Innate and Adaptive Immunity in Parkinson Disease

帕金森氏病(PD)神经保护策略的发展是一个重要的未得到满足的需求。正如在提交给NINDS理事会的报告(PD2014)中所述，“专注于帕金森病的调查者社区现在正在努力创造有意义地减缓或阻止帕金森病所有症状背后的疾病机制的治疗方法”。阿拉巴马州Udall中心就是对这些需求的回应，也是我们在NINDS帕金森氏病研究探索性资助计划(P20NS092530)下工作的产物。长期以来，人们一直认为帕金森氏病死后的脑组织中存在天然免疫系统的激活，黑质中明显的小胶质细胞增多，同时细胞因子和趋化因子的产生增加。最近发现，适应性免疫也被激活，T细胞的渗透和免疫球蛋白在神经周积聚。我们预计，更好地了解帕金森病的免疫变化将确定阻止神经变性的特定靶点和治疗策略。该中心将致力于两个总体的科学目标：1)确定早期人类帕金森病免疫激活的程度和性质；2)确定抑制LRRK2和JAK/STAT信号通路是否可以阻断导致α-突触核蛋白相关神经变性的免疫反应。我们的中心假设是，先天性和获得性免疫细胞，特别是单核细胞和T细胞，在疾病早期被激活，阻断这些细胞中的LRRK2或JAK/STAT信号将防止神经退化。我们将利用先进的小分子配体和抑制剂、遗传方法、免疫细胞亚群的详细研究和骨髓移植方法来验证这一假设。每个项目都以临床核心和动物模型核心为基础，临床核心将提供来自人类受试者的样本，动物模型核心将协调帕金森病的阿尔法突触核蛋白小鼠纤维模型的临床前研究。阿拉巴马州乌德尔中心还有与培训和外联有关的重要任务。我们寻求培训下一代科学家和医生，以加快未来帕金森病治疗和治愈的进展。我们将让帕金森病患者社区作为我们的合作伙伴参与这些努力。我们寻求创建一个专注于识别对帕金森病发病机制至关重要的先天和获得性免疫反应的团队和环境，并迅速推进一个创新的、跨学科的、高度有影响力的研究计划。

The development of neuroprotective strategies for Parkinson’s disease (PD) is a vital unmet need. As stated in the Report to the NINDS Council (PD2014), “the community of investigators focused on PD now strives to create therapies that meaningfully slow or stop the disease mechanisms that underlie all symptoms of PD”. The Alabama Udall Center is a response to these needs, and a product of our work under an NINDS Exploratory Grant Program in Parkinson's Disease Research (P20NS092530). It has long been recognized that in post-mortem brain tissue from PD there is activation of the innate immune system, with prominent microgliosis in the substantia nigra together with enhanced production of cytokines and chemokines. Recently, it has become clear that there is also activation of adaptive immunity, with infiltration of T-cells and accumulation of immunoglobulins in perineural regions. We envisage that a better understanding of immune changes in PD will identify specific targets and therapeutic strategies that will block neurodegeneration. This Center will address two overall scientific Aims: 1) to determine the extent and nature of immune activation in early human PD; and 2) to determine whether inhibiting LRRK2 and JAK/STAT signaling pathways can block immune responses that underlie alpha-synuclein linked neurodegeneration. Our central hypothesis is that innate and adaptive immune cells, particularly monocytes and T-cells, are activated early in disease, and that blocking LRRK2 or JAK/STAT signaling in these cells will protect from neurodegeneration. We will utilize advanced small molecule ligands and inhibitors, genetic approaches, detailed studies of subsets of immune cells and bone marrow transplantation approaches to test the hypothesis. Each project is anchored through the Clinical Core that will provide samples from human subjects, and the Animal Models Core that harmonizes pre-clinical studies in the alpha-synuclein mouse fibril model of PD. The Alabama Udall Center also has important missions related to training and outreach. We seek to train the next generation of scientists and physicians, to accelerate progress towards PD treatments and cures of the future. We will engage the community of persons with PD who are our partners in these efforts. We seek to create a team and environment focused on the identification of innate and adaptive immune responses critical to PD pathogenesis, and rapidly advance an innovative, interdisciplinary, highly impactful research program.