Osteoimmunological Interactions at the Switch from Acute to Chronic Arthritis

风湿性关节炎的特征是炎症、软骨破坏和骨质侵蚀。致病组织对炎症刺激的反应对于关节炎的发病机制至关重要。然而，发病机制中的关键事件尚不清楚。一个这样的未知的关键事件是从急性到慢性炎症的转变，以及慢性炎症对内源性调节和治疗抑制机制的抗性。我们在小鼠关节炎模型中发现，调节性T辅助淋巴细胞的短暂早期耗竭将通常急性的、自限性的关节炎病程转变为非缓解性的、破坏性的关节炎。发病机制的关键转变发生在早期，即关节炎的临床前阶段。我们现在想使用这个系统，在这个系统中，关节炎可以随意从急性、自限性转变为非缓解性、破坏性，以确定转变为慢性关节炎的相关分子开关。初步数据表明，T辅助淋巴细胞指导滑膜成纤维细胞和破骨细胞成为非缓解性破坏性关节炎的驱动因素。我们的目标是定义致病性T淋巴细胞的指导性信号;识别和识别负责非缓解性破坏性关节炎的效应细胞中的分子改变;并找到调节它们的方法。

Rheumatoid arthritis is characterised by inflammation, cartilage destruction, and bone erosion. The pathogenic tissue response to inflammatory stimuli is of paramount importance for arthritis pathogenesis. Still, key events in the pathogenesis are not understood. One such unknown key event is the transition from acute to chronic inflammation, and the resistance of chronic inflammation to endogenous mechanisms of regulation and therapeutic suppression. We have found in a mouse model of arthritis that transient early depletion of regulatory T helper lymphocytes switches the usually acute, self-limiting course of arthritis to nonremitting, destructive arthritis. The critical switch in pathogenesis occurs early, in the preclinical phase of arthritis. We now want to use this system, in which arthritis can be switched ad libitum from acute, self limiting, to non-remitting, destructive, to identify the relevant molecular switches for the transition to chronic arthritis. Preliminary data suggest that T helper lymphocytes instruct synovial fibroblasts and osteoclasts to become the drivers of non-remitting destructive arthritis. We aim at defining the instructive signals from pathogenic T-lymphocytes; identify and characterise the molecular alterations in the effector cells responsible for non-remitting destructive arthritis; and find ways to modulate them.