Dissecting the role of the adaptive immunity in the Parkinson's phenotypes using deep data

背景：帕金森病是一种毁灭性的神经退行性疾病，在英国每10万人中有160人受到影响。由于人口增长和人口日益老龄化，预计英国帕金森病的患病率和发病率将会增加。目前还没有治愈帕金森病(或任何其他神经退行性疾病)的方法。随着患者帕金森病的进展，疾病成本不断上升，给医疗保健系统和社会带来经济负担，并影响患者及其家人的生活。帕金森病与表达一种名为多巴胺的化学物质的神经元丢失有关。多项研究补充了越来越多的证据表明，帕金森氏症也是一种自身免疫性疾病。这些研究表明，确诊后不久，患者血液中有许多免疫记忆T细胞，它们对一种名为α-突触核蛋白的蛋白质有特异性反应。这种蛋白质是帕金森氏症的标志，积聚在帕金森氏症患者的大脑神经元中。记忆T细胞是记忆过去感染或自身免疫反应的特定分子特征的免疫细胞。然而，所有这些研究都没有确定自身免疫是否是主要原因，而不是次要反应。此外，这些研究集中在血液中的T细胞，并没有带来这些细胞针对帕金森氏症患者大脑中的神经元的直接证据。在这项研究计划中，我们将对不同阶段收集的帕金森氏症患者死后脑组织中的T细胞及其细胞环境进行测序，以发现情况是否如此。针对适应性免疫系统的治疗在许多疾病中都取得了成功，例如癌症/自身免疫性疾病/传染病。如果我们充分了解T细胞在PD中的作用(目标1)，这些治疗策略可能很快在PD中改变用途。无论如何，即使T细胞的反应性是次要的，这些观察表明，监测这些T细胞可能会在症状前识别帕金森患者，使早期干预能够在高危人群中保留神经元。到目前为止，快速眼动(REM)睡眠行为障碍(RBD)的存在是帕金森病最好的早期指标，80%的患者进展为帕金森病。我们收集和储存了RBD患者的血液样本，在他们被诊断为任何神经退行性疾病之前。对RBD患者的血液进行分析，可以追溯到反映转化为PD的免疫系统的变化。在这里，我们将对RBD患者的血细胞进行测序，目的是识别免疫系统特定细胞的变化。这些指标(生物标记物)为患者提供了更好的早期诊断和有针对性的及时治疗的机会，改善了生活质量，并为未来的研究产生了丰富的数据集(目标2)。确定T细胞在帕金森病中的因果关系的最后一个障碍是每个患者的临床表现差异很大，这表明存在不同的亚型和影响。最近对帕金森病患者的医学成像研究以及来自生物库的活检组织和肠道和脑组织的研究指出，在一些患者中，大脑先于(大脑优先)周围神经系统(身体优先)受到影响。一些早期PD患者出现胃肠道症状，如便秘，这一事实支持了身体第一亚型的存在。我们假设T细胞可能在身体优先与脑优先的帕金森病的病因中扮演不同的角色。通过将不同的PD特异性T细胞特征与不同的生物医学数据相结合，我们将确定哪些PD临床亚型T细胞在其中起着突出的作用。在我们确定谁将从中受益以及何时提供治疗之前，预防疾病发生或减缓疾病进展的治疗方法的发展价值有限(目标3)。

Background: Parkinson's disease (PD) is a devastating neurodegenerative disease that affects 160 people per 100,000 in the United Kingdom. Because of population growth and an increasingly aged population, the estimated prevalence and incidence of PD in the UK is expected to increase. There is currently no cure for PD (or any other neurodegenerative disease). The cost of illness escalates as a patient's PD progresses, placing an economic burden on the healthcare system and society and impacting the lives of patients and their families. PD is associated with a loss of neurons expressing a chemical called dopamine. Multiple studies added increasing evidence that PD is also an auto-immune disease. These studies show that patients shortly after their diagnosis have many immune memory T cells in their blood that respond specifically to a protein called alpha-synuclein. This protein, the hallmark of PD, accumulates inside brain's neurons of PD patients. Memory T cells are immune cells that remember the specific molecular features of past infections or auto-immune reactions.However, all these studies don't establish whether autoimmunity is a prime cause rather than a secondary reaction. In addition, these studies focused on T cells in the blood and did not bring direct evidence that these cells target neurons in the brains of people with Parkinson's. In this research program, we will sequence T cells and their cellular environment in the post-mortem brain tissue collected in PD patients at different stages to discover whether this is the case. Therapies targeting the adaptive immune system have been successful in many disorders e.g. cancer/auto-immune disease/infectious disease. These therapeutic strategies could be quickly repurposed in PD if we fully understand the role of T cells in PD (Objective 1).In any case, even if the T cell reactivity was secondary, these observations suggest that monitoring these T cells might identify Parkinson's individuals pre-symptomatically, enabling earlier interventions to preserve neurons while at-risk populations. To date, the presence of rapid eye movement (REM) sleep behaviour disorder (RBD), an abnormal condition where people physically act out dreams, is the best early indicator for PD, with 80% of patients progressing to PD. We have collected and banked blood samples from RBD patients before they have been diagnosed with any neurodegenerative condition. Analysing the blood of RBD patients could retrospectively identify changes in the immune system that reflect conversion to PD. Here, we will sequence blood cells from RBD individuals with the aim of identifying changes in specific cells of the immune system. These indicators ("biomarkers") offer a better chance of early diagnosis and targeted, timely treatment of patients, improving quality of life, and generating a rich dataset for future research (Objective 2).One final obstacle to establishing the causality of T cells in PD is that the clinical presentations of each patient vary so greatly, suggesting the existence of different subtypes and influences. Medical imaging studies of PD patients and studies of biopsies and gut and brain tissue from biobanks recently pointed out that in some patients, the brain is affected before (brain-first) the peripheral nervous system (body-first). The existence of the body-first subtype is supported by the fact that some PD patients at an earlier stage present gastrointestinal symptoms e.g. constipation. We hypothesise that T-cells may play distinct roles in body-first vs brain-first PD aetiologies. By integrating different T cell signature specific to PD with different biomedical data, we will determine in which PD clinical subtype T cells play a prominent role. The development of therapies that prevent disease onset or slow down the disease progression are of limited value until we can identify who would benefit from them and when to deliver treatment (Objective 3).