HistioNode: The MRC Rare Disease Platform Node for Histiocytic Disorders

组织细胞疾病是一种罕见的疾病，其中被称为巨噬细胞的免疫细胞（又名“组织细胞”）会对身体造成附带损害。巨噬细胞由白细胞发育而来，通常在组织中巡逻，寻找损伤和感染。它们携带着强大的分子武器来保护我们免受伤害。然而，在组织细胞增多症中，巨噬细胞异常活化并对组织造成损伤，从而导致危及生命的疾病。在组织细胞肿瘤中，巨噬细胞在控制其行为的基因中获得突变，导致它们变得叛变，并使炎症自发发生。在HLH （Haemophagocytic lymphoo hitiocytosis的简称）中，巨噬细胞被触发进入超速状态，导致骨髓衰竭和广泛的器官功能障碍。人们对HLH的了解较少，但它很可能是遗传遗传因素和免疫系统遇到病毒或淋巴瘤（一种血癌）时的异常行为的结合。HistioNode是一项倡议，将MRC罕见疾病平台内的医生，科学家和患者团体聚集在一起，以解决由组织细胞疾病引起的最紧迫问题。这些疾病自然涉及许多不同的器官，HLH与多种不同的触发因素有关。因此，hitionode与影响特定器官的其他罕见疾病存在内在联系。在为期五年的项目中，我们将通过我们的患者参与合作伙伴Histio UK与患者和家属进行接触，讨论有组织细胞增多症生活经验的患者的优先事项。为了解决实验室中的研究问题，我们还需要在生物银行中收集患者样本和临床数据。这一直是具有挑战性的，特别是在患者生病非常快的HLH中，但通过Node的资助将使我们能够在英国组织细胞增多症登记处招募参与者并收集研究材料。我们还将与所有四个国家的国家疾病登记服务机构合作，更多地了解组织细胞增多症患者的医疗需求，包括他们在不同地区的治疗方式，以及是否与其他疾病有意想不到的联系。作为研究计划的一部分，我们将针对我们认为需要进一步了解的三个领域。其中两例属于高肝炎，因为目前大龄儿童和成人的死亡率为50%。在HLH患者中，我们将使用新技术检测病毒感染和淋巴瘤，这是两个主要的触发因素。目前尚不清楚为什么HLH患者对常见病毒有异常的免疫反应，因此我们也将研究感染的模式和身体的反应，以寻找非典型特征。在淋巴瘤中，诊断往往是困难和延迟的，因此我们将开发血液DNA测序，也称为“液体活检”，以提高早期发现和生存的机会。在第三个项目中，我们将对所有患者的遗传DNA进行测序，看看是否有基因会增加患组织细胞疾病的几率。我们还将寻找发生在个体患者骨髓和血液中的突变，看看这是否会改变他们的风险或疾病模式。在组织细胞肿瘤中，如朗格汉斯细胞组织细胞增多症和Erdheim Chester病，在组织细胞内的炎症组织中存在突变。然而，并不是所有的突变都被解释了，所以我们将做进一步的测序，目的是在每个病人身上找到基因诊断。我们还将测量液体活检中的突变，以帮助诊断和风险评估。我们已经是一个紧密的合作网络，但MRC罕见疾病平台将使我们能够更有效地推动研究向前发展，造福患者。这将改善组织细胞疾病患者的预后，并通过在平台上分享我们的见解和技能，对整个罕见疾病谱系产生影响。

Histiocytic disorders are rare diseases in which immune cells called macrophages (aka 'histiocytes') cause collateral damage to the body. Macrophages develop from white blood cells and normally patrol through the tissues, looking for injury and infection. They carry a potent armoury of molecular weapons to protect us from harm. However, in histiocytosis, macrophages become abnormally activated and cause damage to tissues that can lead to life-threatening illness. In Histiocytic Neoplasms, macrophages gain a mutation in genes governing their behaviour causing them to become mutinous and make inflammation happen spontaneously. In HLH, (short for Haemophagocytic Lympho Histiocytosis) macrophages are triggered to go into overdrive, causing bone marrow failure and widespread organ dysfunction. HLH is less well understood but is likely to be combination of inherited genetic factors and unusual behaviour of the immune system when it meets a virus or lymphoma, a type of blood cancer.HistioNode is an initiative to bring together doctors, scientists and patient groups within the MRC Rare Disease Platform to tackle the most pressing problems caused by Histiocytic Disorders. These diseases naturally involve many different organs, and HLH is associated with multiple different triggers. HistioNode is therefore inherently linked to other rare diseases that affect specific organs. In the five year programme, we will engage with patients and families through our patient involvement partner Histio UK to discuss the priorities of people with a lived experience of histiocytosis. To tackle research question in the laboratory we also need to collect patient samples and clinical data in a Biobank. This has been challenging especially in HLH where patients become ill very quickly, but funding through the Node will enable us to enrol participants in the UK Histiocytosis Registry and gather material for research. We will also collaborate with the National Disease Registration Services in all four nations to find out more about the medical needs of patients with histiocytosis, including how they are treated in different regions and whether there are unexpected associations with other illnesses.As part of the programme of research we will target three areas where we think there is a need to find out more. Two of these are in HLH because it currently has a 50% death rate in older children and adults. In patients with HLH we will use new technology to detect viral infection and lymphoma which are two of the main triggers. It is not known why patients with HLH have an abnormal immune response to common viruses, so we will also study the patten of infection and the response of the body, to look for atypical features. In lymphoma, the diagnosis is often difficult and delayed, so we will develop DNA sequencing of blood, also known as 'liquid biopsy, to improve the chance of early detection and survival. In the third project we will sequence the inherited DNA of all patients to see if there are genes that increase the chance of getting a histiocytic disorder. We will also look for mutations that occur in the bone marrow and blood of individual patients to see if this changes their risk or pattern of disease. In Histiocytic Neoplasms like Langerhans cell histiocytosis and Erdheim Chester disease, there are mutations in the inflamed tissues inside histiocytes. However, not all mutations are accounted for so we will do further sequencing aiming to find a genetic diagnosis in every patient. We will also measure mutation in liquid biopsies to help with diagnosis and risk assessment.We are already a closely collaborative network but the MRC Rare Disease Platform will enable us to drive research forward for benefit to patients much more effectively. This will improve outcomes for patients with histiocytic disorders and, through sharing our insights and skills across the Platform, have an impact on the whole spectrum of rare diseases.