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

使用深度数据剖析适应性免疫在帕金森病表型中的作用

• 批准号: MR/X032892/1
• 负责人: Cynthia Sandor
• 金额: $ 182.9万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX032892%2F1
• 关键词: Dissecting; role; adaptive; immunity; Parkinson

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).

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 万人中就有 160 人受到影响。由于人口增长和人口老龄化，英国帕金森病的患病率和发病率预计将会增加。目前还无法治愈帕金森病（或任何其他神经退行性疾病）。随着患者帕金森病的进展，疾病成本不断增加，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 与表达多巴胺化学物质的神经元丧失有关。多项研究增加了越来越多的证据表明帕金森病也是一种自身免疫性疾病。这些研究表明，患者在确诊后不久，血液中就会出现许多免疫记忆 T 细胞，它们对一种名为 α-突触核蛋白的蛋白质产生特异性反应。这种蛋白质是帕金森病的标志，在帕金森病患者的大脑神经元内积聚。记忆T细胞是能够记住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继发反应。此外，这些研究重点关注血液中的 T 细胞，并没有提供直接证据证明这些细胞针对帕金森病患者大脑中的神经元。在这个研究项目中，我们将对PD患者不同阶段的死后脑组织中的T细胞及其细胞环境进行测序，以发现情况是否如此。针对适应性免疫系统的疗法已成功治疗许多疾病，例如：癌症/自身免疫性疾病/传染病。如果我们完全了解 T 细胞在 PD 中的作用（目标 1），这些治疗策略可以很快在 PD 中重新调整用途。无论如何，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 细胞可能会识别帕金森病个体在出现症状前，能够进行早期干预以保护高危人群的神经元。迄今为止，快速眼动 (REM) 睡眠行为障碍 (RBD) 是一种人们在身体上表现出梦境的异常状况，是 PD 的最佳早期指标，80% 的患者会进展为 PD。在 RBD 患者被诊断患有任何神经退行性疾病之前，我们已经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”）提供了更好的机会进行早期诊断和有针对性的及时治疗患者，改善生活质量，并为未来研究生成丰富的数据集（目标 2）。建立 T 细胞因果关系的最后一个障碍PD 的一个特点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。对帕金森病患者的医学影像研究以及对生物样本库的活检、肠道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。一些早期帕金森病患者会出现胃肠道症状，例如胃肠道症状，这一事实支持了身体优先亚型的存在。便秘。我们假设 T 细胞可能在身体优先与大脑优先的 PD 病因学中发挥不同的作用。通过将针对 PD 的不同 T 细胞特征与不同的生物医学数据相结合，我们将确定哪种 PD 临床亚型 T 细胞发挥着重要作用。在我们能够确定谁将从中受益以及何时提供治疗之前，预防疾病发作或减缓疾病进展的疗法的开发价值有限（目标 3）。