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Molecular determinants of immune tolerance in Graves' disease

格雷夫斯病免疫耐受的分子决定因素

基本信息

批准号：
MR/S001611/1
负责人：
Laura Claire Lane
金额：
$ 28.24万
依托单位：
Newcastle University
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS001611%2F1
关键词：
Molecular determinants immune tolerance Graves

项目摘要

Autoimmune thyroid diseases are the most prevalent of the autoimmune conditions, with Graves' disease (GD) affecting close to 2% of women over a lifetime and impacting 7.5 million worldwide. In GD, the immune system generates antibodies that stimulate the thyroid gland leading to excessive thyroid hormone production (hyperthyroidism). Excess thyroid hormone affects multiple systems within the body including the heart, circulation, nervous system, skin and metabolic regulation, causing diverse symptoms such as elevated heart rate, irritability, sweating and weight loss. Thyroid eye disease, a complication of GD, also causes facial disfigurement with protuberance of the eyes, double vision and occasionally loss of vision. The current treatment for GD has remained largely unchanged since 1951, when the antithyroid drug carbimazole was introduced. Following a 6 month or longer course of carbimazole tablets about 50% of people will have a durable remission of their condition, whereas the other 50% will relapse, which is the rule in younger people. Relapsing patients may ultimately require radio-iodine treatment or surgical intervention to remove the thyroid gland, both leading to lifelong dependence on thyroid hormone replacement, with attendant monitoring costs.Graves' disease runs strongly in families and 80% of the risk has been shown to be owing to genetic factors. In addition, the exact cause of the thyroid overactivity is known: antibodies that mimic the shape of thyroid stimulating hormone (TSH) which persistently stimulate the TSH-receptor. Given the central role of these anti-TSH receptor antibodies (TRAbs) in causing GD, we need to understand more about why these antibodies are produced by the antibody-producing arm of the immune system (also known as the humoral immune system). Bone marrow-derived B lymphocytes, and their derivative cell types, plasmablasts and plasma cells are responsible for making these TRAb antibodies. My fellowship aims to understand what is different about the humoral immune system in GD patients who sustain a prolonged remission with disappearance of TRAbs following antithyroid drugs, compared to those whose TRAbs persist and who immediately relapse following the same medication.The study will involve a group of 120 adult GD patients who are about to stop taking the usual antithyroid drug therapy. I will compare many factors between the half who will remain cured of their thyroid disease (remission group) and those whose thyroid overactivity is about to come back (relapse group). Firstly, several blood markers of B lymphocyte production rate and development will be measured, including TRAbs, circulating B cell growth factors (eg. BAFF) and small DNA loops known as KRECs which indicate the rate of B lymphocyte production. Then the quantity of different gene-products in purified B cells from each group will also be examined using the powerful technique of RNA-sequencing. This will allow me to identify a B cell molecular fingerprint that distinguishes people entering disease remission vs those headed for relapse. Lastly, we will look at the genetic variations underlying these differences in gene expression and use this to confirm an inherited (genomic) underpinning for the relapse or remission phenomena. This will provide a catalogue of molecular differences (both RNA and genomic) in B cells between people with sustained remission and those who relapsed, along with functional information about their humoral immune response. This will give novel insights into how the immune system is able to become tolerant again following an autoimmune disease, which will help to advance the development of new treatments. Understanding the factors that determine the response to therapy will also give prognostic information and allow treatment to be tailored to the individual. Many other autoimmune diseases have a relapsing and remitting course, so this work may have widespread relevance.

自身免疫性甲状腺疾病是最普遍的自身免疫性疾病，其中Graves病（GD）在一生中影响近2%的女性，并影响全球750万人。在GD中，免疫系统产生刺激甲状腺的抗体，导致过量的甲状腺激素产生（甲状腺功能亢进症）。过量的甲状腺激素会影响身体内的多个系统，包括心脏、循环、神经系统、皮肤和代谢调节，导致各种症状，如心率加快、易怒、出汗和体重减轻。甲状腺眼病是GD的一种并发症，也会导致面部畸形，包括眼睛突起、复视和偶尔的视力丧失。自1951年引入抗甲状腺药物卡比马唑以来，目前GD的治疗基本保持不变。经过6个月或更长的疗程，大约50%的人会有一个持久的缓解，而其他50%的人会复发，这是年轻人的规则。复发的患者可能最终需要放射性碘治疗或手术切除甲状腺，这两种治疗都导致终身依赖甲状腺激素替代治疗，并伴随着监测费用。格雷夫斯病在家族中很常见，80%的风险被证明是由于遗传因素。此外，甲状腺过度活跃的确切原因是已知的：模仿促甲状腺激素（TSH）形状的抗体持续刺激TSH受体。鉴于这些抗TSH受体抗体（TRAb）在引起GD中的核心作用，我们需要更多地了解为什么这些抗体是由免疫系统的抗体产生臂（也称为体液免疫系统）产生的。骨髓来源的B淋巴细胞及其衍生细胞类型、浆母细胞和浆细胞负责产生这些TRA B抗体。我的研究项目旨在了解抗甲状腺药物治疗后TRAb持续消失的GD患者与TRAb持续存在并在相同药物治疗后立即复发的GD患者的体液免疫系统有何不同。该研究将涉及一组120名即将停止常规抗甲状腺药物治疗的成年GD患者。我将比较甲状腺疾病治愈的一半（缓解组）和甲状腺过度活跃即将复发的一半（复发组）之间的许多因素。首先，将测量B淋巴细胞产生率和发育的几种血液标志物，包括TRAb、循环B细胞生长因子（例如，BAFF）和称为KREC的小DNA环，其指示B淋巴细胞产生的速率。然后，还将使用强大的RNA测序技术检查来自每组的纯化B细胞中不同基因产物的量。这将使我能够确定一个B细胞分子指纹，区分进入疾病缓解期的人与那些走向复发的人。最后，我们将研究这些基因表达差异背后的遗传变异，并以此来确认复发或缓解现象的遗传（基因组）基础。这将提供一个目录的分子差异（RNA和基因组）之间的人与持续缓解和那些谁复发，沿着功能信息，他们的体液免疫反应的B细胞。这将为免疫系统如何在自身免疫性疾病后再次变得耐受提供新的见解，这将有助于推进新治疗方法的开发。了解决定对治疗反应的因素也将提供预后信息，并允许治疗针对个人。许多其他自身免疫性疾病有复发和缓解的过程，因此这项工作可能具有广泛的相关性。