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.

项目摘要/摘要 亚急性小脑共济失调的患者已经报道了SEZ6L2自身抗体。 患者患有共济失调，言语和眼运动症状。还有一些患者 发展肢体共济失调，认知缺陷，胸肌和/或帕金森氏症。这些案例研究有 导致假说，即对SEZ6L2的自身免疫会直接引起小脑损伤 进行共济失调。 SEZ6L2是一种由大脑中大多数神经元表达的跨膜蛋白 小脑的Purkinje细胞和颗粒细胞。目前，尚未进行动物研究 为了帮助了解SEZ6L2自身抗体是否直接病理，它们是否是生物标志物 基于细胞的自身免疫性对SEZ6L2，或者是否仅仅是小脑病理的多余。 我们计划测试SEZ6L2自身免疫性的两个鼠标模型，以了解机制 与SEZ6L2自身抗体相关的小脑共济失调的基础。该项目的目标1将 确定用SEZ6L2蛋白免疫的小鼠是否发展为小脑共济失调。我们还将寻求 使用行为评估，免疫组织化学和流动了解疾病机制 浸润免疫细胞群体的细胞仪分析。 AIM 2将确定SEZ6L2是否 仅抗体就会导致小鼠小脑共济失调，或阻塞SEZ6L2的完成抑制功能 体外。我们预计这些研究将提供强大的机械证据表明抗体 和/或对SEZ6L2的完全免疫响应是共济失调和相关符号的病理原因。这些 与目前报道的人类案例研究相结合的研究应鼓励及时和常规 在怀疑的小脑共济失调中对SEZ6L2自身抗体的筛查。 疾病机制的结果还可以帮助临床医生进行可能的免疫疗法 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。