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: 10526475
• 负责人: JENNETTA W HAMMOND
• 金额: $ 42.35万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526475
• 关键词: Abnormal coordination; Animal Model; Animals; Antibodies; Antibody Formation; Ataxia; Autoantibodies; Autoimmunity; Behavior assessment; Behavioral; Biological Markers; Bradykinesia; Brain; Brain region; C57BL/6 Mouse; Case Study; Cells; Cerebellar Ataxia; Cerebellum; Cerebrospinal Fluid; Clinical; Cognitive deficits; Complement; Coupled; Deposition; Diagnosis; Disease; Disease Progression; Early treatment; Enzyme-Linked Immunosorbent Assay; Epitopes; Etiology; Flow Cytometry; Freund' s Adjuvant; Future; Gait; Gait Ataxia; Gliosis; Hour; Human; Immune; Immune response; Immune system; Immunize; Immunohistochemistry; Immunosuppression; Immunotherapy; Impairment; In Vitro; Injections; Integral Membrane Protein; Lead; Limb Ataxia; Link; Maps; Mediating; Motor; Movement; Mus; Neurons; Parkinsonian Disorders; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Phase; Physicians; Population; Preclinical Testing; Proteins; Purkinje Cells; Reporting; Research; Risk; Rotarod Performance Test; Serum; Speech; Stains; Symptoms; System; Testing; Therapeutic; Time; TimeLine; Tissues; Tumor-infiltrating immune cells; autoimmune pathogenesis; base; cisterna magna; cohort; falls; granule cell; immunomodulatory therapies; in vitro Assay; innovation; motor symptom; mouse model; neuron loss; novel; novel therapeutics; oculomotor; routine screening; therapeutic evaluation

Project Summary/Abstract 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.

项目概要/摘要 据报道，亚急性小脑共济失调患者出现 Sez6L2 自身抗体。 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。这些案例研究有 导致了这样的假设：针对 Sez6L2 的自身免疫可以直接引起小脑损伤，从而导致 至共济失调。 Sez6L2 是一种跨膜蛋白，由大脑中的大多数神经元表达，包括 小脑的浦肯野细胞和颗粒细胞。目前尚未进行动物研究 帮助了解 Sez6L2 自身抗体是否是直接病理性的，它们是否是以下疾病的生物标志物： 对 Sez6L2 的基于细胞的自身免疫，或者对于小脑病理学来说是否只是多余的。 我们计划测试两种 Sez6L2 自身免疫小鼠模型，以了解其机制 与 Sez6L2 自身抗体相关的潜在小脑性共济失调。该项目的目标 1 将 确定用 Sez6L2 蛋白免疫的小鼠是否会出现小脑共济失调。我们还将寻求 使用行为评估、免疫组织化学和血流了解疾病机制 浸润免疫细胞群的细胞计数分析。目标2将确定Sez6L2是否 单独使用抗体可导致小鼠小脑共济失调，或阻断 Sez6L2 的补体抑制功能 体外。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，加上目前报告的人类案例研究，应鼓励及时和常规 在疑似免疫介导的小脑性共济失调中筛查 Sez6L2 自身抗体。 关于疾病机制的结果还可以帮助指导临床医生进行可能的免疫治疗。 对患者最有效，并有助于证明长期免疫抑制的风险是合理的。