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

自身免疫和免疫介导的炎症性疾病（IMIDs）的发病率正在上升。这些疾病往往与导致残疾和死亡的慢性病共存。因此，预计多发病是即将到来的全球卫生挑战。对共存条件的研究几乎总是分开进行，阻碍了发现将系统性免疫失调与不同组织的并发损伤联系起来的共同机制。该项目旨在增加我们对主要受IMIDs影响的组织和共同/多重发病部位中活跃的并发免疫机制的理解。这一见解有可能为设计针对IMIDs和复杂合并症患者的改进干预措施提供信息。炎性关节炎患者患心血管（CV）疾病的风险较高。强有力的证据表明，全身性炎症导致了这种风险。葡萄膜炎和关节炎也共存于脊椎关节病和幼年特发性关节炎患者。为了获得支持合并症的组织事件的新视角，我们的研究结合了关节炎炎症关节的评估，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CD4 T细胞的控制关键地决定了关节炎的进展，但也决定了免疫细胞向CV组织和眼睛的募集。结合rna测序和免疫检测方法，我们已经确定了细胞因子网络和T细胞效应程序共存于关节炎关节，CV和眼部组织。我们建议靶向这些途径治疗关节炎相关的CV疾病和葡萄膜炎。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），这突出了它们具有重新利用的潜力。研究训练目标确定实验性关节炎期间CV和眼组织中共存的免疫机制。使用我们最新的rna测序数据集进行生物信息学、途径分析和数据可视化方面的培训，将使学生能够选择他们感兴趣的可处理的免疫靶点。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引起的CV组织和眼睛的免疫激活机制。目标2。靶向决定CD4 T细胞致病性的效应功能。人类和小鼠CD4 T细胞培养将确定Aim 1的靶点如何在T细胞中受到调节，以及抑制作用（如抗体阻断、小分子抑制剂、基因敲低）如何改变其功能和致病性。该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（Agilent Seahorse，与斯旺西大学的N. Jones博士合作）在内的影响。目标3。测试靶抑制对关节炎相关合并症的影响。将在小鼠中诱导关节炎，目标抑制对关节炎严重程度的影响，以及共存的CV和眼部炎症，将通过临床评估、影像学、组织病理学和血管功能测量来确定（与加的夫大学的A. Williams教授一起）。该学生将受益于与临床风湿病学家和眼科医生（布里斯托尔医学院的Ramanan和Dick教授），学者（N. Jones博士，Williams教授）和行业（例如葛兰素史克公司）的合作，该项目将为平行研究提供信息。该学生将通过同行评审的出版物和在内部、GW4、国家和国际科学会议上的演讲来交流研究。与我们的患者洞察合作伙伴的合作将确保研究解决未满足的患者需求，并通过参与活动有效沟通。

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.