Tissue-resident CD8+ memory T cell and fibroblast cross-talk in juvenile idiopathic arthritis

背景：青少年特发性关节炎是儿童时期最常见的自身免疫性疾病之一，发生在免疫系统错误地攻击关节时，导致炎症和疼痛。在英国，大约有1万名儿童患有这种使人衰弱的疾病。目前，即使经过十年的治疗，大多数患者的疾病仍在持续。因此，需要对如何治愈这种疾病进行更多的研究，而不仅仅是控制。当免疫系统对某些东西发起攻击时，一些免疫细胞类型会留下来；保持对它试图摧毁的目标的记忆（“记忆细胞”）。记忆细胞确保免疫系统能够在目标再次出现时发动快速有效的攻击。在患有关节炎的老鼠的关节中发现了一种特殊类型的记忆细胞，这种细胞在关节炎消退后具有再次激活炎症的能力。在患有幼年特发性关节炎的儿童中，与血液相比，在取自关节的液体中发现的类似于这种记忆细胞的细胞含量要高得多，这表明它们在疾病发生的地方积聚。在身体的其他部位，其他类型的细胞锚定记忆细胞，以确保它们留在需要它们的位置，并提供信号，以确保记忆细胞存活很长时间。目前尚不清楚哪些细胞可能在关节中起这种作用，记忆细胞在幼年特发性关节炎中起什么作用。目的和目的：我的目的是测试一个问题，即是否这些记忆细胞留在关节中，抵抗治疗，在患有幼年特发性关节炎的儿童中反复发生炎症。特别是，我将研究成纤维细胞是否与这些记忆细胞相互作用，以帮助它们在关节中存活并持续存在。成纤维细胞是关节结缔组织的组成部分。该计划是表征患有关节炎的儿童关节中的这些细胞，识别细胞使用的信号通路和过程。技术的进步意味着现在有可能观察单个细胞的水平，看看这些细胞正在制造哪些蛋白质，提供细胞活动的微小分辨率。我将研究这些细胞在患有严重疾病的儿童身上有何不同。最后，在患有关节炎的转基因小鼠中，有可能消除各种成纤维细胞；我将研究这是如何影响关节中的记忆细胞的。潜在的应用和益处：随着疾病的发展，引发炎症的过程可能与使炎症持续存在的过程不同。了解导致关节炎关节持续炎症的细胞和过程可能是最终治愈儿童和成人自身免疫性关节炎的关键。目前，这些记忆细胞还没有被任何可用的治疗方法直接靶向。如果记忆细胞导致了持续的炎症，我们需要知道它们在关节中对哪些信号做出反应，以有效地针对它们。影响成纤维细胞的成人治疗方法正在开发中，但需要进一步了解成纤维细胞在儿童关节炎中的作用，以确定这些治疗方法是否也可能对儿童有效。关节中的液体比关节组织更容易获得，但缺点是它比结缔组织细胞（如成纤维细胞）更容易捕获免疫细胞。由于我们将收集和分析来自同一关节的组织和液体，我们将了解液体中的细胞如何反映关节组织中的生物学。这一认识为开发针对成纤维细胞的新疗法和改进治疗选择的新测试提供了一个起点。

Background: Juvenile idiopathic arthritis is one of the most common autoimmune conditions of childhood, occurring when the immune system mistakenly attacks joints, leading to inflammation and pain. Around 10,000 children in the UK suffer from this debilitating condition. Currently, the majority of patients have ongoing disease even after a decade of treatment. Therefore, more research is needed into how the disease can be cured, rather than just controlled. When the immune system mounts an attack against something, some immune cell types remain behind; keeping a memory of the target it was trying to destroy ('memory cells'). Memory cells ensure the immune system can mount a rapid and effective attack if the target is found again in the body. With arthritis in mice, a specific type of memory cell has been found in the joint, which has the ability to activate inflammation again after the arthritis has resolved. In children with juvenile idiopathic arthritis, cells that resemble this type of memory cell have been found in much higher levels in fluid taken from the joints compared to the blood stream, suggesting they are accumulating where the disease is occurring. In other parts of the body, other cell types anchor memory cells to ensure they remain at sites where they are needed and provide signals to ensure memory cells survive for a long time. It is not clear at present which cells might be doing this in the joint and what role memory cells have in juvenile idiopathic arthritis. Aims and Objectives:I aim to test the question of whether repeat flares of inflammation keep occurring in children with juvenile idiopathic arthritis because these memory cells remain in the joint, resisting treatment. In particular I will investigate whether cells known as fibroblasts, which contribute to the connective tissue of the joint, interact with these memory cells to help them to survive and persist in the joint. The plan is to characterise these cells in the joints of children with arthritis, identifying signalling pathways and processes used by the cells. Advances in technology mean that it is now possible to look at the level of individuals cells to see which proteins these cells are making, providing minute resolution of the cell activities. I will investigate how these cells differ in children who get very severe disease. Finally, in genetically-modified mice with arthritis it is possible to eliminate types of fibroblast cells; I will investigate how this impacts the memory cells in joints. Potential Applications and Benefits:The processes that initiate inflammation may not be the same as those perpetuating it, as the disease process evolves. Understanding the cells and processes causing ongoing inflammation in arthritic joints will likely be key for finally achieving a cure for children and adults with autoimmune arthritis. Currently these memory cells are not directly targeted by any available treatments. If memory cells are contributing to ongoing inflammation, we need to know which signals they are responding to in the joint to target them effectively. Treatments affecting the fibroblasts are under development for adults, but further understanding of fibroblasts in childhood arthritis is needed to determine whether these therapies are also likely to be effective in children. Fluid from the joint is easier to obtain than joint tissue, but the downside is that it captures immune cells much better than connective tissue cells, like fibroblasts. Since we will collect and analyse the tissue and the fluid from the same joints, we will learn how the cells in the fluid reflect the biology in the joint tissue. This understanding provides a starting point for developing new therapies that target fibroblasts and novel tests that improve our selection of treatment.