Somatic mutation in Primary Sjögren's Syndrome

原发性干燥综合征的体细胞突变

• 批准号: MR/P002005/1
• 负责人: Matthew Collin
• 金额: $ 76.94万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP002005%2F1
• 关键词: Somatic; mutation; Primary; Sj; gren

Autoimmune diseases affect 5% of the population and cause a wide range of painful disabilities that affect quality of life and may lead to life-threatening complications and early death. The most common autoimmune diseases in order of prevalence are rheumatoid arthritis, primary Sjögren's syndrome (PSS) and SLE or 'lupus'. In all these conditions, the immune system becomes hyperactive and damages tissues of the body including the joints, skin, mucous membranes, glands and vital organs. In health, immune responses are closely regulated so that auto-immunity dose not occur. Although research has identified many new ways to suppress auto-immunity, the 'aetiology' or fundamental reason that the immune system escapes control, is completely unknown.Through this research we are testing a new hypothesis that could explain why immune responses escape control in autoimmune disease. Throughout life, tissues of the body accumulate genetic mutations due to random errors in copying the DNA when cells divide. These mutations are known as 'somatic' mutations to indicate that they occur within an individual's lifetime and are not inherited from one generation to the next. Somatic mutations are the cause of cancer and may play an important role in many chronic and age-related diseases. Our research aims to test whether somatic mutations also cause autoimmunity. The idea is that genes that control immune responses may become defective so that immune cells escape from normal regulatory signals. There is evidence to support this idea from rare patients who are born with mutations that develop autoimmunity at a young age. We also know that patients with autoimmunity, especially those with PSS, are at risk of developing lymphoma and that some patients with lymphoma-related diseases get autoimmune problems. Our hypothesis suggests that somatic mutation is the factor linking both autoimmunity and lymphomaThe evidence we are looking for is whether patients with PSS have somatic DNA mutations in the immune cells that are causing their disease. Patients with PSS suffer dryness and severe irritation because their tear glands, salivary glands and other glands are attacked by immune cells. They are invited to join a UK Register and to allow their tissue biopsies to be used for research. We will use the latest tissue dissection methods to purify small populations of immune cells from the salivary glands of PSS patients and then ultra-sensitive DNA sequencing to detect somatic mutations in the DNA of the cells. If we find mutations, we will then determine which particular cell or cells of the immune system have the mutations and what problems the mutations cause in order to understand exactly how a mutation leads to the disease.This research promises to change our understanding of autoimmunity. If the hypothesis is correct then we anticipate that DNA mutation testing will become a new way to diagnose autoimmune disease, to predict how serious the condition will be and to monitor treatment. It will also provide specific information that will enable drugs to be targeted to individual somatic mutations. Ultimately this will improve the treatment of patients with autoimmune disease, enhancing their health and economic welfare and reducing the burden of autoimmune disease upon society.

自身免疫性疾病影响5%的人口，并导致各种痛苦的残疾，影响生活质量，并可能导致危及生命的并发症和过早死亡。最常见的自身免疫性疾病按患病率顺序为类风湿性关节炎、原发性干燥综合征（PSS）和SLE或“狼疮”。在所有这些情况下，免疫系统变得过度活跃并损害身体组织，包括关节，皮肤，粘膜，腺体和重要器官。在健康的情况下，免疫反应受到密切调节，因此不会发生自身免疫。尽管研究已经发现了许多抑制自身免疫的新方法，但免疫系统逃脱控制的“病因”或根本原因是完全未知的。通过这项研究，我们正在测试一个新的假设，可以解释为什么免疫反应在自身免疫性疾病中逃脱控制。在整个生命过程中，由于细胞分裂时复制DNA的随机错误，身体组织会积累基因突变。这些突变被称为“体细胞”突变，表明它们发生在个体的一生中，而不是从一代遗传到下一代。体细胞突变是癌症的原因，并可能在许多慢性和年龄相关疾病中发挥重要作用。我们的研究旨在测试体细胞突变是否也会导致自身免疫。这个想法是，控制免疫反应的基因可能会变得有缺陷，从而使免疫细胞逃避正常的调节信号。有证据支持这一观点，来自罕见的患者，他们出生时就有突变，在年轻时就会产生自身免疫。我们还知道，自身免疫患者，尤其是PSS患者，有患淋巴瘤的风险，并且一些患有淋巴瘤相关疾病的患者会出现自身免疫问题。我们的假设表明，体细胞突变是连接自身免疫和淋巴瘤的因素。我们正在寻找的证据是，PSS患者的免疫细胞中是否存在导致其疾病的体细胞DNA突变。PSS患者遭受干燥和严重刺激，因为他们的泪腺，唾液腺和其他腺体受到免疫细胞的攻击。他们被邀请加入英国注册，并允许他们的组织活检用于研究。我们将使用最新的组织解剖方法从PSS患者的唾液腺中纯化小群免疫细胞，然后进行超灵敏的DNA测序来检测细胞DNA中的体细胞突变。如果我们发现了突变，我们将确定免疫系统的哪个或哪些特定细胞有突变，以及突变会导致什么问题，以便准确了解突变是如何导致疾病的。这项研究有望改变我们对自身免疫的理解。如果这一假设是正确的，那么我们预计DNA突变检测将成为诊断自身免疫性疾病、预测病情严重程度和监测治疗的新方法。它还将提供特定的信息，使药物能够针对个体体细胞突变。最终，这将改善自身免疫性疾病患者的治疗，提高他们的健康和经济福利，减少自身免疫性疾病对社会的负担。

项目成果

Genome-wide association study identifies susceptibility loci for acute myeloid leukemia.

• DOI: 10.1038/s41467-021-26551-x
• 发表时间: 2021-10-29
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Lin WY;Fordham SE;Hungate E;Sunter NJ;Elstob C;Xu Y;Park C;Quante A;Strauch K;Gieger C;Skol A;Rahman T;Sucheston-Campbell L;Wang J;Hahn T;Clay-Gilmour AI;Jones GL;Marr HJ;Jackson GH;Menne T;Collin M;Ivey A;Hills RK;Burnett AK;Russell NH;Fitzgibbon J;Larson RA;Le Beau MM;Stock W;Heidenreich O;Alharbi A;Allsup DJ;Houlston RS;Norden J;Dickinson AM;Douglas E;Lendrem C;Daly AK;Palm L;Piechocki K;Jeffries S;Bornhäuser M;Röllig C;Altmann H;Ruhnke L;Kunadt D;Wagenführ L;Cordell HJ;Darlay R;Andersen MK;Fontana MC;Martinelli G;Marconi G;Sanz MA;Cervera J;Gómez-Seguí I;Cluzeau T;Moreilhon C;Raynaud S;Sill H;Voso MT;Lo-Coco F;Dombret H;Cheok M;Preudhomme C;Gale RE;Linch D;Gaal-Wesinger J;Masszi A;Nowak D;Hofmann WK;Gilkes A;Porkka K;Milosevic Feenstra JD;Kralovics R;Grimwade D;Meggendorfer M;Haferlach T;Krizsán S;Bödör C;Stölzel F;Onel K;Allan JM
• 通讯作者: Allan JM

GATA2 deficiency phenotype associated with tandem duplication of GATA2 and overexpression of GATA2-AS1.

• DOI: 10.1182/bloodadvances.2021005217
• 发表时间: 2021-12-28
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Singh P;Heer M;Resteu A;Mikulasova A;Reza M;Largeaud L;Dufrechou S;Prade N;Dickinson RE;Bustamante J;Neven B;Bigley V;Delabesse E;Rico D;Pasquet M;Collin M
• 通讯作者: Collin M