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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要家长资助项目：已报道亚急性小脑患者出现 Sez6L2 自身抗体共济失调。患者出现步态共济失调、言语不清和眼部运动症状。有些患者还出现肢体共济失调、认知缺陷、运动迟缓和/或帕金森症。这些案例研究导致假设针对 Sez6L2 的自身免疫可直接引起小脑损伤，导致共济失调。塞兹6L2 是一种跨膜蛋白，由大脑中的大多数神经元表达，包括浦肯野细胞和颗粒细胞小脑。目前，尚未进行动物研究来帮助了解 Sez6L2 是否自身抗体是直接病理性的，无论它们是针对 Sez6L2 的细胞自身免疫的生物标志物，还是是否对于小脑病理学来说都是多余的。我们计划测试两种 Sez6L2 鼠标模型自身免疫，以了解与 Sez6L2 相关的小脑共济失调的机制自身抗体。该项目的目标 1 将确定用 Sez6L2 蛋白免疫的小鼠是否发育小脑性共济失调。我们还将寻求使用行为评估来了解疾病机制，浸润免疫细胞群的免疫组织化学和流式细胞术分析。目标 2 将决定单独使用 Sez6L2 抗体是否会导致小鼠小脑共济失调，或阻断 Sez6L2 的补体抑制作用在体外发挥作用。我们预计这些研究将提供强有力的机制证据，证明抗体和/或对 Sez6L2 的完全免疫反应是共济失调和相关症状的病理原因。这些研究，结合目前报告的人类案例研究，应鼓励及时进行常规筛查 Sez6L2 自身抗体在疑似免疫介导的小脑性共济失调中的表现。疾病结果机制还可以帮助指导临床医生采取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是合理的。支持健康相关研究项目多样性的行政补充：本补充品将支持代表性不足的少数族裔毕业生的研究和职业发展学生。候选人的研究项目将扩展目标 1，以测试不同小鼠品系的自身免疫能力对 Sez6L2 免疫和基于新病毒载体的异源初免-加强免疫的敏感性战略。它还将测试 Sez6L2 免疫小鼠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为候选人毕业并获得有竞争力的博士后职位以继续学习做好准备神经免疫学的跨学科领域。