Autoimmune features of neurodegenerative disorders

摘要： 神经退行性疾病的特点是特定蛋白质的错误加工，但如何以及如果这 导致细胞死亡的原因尚不清楚。该提案支持免疫学之间的合作研究， 和神经科学实验室与疾病专家追求新的发现，需要这样的跨学科 协作我们的联合初步结果提供了第一个直接证据，表明帕金森病（PD）， 长期以来，人们都知道它具有突出的神经炎症成分， 部分是一种自身免疫性疾病，以抗原呈递和特异性T细胞反应为特征。结果 表明PD与包括1型在内的经典自身免疫性疾病具有基本特征， 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- 衍生的新抗原在衰老或疾病状况中变得越来越多地表达。我们的总体目标是 识别与PD和阿尔茨海默病（AD）相关的抗原反应。我们将确定 α-突触核蛋白衍生的和tau衍生的新抗原在这些患者中的表达，并比较这些患者中的特征。 PD、AD、年龄匹配对照和年轻对照。我们将1）鉴定在PD中充当新抗原的表位 和AD; 2）表征应答性T细胞; 3）表征抗原呈递和T细胞- 通过表达与PD相关的HLA等位基因的动物模型介导神经元死亡， α-syn表位。如果自身免疫性特征得到证实，用于治疗其他自身免疫性疾病的疗法 例如耐受化可用于治疗PD。

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.