Therapeutic targeting of fibroblast subsets in inflammatory arthritis

炎症是对组织损伤的一种健康反应，有助于消除有害微生物和修复器官。引起炎症和随后的组织损伤的因素通常受到非常严格的调节，并与促进消退和修复的因素相对抗。健康的炎症反应具有快速发作和有序消退阶段，在此阶段，最初从血液中招募的活化免疫细胞（称为白细胞）退出炎症组织，而驻留的组织细胞（称为成纤维细胞）返回到其静止状态。然而，目前尚不清楚疾病“生态系统”的各个组成部分是如何联系在一起，以最小的损伤恢复受影响组织的正常功能的。针对白细胞的治疗，传统上被认为是关节炎的罪魁祸首，已被证明在永久消除炎症和防止组织损伤方面的能力有限。我们的工作使用了新的方法来直接观察关节炎进展过程中关节中的成纤维细胞发生了什么。成纤维细胞通常被描述为关节的管家，执行维护工作以保持关节的良好秩序。然而，在类风湿性关节炎中，成纤维细胞的一个亚群发生了根本性的改变。它们过度生长，导致关节内产生多余的液体和肿胀。此外，这些成纤维细胞转而对抗关节，并开始分解软骨和骨骼。然而，当涉及到靶向这些细胞时，存在一个问题，因为它们有不同的品种或亚群，只有其中一些在疾病中发生改变。我们的目的是确定哪些亚群在关节炎的发展中最重要，并探索改变它们是否能改善疾病。由于不同的成纤维细胞在关节中发挥着不同的功能，一个关键的目标将是确定哪些成纤维细胞是可以靶向的，哪些是可以忽略的。人们对成纤维细胞亚群在人类关节炎过程中如何变化知之甚少。关节取样的困难和缺乏良好的成纤维细胞标记物都是这种工作的障碍。在过去的几年里，我们在伯明翰早期关节炎诊所解决了这些限制。令人兴奋的是，在牛津，伯明翰和波士顿（美国）的同事之间的一项新合作中，我们发现我们的新成纤维细胞标记可以区分介导炎症和软骨和骨损伤的成纤维细胞。我们现在计划使用相同的标记来探索成纤维细胞的命运和功能，试图改变它们的行为。以这种方式靶向成纤维细胞将为治疗炎性关节炎提供一种全新的方法；我们在这方面处于独特的领导地位。类风湿性关节炎患者临床缓解后，一旦停药后又复发。这表明，负责完全解决炎症的因素仍有待发现。这就是我们对成纤维细胞感兴趣的原因。我们的计划是改变成纤维细胞，这样关节就能修复。然而，在我们尝试在人类身上做这个之前我们必须确保我们知道关节中有多少成纤维细胞亚群，它们之间的关系是什么以及哪种成纤维细胞会导致炎症哪些会导致组织损伤。此外，我们需要确定在疾病发展过程中的什么时候更换土壤是最好的。在错误的时间改变成纤维细胞可能会使关节炎恶化。在适当的时候改变成纤维细胞可能会治愈这种疾病

Inflammation is a healthy response to tissue damage, which helps to eliminate harmful microbes and repair organs. The factors that cause inflammation and subsequent tissue damage are usually very tightly regulated and opposed by factors that promote resolution and repair. A healthy inflammatory response has a rapid onset and an orderly resolution phase, in which activated immune cells initially recruited from the blood (called leucocytes) , exit the inflamed tissue and the resident tissue cells (called fibroblasts) return to their resting state. However it is not known how the various components of the "ecosystem" in disease are linked together to allow normal function of the affected tissue to be restored with minimal damage. Treatments aimed at leucocytes, traditionally thought to be the villains in arthritis, have proven to be limited in their ability to permanently switch off inflammation and prevent tissue damage. Our work uses new approaches to look directly at what happens to fibroblasts in the joint as arthritis progresses. Fibroblasts are often portrayed as the joint's housekeepers, performing maintenance jobs to keep the joint in good order. However in rheumatoid arthritis, a subset of fibroblasts becomes fundamentally altered. They overgrow, leading to the production of excess fluid and swelling within the joint. Furthermore these fibroblasts turn against the joint and begin to break down cartilage and bone. However there is a problem when it comes to targeting these cells as they come in different varieties, or subsets, only some of which become altered in disease. Our aim is to identify which subsets are most important in the development of arthritis and to explore whether changing them improves disease. Since different fibroblasts perform different functions in the joint, a key objective will be to determine which fibroblasts to target and which to ignore.Very little is known about how fibroblast subsets change during the course of human arthritis. Difficulties in sampling the joints involved and the lack of good fibroblast markers have all proved obstacles to such work. In the last few years we have addressed these limitations head on in the Birmingham Early Arthritis Clinic. Excitingly, in a new collaboration between colleagues in Oxford, Birmingham and Boston (USA) we have found that our new fibroblast markers can discriminate between fibroblasts that will mediate inflammation and cartilage and bone damage. We now plan to use the same markers to explore the fate and function of fibroblasts in an attempt to alter their behaviour. Targeting fibroblasts in this way will lead to a completely new approach to treating inflammatory arthritis; an approach that we are in a unique position to lead. Patients with rheumatoid arthritis in whom clinical remission has been achieved, subsequently relapse once drugs are withdrawn. This suggests that the factors responsible for complete resolution of inflammation remain to be discovered. This is why we are interested in fibroblasts. Our plan is to change the fibroblasts so that the joint can repair. However before we can attempt to do this in humans we have to be sure that we know how many subsets of fibroblasts exist in the joint, what their relationship is to one another and which variety of fibroblasts are responsible for inflammation and which is responsible for tissue damage. Furthermore we need to determine at what point during the course of the disease it is best to change the soil. Altering fibroblasts at the wrong time may make arthritis worse. Altering fibroblasts at the right time might cure the disease