Determination of the trafficking kinetics and role of mononuclear phagocyte subsets in treatment-naive psoriatic arthritis.

银屑病关节炎是一种由关节炎症引起的疾病，导致关节疼痛、僵硬和肿胀。这些症状是由免疫系统细胞进入关节并造成损伤引起的。它还会导致其他健康问题，并减少约3年的预期寿命。这种病的治疗费用非常昂贵，NHS每年要花费约1.83亿英镑。免疫系统在银屑病关节炎的发展中很重要。银屑病关节炎的研究比其他疾病少，这需要解决。这项研究着眼于一组被称为“单核吞噬细胞”的细胞，这些细胞可以吸引并激活其他免疫细胞，从而导致持续损伤的循环。正常情况下，免疫细胞在血液中四处移动，只有当它们感觉到感染或损伤时才会移动到其他地方。因此，健康的关节含有很少的免疫细胞。在银屑病关节炎中，包括单核吞噬细胞在内的免疫细胞进入关节，造成疼痛和损伤。我们不知道是什么导致细胞以这种方式运动。确定是什么原因导致细胞在关节中移动并控制它们的行为，可以提供一种防止免疫细胞进入关节的方法，从而导致新的治疗方法。最近我们对单核吞噬细胞的理解取得了进展，包括更好的方法来识别细胞和发现在其他疾病中重要的新的“炎症”细胞。这些发现尚未应用于关节炎。我的目标是使用最新的信息和应用新技术来更好地了解细胞的行为，并跟踪银屑病关节炎患者的细胞行为。我将把它与健康人的血液和关节中的细胞，以及患有其他形式关节炎的人的细胞进行比较，看看为什么银屑病关节炎的表现不同。研究计划：我将识别和比较来自关节炎诊所和非关节炎患者的临床样本的血液和关节中的免疫细胞，因此我们的发现反映了真实的患者。我计划调查关节炎患者关节中的免疫细胞与非关节炎患者有何不同。我想看看血液和关节中都有哪些免疫细胞，这些细胞在关节中有什么作用，它们释放了哪些破坏关节的物质。这将告诉我们是哪些免疫细胞导致了关节炎，它们从血液转移到关节的速度有多快，以及是什么使得银屑病关节炎中的免疫细胞与健康人的免疫细胞表现不同。我将在实验室里研究这些细胞，以确定它们是如何与血管相互作用，进入关节的，以及在不同的触发条件下，它们会释放出哪些破坏关节的物质。最后，我将“标记”参与者的免疫细胞，这样就可以用特殊的相机看到它们。然后将这些细胞重新注入同一个人的血液中，观察细胞如何进入关节。谁和在哪里我将在剑桥大学进行这个项目，我们已经开发了进行这些实验的技术。作为一名研究人员，我也是一名风湿病专家，一名专门研究关节和关节疾病的医生。这是一项以实验室为基础的研究，旨在了解引起关节炎及其症状的细胞如何进入关节并引发疾病。这些知识可以用来设计新的治疗方法来阻止或防止免疫细胞不适当地进入关节。这可能会使治疗效果更好，减少副作用。这种“标记”细胞并观察它们在体内去向的方法也将有助于测试药物是否对某些情况有效。此外，这些发现可能有助于了解其他单核吞噬细胞重要的疾病，如动脉粥样硬化和炎症性肠病，并开发新的治疗方法。

BackgroundPsoriatic arthritis is a condition caused by inflammation in the joints, leading them to become painful, stiff, and swollen. These symptoms are caused by immune system cells which travel into joints and cause damage. It can also cause other health problems, and a loss of about 3 years of life expectancy. The condition is expensive to treat, costing about £183 million per year to the NHS. The immune system is important in the development of psoriatic arthritis. Psoriatic arthritis is less studied than other conditions and this needs to be addressed.ContextThis research looks at a group of cells called "mononuclear phagocytes" which can attract and turn on other immune cells, causing a cycle of ongoing damage. Normally, immune cells move around the body in the blood, and only move into other places when they sense infection or damage. Healthy joints therefore contain few immune cells. In psoriatic arthritis, immune cells including mononuclear phagocytes move into the joints where they cause pain and damage. We do not understand what causes cells to move in this way. Identifying what causes the cells to move and controls their behaviour in the joint could provide a way of preventing immune cells from entering the joints, leading to new treatments. Recent advances in our understanding of mononuclear phagocytes have been made, including better ways to identify cells and discovery of new "inflammatory" cells important in other diseases. These findings have not been applied to arthritis. I aim to use the latest information and apply new techniques to better understand the behaviour of cells and track them in people with psoriatic arthritis. I will compare this against cells in the blood and joints of healthy people, and people with other forms of arthritis to see why psoriatic arthritis behaves differently.Research planI will identify and compare the immune cells in the blood and joints from clinical samples from arthritis clinics to those from people without arthritis, so our findings reflect real patients. I plan to investigate how the immune cells in the joints of people with arthritis are different from those without arthritis. I want to see which kinds of immune cells are in both the bloodstream and the joints, what the cells do in the joint, and what joint-damaging substances they release. This will tell us which immune cells are driving arthritis, how quickly they move from the blood into joints, and what makes the immune cells in psoriatic arthritis behave differently to those in healthy people. I will study the cells in the lab to determine how they interact with blood vessels to get into joints, and what joint-damaging substances they release when different triggers are applied. Finally, I will "tag" immune cells from participants so they can be seen using a special camera. These will then be reinjected into the bloodstream of the same person to watch how the cells move into the joints.Who and whereI will carry out this project at the University of Cambridge where we have developed the techniques to carry out these experiments. As well as being a researcher, I am a training rheumatologist, a doctor who specialises in joints and joint disease.ImportanceThis is a laboratory-based research study designed to understand how the cells that cause arthritis and its symptoms move into joints to trigger disease. This knowledge can then be used to design new treatments to stop or prevent immune cells from inappropriately entering joints. This may make treatments work better and reduce side-effects. The methods of "tagging" cells and seeing where they go in the body will also help to test if medications work for certain conditions. In addition, these findings may help understand other diseases where mononuclear phagocytes are important such as atherosclerosis and inflammatory bowel disease and develop new treatments for them.