Characterisation of a novel innate-like T cell in the eye as a target tissue in uveitis, spondyloarthropathy (SpA) and related diseases

眼部新型先天性 T 细胞作为葡萄膜炎、脊柱关节病 (SpA) 及相关疾病靶组织的表征

• 批准号: MR/T024682/1
• 负责人: Srilakshmi Sharma
• 金额: $ 34.9万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT024682%2F1
• 关键词: Characterisation; novel; innate; like; cell

Uveitis is a condition affecting a part of the eye called the uvea. It causes painful inflammation, sight loss and blindness in about 22% of patients worldwide. Uveitis mainly occurs in patients who are young or of working age so sight loss and frequent visits to hospital also make it difficult to maintain employment and cause other problems including depression. Uveitis also occurs in 40% of patients suffering from a condition called spondyloarthropathy. This is a disease of the immune system affecting the joints, the entheses (the structures connecting tendons to bone), eyes, bowel and skin and causes a great deal of disability. Currently we do not understand why and how uveitis occurs. At present, there are very few treatments for uveitis. They do not treat all patients and can have serious side effects which can cause blindness in their own right.Research shows us that one type of immune cell, the T cell existing within the organ itself, could be responsible for much of the disease and disability caused by spondyloarthropathy but we do not know that this for the eye . If we knew the type of immune cell present in the eye which causes inflammation it would help us design much better treatments for uveitis as well as spondyloarthropathy. The similarities and differences between the immune cells in different tissues in spondyloarthropathy will help us design the most effective treatments for patients suffering from spondyloarthropathy as well as uveitis. Studying these immune cells has already resulted in very successful treatment for organs which are affected by spondyloarthropathy such as the skin. The goal of our research is to use new methods to discover the types of immune cells, and genes which are responsible for uveitis and to develop successful treatments based on our results. We are expecially interested in one type of T cell which has recently been found by members of the research team to be present in spondyloarthropathy.The Kennedy Institute of Rheumatology has special expertise in research into the cause of diseases which cause inflammation in the body including spondyloarthropathy. Our research group has expertise in a cutting-edge technique called 'single cell RNA sequencing' , This will allow us to use fairly small numbers of cells from the eye to understand which genes and which cells become active in inflammation. This information can be viewed rather like a map and will tell us where the inflammation is located , which cells are causing it and which genes are active when the eye becomes inflamed. It is likely that similar cells will cause inflammation elsewhere in the body in spondyloarthropathy. We can analyse the functions of these genes and cells in order to understand how uveitis and spondyloarthropathy is caused and how it might be successfully controlled. We expect this research will lead to new treatments.We have agreement from a number of specialist surgical centres to provide a small sample from the eye when they are performing a common surgical procedure called a trabeculectomy. This sample is routinely removed as a part of this type of surgery and while it is normally discarded, we now have ethical approval to use it for single cell RNA sequencing in the human eye. This research will take up 40% of Dr Sharma's time and will last for 33 months in total. Dr Sharma has experience in research in eyes and in studying genes involved in uveitis and spondyloarthropathy. Our research team consists of a wide variety of experts in their respective fields to make sure that we complete this research on time and get results of the highest quality and ultimately, to help patients with uveitis and spondyloarthropathy.

