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并修复器官。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控，并受到促进分解和修复的因素的反对。健康的炎症反应有一个快速的起效和一个有序的消退阶段，在这个阶段，最初从血液中招募的激活的免疫细胞(称为白细胞)离开炎症组织，常驻的组织细胞(称为成纤维细胞)返回到它们的静止状态。然而，目前尚不清楚疾病中“生态系统”的不同组成部分是如何联系在一起的，从而使受影响组织的正常功能得以恢复，并造成最小的损害。针对白细胞的治疗传统上被认为是关节炎的罪魁祸首，但事实证明，针对白细胞的治疗在永久关闭炎症和防止组织损伤方面的能力有限。我们的工作使用新的方法来直接观察随着关节炎的进展关节中成纤维细胞发生了什么。成纤维细胞通常被描绘成关节的管家，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，成纤维细胞的一部分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，这些成纤维细胞转向关节，开始破坏软骨和骨骼。然而，当涉及到靶向这些细胞时，存在一个问题，因为它们来自不同的品种或亚群，其中只有一些在疾病中发生了变化。我们的目标是确定哪些子集在关节炎的发展中最重要，并探索改变它们是否会改善疾病。由于不同的成纤维细胞在关节中发挥不同的功能，一个关键的目标将是确定哪些成纤维细胞为目标，哪些被忽略。人们对成纤维细胞亚群在人类关节炎过程中的变化知之甚少。对涉及的关节进行采样的困难，以及缺乏良好的成纤维细胞标志物，都证明了这项工作的障碍。在过去的几年里，我们在伯明翰早期关节炎诊所正面解决了这些局限性。令人兴奋的是，在牛津、伯明翰和波士顿(美国)的同事们的一项新合作中，我们发现我们的新成纤维细胞标记物可以区分将介导炎症、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导致一种治疗炎症性关节炎的全新方法；我们处于独特的领导地位。临床缓解的类风湿性关节炎患者，一旦停药就会复发。这表明导致炎症完全消退的因素仍有待发现。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，以便关节能够修复。然而，在我们尝试在人类身上做这项工作之前，我们必须确保我们知道关节中存在多少成纤维细胞亚群，它们之间的关系以及哪些成纤维细胞负责炎症，哪些成纤维细胞负责组织损伤。此外，我们需要确定在疾病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。在适当的时间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