the cerebellar pathology. We plan to test two mouse models of Sez6L2 autoimmunity in order to understand the mechanisms underlying cerebellar ataxia with associated Sez6L2 autoantibodies. Aim 1 of this project will determine whether mice immunized with Sez6L2 protein develop cerebellar ataxia. We will also seek to understand the disease mechanisms using behavioral assessments, immunohistochemistry, and flow cytometry analysis of infiltrating immune cell populations. Aim 2 will determine whether Sez6L2 antibodies alone can cause cerebellar ataxia in mice, or block Sez6L2's complement inhibitory functions in vitro. We anticipate that these studies will provide strong mechanistic evidence that the antibody and/or full immune response to Sez6L2 is a pathological cause of ataxia and related symptoms. These studies, coupled with the presently reported human case studies, should encourage prompt and routine screening for Sez6L2 autoantibodies in suspected immune-mediated presentations of cerebellar ataxia. The results on disease mechanisms could also help guide clinicians to the immunotherapies that may be most effective for patients and help justify the risks of prolonged immunosuppression. Administrative Supplement to Support Diversity in Health-Related Research Project: This supplement will support the research and career development of an under-represented minority graduate student. The candidate's research project will expand Aim 1 to test different mouse strains for autoimmune susceptibility to Sez6L2 immunization and a new viral-vector based heterologous prime-boost immunization strategy. It will also test whether the ataxia phenotype in Sez6L2 immunized mice requires functional cytotoxic T cells or B cells. The mentored research and career development activities of this application will help prepare the candidate for graduation and obtaining a competitive postdoctoral position for continued study in the interdisciplinary field of neuroimmunology.

项目总结/摘要 父母资助项目：Sez 6L 2自身抗体已在亚急性小脑胶质瘤患者中报告 共济失调患者表现为步态共济失调、言语不清和眼部运动症状。一些患者还 出现肢体共济失调、认知缺陷、运动迟缓和/或帕金森综合征。这些案例研究导致了 假设针对Sez 6L 2的自身免疫可直接引起小脑损伤，导致共济失调。Sez6L2 是一种跨膜蛋白，由大脑中的大多数神经元表达，包括浦肯野细胞和小脑颗粒细胞。 小脑目前，还没有进行动物研究来帮助理解Sez 6L 2是否 自身抗体是直接病理性的，无论它们是Sez 6L 2的基于细胞的自身免疫的生物标志物，还是 对小脑病理学来说是否只是多余的我们计划测试Sez 6L 2的两个小鼠模型 自身免疫，以了解小脑共济失调与Sez 6L 2相关的机制 自身抗体本项目的目的1将确定Sez 6L 2蛋白免疫的小鼠是否发育 小脑性共济失调我们还将寻求通过行为评估来了解疾病机制， 免疫组织化学和流式细胞术分析浸润免疫细胞群体。目标2将决定 是否Sez 6L 2抗体单独可以引起小鼠小脑共济失调，或阻断Sez 6L 2的补体抑制 在体外发挥作用。我们预计这些研究将提供强有力的机制证据， 和/或对Sez 6L 2的完全免疫应答是共济失调和相关症状的病理原因。这些研究， 再加上目前报道的人类病例研究，应该鼓励及时和例行筛查， Sez 6L 2自身抗体在疑似免疫介导的小脑共济失调中的作用疾病的结果 这些机制也可以帮助指导临床医生使用对患者最有效的免疫疗法。 并有助于证明长期免疫抑制的风险。 支持健康相关研究项目多样性的行政补充：这 补助金将支持代表性不足的少数民族毕业生的研究和职业发展 学生.候选人的研究项目将扩展Aim 1以测试不同小鼠品系的自身免疫性 对Sez 6L 2免疫的易感性和基于新病毒载体的异源初免-加强免疫 战略还将测试Sez 6L 2免疫小鼠中的共济失调表型是否需要功能性细胞毒性 T细胞或B细胞。该应用程序的指导研究和职业发展活动将有助于 准备毕业的候选人，并获得一个有竞争力的博士后职位，继续研究在 神经免疫学的跨学科领域