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

背景：帕金森病（PD）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老龄化，预计英国PD的估计患病率和发病率将增加。目前还没有治愈PD（或任何其他神经退行性疾病）的方法。疾病的成本随着患者PD的进展而上升，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。PD与表达一种称为多巴胺的化学物质的神经元的损失有关。多项研究增加了越来越多的证据表明PD也是一种自身免疫性疾病。这些研究表明，在诊断后不久，患者血液中有许多免疫记忆T细胞，这些细胞对一种称为α-突触核蛋白的蛋白质有特异性反应。这种蛋白质是PD的标志，在PD患者的大脑神经元内积累。记忆性T细胞是一种免疫细胞，它能记住过去感染或自身免疫反应的特定分子特征。然而，所有这些研究都没有确定自身免疫是否是一个主要原因，而不是一个次要反应。此外，这些研究主要集中在血液中的T细胞上，并没有直接证据表明这些细胞靶向帕金森病患者大脑中的神经元。在这项研究计划中，我们将对PD患者在不同阶段收集的死后脑组织中的T细胞及其细胞环境进行测序，以发现情况是否如此。靶向适应性免疫系统的疗法已在许多病症中获得成功，例如癌症/自身免疫疾病/传染病。如果我们充分了解T细胞在PD中的作用，这些治疗策略可以迅速在PD中重新定位（目标1）。在任何情况下，即使T细胞反应性是次要的，这些观察结果表明，监测这些T细胞可能会在帕金森病患者发病前识别帕金森病患者，使早期干预能够在高危人群中保护神经元。到目前为止，快速眼动（REM）睡眠行为障碍（RBD）的存在是PD的最佳早期指标，80%的患者进展为PD。我们在RBD患者被诊断患有任何神经退行性疾病之前收集并储存了他们的血液样本。分析RBD患者的血液可以回顾性地识别反映PD转化的免疫系统变化。在这里，我们将对RBD个体的血细胞进行测序，目的是识别免疫系统特定细胞的变化。这些指标（“生物标志物”）提供了更好的早期诊断和针对性的机会，及时治疗患者，改善生活质量，并为未来的研究产生丰富的数据集（目标2）。建立PD中T细胞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，表明存在不同的亚型和影响。PD患者的医学成像研究以及生物库中活检和肠和脑组织的研究最近指出，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。身体优先亚型的存在得到以下事实的支持：一些早期PD患者出现胃肠道症状，例如便秘。我们假设T细胞可能在身体优先与脑优先的PD病因中发挥不同的作用。通过将PD特异性的不同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细胞起着重要作用。预防疾病发作或减缓疾病进展的治疗方法的开发价值有限，直到我们能够确定谁将从中受益以及何时提供治疗（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).