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

项目摘要/摘要 亚急性小脑性共济失调患者中有Sez6L2自身抗体的报道。 患者出现步态共济失调、说话含糊和眼球运动症状。一些患者还 出现肢体共济失调、认知障碍、运动迟缓和/或帕金森症。这些案例研究具有 导致了针对Sez6L2的自身免疫可以直接导致小脑损伤的假设 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，还没有进行动物研究。 为了帮助了解Sez6L2自身抗体是否直接致病，它们是否是 对Sez6L2的基于细胞的自身免疫，或者是否只是小脑病理的多余。 我们计划测试两种Sez6L2自身免疫的小鼠模型，以了解其机制 潜在的小脑性共济失调与相关的Sez6L2自身抗体。该项目的目标1将 确定Sez6L2蛋白免疫的小鼠是否出现小脑性共济失调。我们还将寻求 使用行为评估、免疫组织化学和FLOW了解疾病机制 浸润性免疫细胞群的细胞学分析。目标2将决定Sez6L2是否 抗体本身可引起小鼠小脑性共济失调，或阻断Sez6L2‘S补体抑制功能 在试管中。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，再加上目前报告的人类病例研究，应该鼓励迅速和常规的 疑似免疫介导性小脑性共济失调患者的Sez6L2自身抗体筛查。 关于疾病机制的结果也有助于指导临床医生进行免疫疗法，这些疗法可能 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。

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.