Identifying immune mechanisms and testing new therapeutic targets for inflammatory arthritis and associated comorbidities

自身免疫性和免疫介导性炎症性疾病(IMID)的发病率正在增加。这些疾病往往与导致残疾和死亡的慢性疾病并存。因此，多发病被预测为即将到来的全球卫生挑战。对共存条件的研究几乎总是单独进行，阻碍了发现将全身免疫失调与不同组织的同时损害联系起来的共同机制。这个项目旨在增加我们对主要受IMID影响的组织和共/多发病部位活跃的并发免疫机制的了解。这种洞察力有可能为IMID患者和复杂合并症患者改进干预措施的设计提供信息。炎症性关节炎患者患心血管疾病的风险更高。强有力的证据表明，系统性炎症是导致这种风险的原因。在脊椎关节病和幼年特发性关节炎患者中，葡萄膜炎和关节炎也共存。为了获得支持并存疾病的组织事件的新视角，我们的研究结合了对关节炎中炎症关节的评估，以及CV组织和眼睛中共存的免疫和功能变化。我们的研究表明，IL-6家族细胞因子对CD4T细胞的控制不仅决定了关节炎的进展，而且还决定了免疫细胞向CV组织和眼睛的募集。结合RNA测序和免疫检测方法，我们已经确定了在关节炎关节、CV和眼组织中共存的细胞因子网络和T细胞效应程序。我们认为，靶向这些通路对关节炎相关的心血管疾病和葡萄膜炎有治疗应用。值得注意的是，针对其中一些靶点的药物在最近的临床试验中显示出良好的安全性(例如在癌症中)，突显了它们重新用途的潜力。研究训练目的1.明确实验性关节炎时CV和眼组织共存的免疫机制。使用我们最近的RNA测序数据集进行的生物信息学、路径分析和数据可视化培训将使学生能够选择他们感兴趣的易处理的免疫目标。他们将使用关节炎模型、体内成像(光学相干断层扫描)和免疫检测(免疫组织化学、光片和荧光显微镜、流式细胞术)来验证和空间定位由于关节炎而引起的CV组织和眼睛中的免疫激活机制。目的2.决定CD4T细胞致病性的靶向效应功能。人类和小鼠的CD4T细胞培养将确定来自AIM 1的靶标如何在T细胞中调节，以及抑制(例如抗体阻断、小分子抑制剂、基因敲除)如何改变它们的功能和致病性。这名学生将跟踪包括增殖、功能(细胞因子分泌、激活标记)和细胞代谢(与斯旺西大学N·琼斯博士合写的Agilent SeaHorse博士)的影响。目的3.测试靶向抑制对关节炎相关并发症的影响。将在小鼠中诱导关节炎，靶向抑制对关节炎严重程度以及共存的CV和眼部炎症的影响将通过临床评估、成像、组织病理学和血管功能测量来确定(与加的夫大学的A·威廉姆斯教授一起)。学生将受益于与临床风湿学家和眼科医生(布里斯托尔医学院的Ramanan教授和Dick教授)、学者(Jones博士、Williams教授)和业界(例如葛兰素史克)的合作，在这些领域，该项目将为平行研究提供信息。知识转移和影响学生将通过同行评议的出版物和在内部、GW4、国家和国际科学会议上的演讲来交流研究成果。与我们的患者洞察合作伙伴合作将确保研究满足未满足的患者需求，并通过参与活动进行有效沟通。

IMPORTANCE The incidence of autoimmune and immune-mediated inflammatory diseases (IMIDs) is increasing. These diseases often coexist with chronic conditions that cause disability and mortality. Consequently, multimorbidity is forecast as an upcoming global health challenge. Research into conditions that coexist is nearly always performed separately, hampering the discovery of shared mechanisms that link systemic immune dysregulation with concurrent damage to different tissues. This project aims to increase our understanding of concurrent immune mechanisms active in tissues primarily affected by IMIDs and sites of co-/multi-morbidity. Such insight has the potential to inform the design of improved interventions for patients with IMIDs and complex comorbidities. Patients with inflammatory arthritis are at higher risk of cardiovascular (CV) disease. Strong evidence points to systemic inflammation in driving this risk. Uveitis and arthritis also coexist in patients with spondyloarthropathies and juvenile idiopathic arthritis. To gain new perspective on tissue events underpinning comorbidities, our studies combine an evaluation of inflamed joints in arthritis, with coexisting immune and functional changes in CV tissues and eyes. Our research reveals that control of CD4 T cells by IL-6 family cytokines critically determines arthritis progression, but also immune cell recruitment to CV tissue and eyes. Combining RNA-sequencing with immunodetection methods, we have identified cytokine networks and T cell effector programmes that coexist across the arthritic joint, CV and ocular tissues. We propose that targeting these pathways has therapeutic application for arthritis-associated CV disease and uveitis. Significantly, drugs against some of these targets show good safety in recent clinical trials (e.g. in cancer) highlighting their potential for repurposing. RESEARCH TRAINING Aim 1. Identify coexisting immune mechanisms in CV and ocular tissue during experimental arthritis. Training in bioinformatics, pathway analysis and data visualisation using our recent RNA-sequencing datasets will enable the student to choose tractable immune targets of interest to them. They will use models of arthritis, in vivo imaging (optical coherence tomography) and immunodetection (immunohistochemistry, Light sheet and fluorescence microscopy, flow cytometry) to validate and spatially localise mechanisms of immune activation in CV tissues and eyes because of arthritis. Aim 2. Targeting effector functions that determine CD4 T cell pathogenicity. Human and mouse CD4 T cell cultures will determine how targets from Aim 1 are regulated in T cells and how inhibition (e.g. antibody blockade, small molecule inhibitors, gene knockdown) alters their function and pathogenicity. The student will track effects including proliferation, function (cytokine secretion, activation markers) and cellular metabolism (Agilent Seahorse, with Dr N. Jones, Swansea University). Aim 3. Testing the impact of target inhibition on arthritis-associated comorbidities. Arthritis will be induced in mice and the effect of target inhibition on arthritis severity, and co-existing CV and ocular inflammation, will be determined by clinical assessments, imaging, histopathology and measuring vascular function (with Prof A. Williams, Cardiff University). ADDED VALUE The student will benefit from collaboration with clinical rheumatologists and ophthalmologists (Profs Ramanan and Dick, Bristol Medical School), academics (Dr N. Jones, Prof Williams) and industry (e.g. GlaxoSmithKline) where the project will inform parallel studies. KNOWLEDGE TRANSFER AND IMPACT The student will communicate research through peer-reviewed publications and presentations at internal, GW4, national and international scientific meetings. Engagement with our patient insight partner will ensure the research addresses unmet patient needs and is effectively communicated through engagement events.