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

项目摘要/摘要 Parent Grant计划：亚急性小脑患者中有Sez6L2自身抗体的报道 共济失调。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。这些案例研究导致了 假设针对Sez6L2的自身免疫可以直接导致小脑损伤，从而导致共济失调。Sez6L2 是一种跨膜蛋白，由大脑中的大多数神经元表达，包括浦肯野细胞和 小脑。目前，还没有进行动物研究来帮助理解Sez6L2 自身抗体直接是病理的，无论它们是基于细胞的对Sez6L2的自身免疫的生物标记物，还是 是否对小脑病理来说简直是多余的。我们计划测试两种小鼠模型的Sez6L2 自身免疫以了解与Sez6L2相关的小脑性共济失调的机制 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会 小脑性共济失调。我们还将通过行为评估来寻求了解疾病的机制， 免疫组织化学和流式细胞术分析浸润性免疫细胞群。目标2将决定 Sez6L2抗体单独能引起小鼠小脑性共济失调，还是阻断Sez6L2‘S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， 再加上目前报告的人类病例研究，应鼓励迅速和常规地筛查 疑似免疫介导的小脑性共济失调表现中的Sez6L2自身抗体。关于疾病的结果 这种机制还可以帮助指导临床医生使用对患者可能最有效的免疫疗法。 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副刊：这 补助金将支持代表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大目标1，以测试不同的小鼠品系的自身免疫 Sez6L2免疫易感性及一种新的基于病毒载体的异源Prime-Boost免疫 策略。它还将测试Sez6L2免疫的小鼠的共济失调表型是否需要功能性细胞毒 T细胞或B细胞。此应用程序的辅导性研究和职业发展活动将有所帮助 为毕业做好准备，并获得一个有竞争力的博士后职位，以便在 神经免疫学的跨学科领域。

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.