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

项目概要/摘要 Sez 6L 2自身抗体在亚急性小脑性共济失调患者中有报道。 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 导致了这样的假设，即针对Sez 6L 2的自身免疫可以直接导致小脑损伤， 共济失调Sez 6L 2是由脑中的大多数神经元表达的跨膜蛋白，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 为了帮助了解Sez 6L 2自身抗体是否直接病理性，它们是否是 基于细胞的自身免疫Sez 6L 2，或是否只是多余的小脑病理。 我们计划测试Sez 6L 2自身免疫的两种小鼠模型，以了解其机制。 潜在的小脑共济失调伴相关Sez 6L 2自身抗体。该项目的目标1将 确定用Sez 6L 2蛋白免疫的小鼠是否发生小脑共济失调。我们还将寻求 使用行为评估，免疫组织化学和血流来了解疾病机制 浸润免疫细胞群体的细胞术分析。目标2将确定Sez 6L 2是否 单独的抗体可以导致小鼠小脑共济失调，或阻断Sez 6L 2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， 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，加上目前报道的人类案例研究，应该鼓励及时和例行的 在疑似免疫介导的小脑性共济失调中筛选Sez 6L 2自身抗体。 关于疾病机制的结果也可以帮助指导临床医生使用免疫疗法， 对患者最有效，并有助于证明长期免疫抑制的风险。

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.