Autoimmune features of neurodegenerative disorders

摘要： 神经退行性疾病的特征是特定蛋白质的错误处理，但这是如何以及是否 细胞死亡的结果尚不清楚。这项提议支持免疫学和免疫学之间的合作研究 以及拥有疾病专家的神经科学实验室，以寻求需要这种跨学科的新发现 协作。我们的联合初步结果首次直接证明帕金森氏病(PD)， 它长期以来一直被认为具有突出的神经炎症成分，至少对许多患者来说是这样的 在一定程度上是一种自身免疫性疾病，以抗原递呈和特定的T细胞反应为特征。结果是 证明帕金森病与包括1型在内的经典自身免疫性疾病的基本特征相同 糖尿病、多发性硬化症和类风湿性关节炎。我们的总体假设是帕金森病与自我相关 在衰老或疾病条件下越来越多地表达的衍生新抗原。我们的总体目标是 确定与帕金森病和阿尔茨海默病(AD)相关的抗原反应。我们将确定 α-突触核蛋白来源的新抗原和tau来源的新抗原在这些患者中的表达情况，并比较 帕金森病、阿尔茨海默病、年龄匹配的对照组和年轻对照组。我们将1)确定在帕金森病中作为新抗原的表位 和AD；2)表征反应性T细胞；3)表征抗原递呈和T细胞的作用- 表达与帕金森病高亲和力相关的HLA等位基因的动物模型介导的神经元死亡 α-SYN表位。如果自身免疫功能得到证实，用于治疗其他自身免疫性疾病的疗法 如耐受性可用于治疗帕金森病。

Abstract: Neurodegenerative diseases are characterized by the misprocessing of specific proteins, but how and if this results in cell death has been unknown. This proposal supports collaborative research between immunology and neuroscience laboratories with disease experts to pursue new findings that require such cross-disciplinary collaboration. Our joint Preliminary Results provide the first direct evidence that Parkinson's disease (PD), which has long been known to feature prominent neuroinflammatory components, is for at least many patients in part an autoimmune disorder that features antigen presentation and specific T cell responses. The results demonstrate that PD shares fundamental features with classical autoimmune disorders including Type-1 diabetes, multiple sclerosis, and rheumatoid arthritis. Our overall hypothesis is that PD is associated with self- derived neoantigens that becomes increasingly expressed in aging or disease conditions. Our overall aim is to identify the antigenic responses associated with PD and Alzheimer's disease (AD). We will identify α-synuclein-derived and tau-derived neoantigens in these patients and compare these profiles in patients with PD, AD, age-matched controls and young controls. We will 1) identify epitopes that act as neoantigens in PD and AD; 2) characterize the responsive T cells; 3) characterize the role of antigen presentation and T cell- mediated neuronal death by animal models that express an HLA allele implicated in PD with high affinity to an α-syn epitope. If the autoimmune features are confirmed, therapies used to treat other autoimmune disorders such as tolerization can be used to treat PD.