葡萄膜炎是一种影响眼睛称为葡萄膜的部分的疾病。它导致全球约 22% 的患者出现疼痛性炎症、视力丧失和失明。葡萄膜炎主要发生在年轻或工作年龄的患者中，因此视力丧失和频繁去医院也导致难以维持就业并导致包括抑郁症在内的其他问题。 40% 患有脊柱关节病的患者也会出现葡萄膜炎。这是一种免疫系统疾病，影响关节、附着点（连接肌腱和骨骼的结构）、眼睛、肠道和皮肤，并导致严重残疾。目前我们还不了解葡萄膜炎发生的原因和方式。目前，葡萄膜炎的治疗方法很少。它们不能治疗所有患者，并且可能产生严重的副作用，甚至可能导致失明。研究表明，一种类型的免疫细胞，即存在于器官本身内的 T 细胞，可能是由脊柱关节病引起的大部分疾病和残疾的原因，但我们不知道这对于眼睛来说也是如此。如果我们知道眼睛中引起炎症的免疫细胞类型，将有助于我们设计出更好的治疗葡萄膜炎和脊柱关节病的方法。脊柱关节病不同组织中免疫细胞之间的异同将有助于我们为患有脊柱关节病和葡萄膜炎的患者设计最有效的治疗方法。研究这些免疫细胞已经对受脊柱关节病影响的器官（例如皮肤）进行了非常成功的治疗。我们研究的目标是使用新方法来发现免疫细胞的类型和导致葡萄膜炎的基因，并根据我们的结果开发成功的治疗方法。我们对研究小组成员最近发现的一种存在于脊柱关节病中的 T 细胞特别感兴趣。肯尼迪风湿病研究所在研究导致体内炎症（包括脊柱关节病）的疾病的病因方面拥有特殊的专业知识。我们的研究小组拥有称为“单细胞RNA测序”的尖端技术的专业知识，这将使我们能够使用相当少量的眼睛细胞来了解哪些基因和哪些细胞在炎症中变得活跃。这些信息可以像地图一样查看，并告诉我们炎症位于何处、哪些细胞引起炎症以及当眼睛发炎时哪些基因处于活跃状态。类似的细胞很可能会在脊柱关节病中引起身体其他部位的炎症。我们可以分析这些基因和细胞的功能，以了解葡萄膜炎和脊柱关节病是如何引起的以及如何成功控制它。我们预计这项研究将带来新的治疗方法。我们与许多专科手术中心达成一致，在他们进行称为小梁切除术的常见外科手术时，从眼睛中提供少量样本。作为此类手术的一部分，该样本通常会被取出，虽然通常会被丢弃，但我们现在已获得伦理批准，可以将其用于人眼中的单细胞 RNA 测序。这项研究将占用Sharma博士40%的时间，总共持续33个月。 Sharma 博士在眼科研究以及葡萄膜炎和脊柱关节病相关基因研究方面拥有丰富的经验。我们的研究团队由各自领域的各类专家组成，以确保我们按时完成这项研究并获得最高质量的结果，并最终帮助葡萄膜炎和脊柱关节病患者。

项目成果

Cohort profile: a collaborative multicentre study of retinal optical coherence tomography in 539 patients with neuromyelitis optica spectrum disorders (CROCTINO).

队列概况：对 539 名视神经脊髓炎谱系疾病 (CROCTINO) 患者进行视网膜光学相干断层扫描的多中心协作研究。

• DOI: 10.1136/bmjopen-2019-035397
• 发表时间: 2020-10-29
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Specovius S;Zimmermann HG;Oertel FC;Chien C;Bereuter C;Cook LJ;Lana Peixoto MA;Fontenelle MA;Kim HJ;Hyun JW;Jung SK;Palace J;Roca-Fernandez A;Diaz AR;Leite MI;Sharma SM;Ashtari F;Kafieh R;Dehghani A;Pourazizi M;Pandit L;Dcunha A;Aktas O;Ringelstein M;Albrecht P;May E;Tongco C;Leocani L;Pisa M;Radaelli M;Martinez-Lapiscina EH;Stiebel-Kalish H;Hellmann M;Lotan I;Siritho S;de Seze J;Senger T;Havla J;Marignier R;Tilikete C;Cobo Calvo A;Bichuetti DB;Tavares IM;Asgari N;Soelberg K;Altintas A;Yildirim R;Tanriverdi U;Jacob A;Huda S;Rimler Z;Reid A;Mao-Draayer Y;de Castillo IS;Yeaman MR;Smith TJ;Brandt AU;Paul F;GJCF International Clinical Consortium for NMOSD
• 通讯作者: GJCF International Clinical Consortium for NMOSD

Modern Solutions for Ancient Pathogens: Direct Pathogen Sequencing for Diagnosis of Lepromatous Leprosy and Cerebral Coenurosis.

• DOI: 10.1093/ofid/ofac428
• 发表时间: 2022-09
• 期刊: Open forum infectious diseases
• 影响因子: 4.2

The use of OCT in good visual acuity MOGAD and AQP4-NMOSD patients; with and without optic neuritis.

• DOI: 10.1177/20552173211066446
• 发表时间: 2021-10
• 期刊: Multiple sclerosis journal - experimental, translational and clinical
• 作者: Roca-Fernández A;Camera V;Loncarevic-Whitaker G;Messina S;Mariano R;Vincent A;Sharma S;Leite MI;Palace J
• 通讯作者: Palace J

A nationwide survey of hydroxychloroquine retinopathy presenting to the hospital eye service in the United Kingdom.

• DOI: 10.1038/s41433-022-02291-0
• 发表时间: 2023-07
• 期刊: Eye (London, England)

The Cellular Composition of the Uveal Immune Environment.

• DOI: 10.3389/fmed.2021.721953
• 发表时间: 2021
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Reekie IR;Sharma S;Foers A;Sherlock J;Coles MC;Dick AD;Denniston AK;Buckley CD
• 通讯作者: Buckley CD