Joint-specific memory, resident memory T cells and the rolling window of opportunity in arthritis

In rheumatoid arthritis, juvenile idiopathic arthritis and other forms of inflammatory arthritis, the immune system targets certain joints but not others. The pattern of joints affected varies by disease and by individual, with flares most commonly involving joints that were previously inflamed. This phenomenon, termed joint-specific memory, is difficult to explain by systemic immunity alone. Mechanisms of joint-specific memory include the involvement of synovial resident memory T cells that remain in the joint during remission and initiate localized disease recurrence. In addition, arthritis-induced durable changes in synovial fibroblasts and macrophages can amplify inflammation in a site-specific manner. Together with ongoing systemic processes that promote extension of arthritis to new joints, these local factors set the stage for a stepwise progression in disease severity, a paradigm for arthritis chronicity that we term the joint accumulation model. Although durable drug-free remission through early treatment remains elusive for most forms of arthritis, the joint accumulation paradigm defines new therapeutic targets, emphasizes the importance of sustained treatment to prevent disease extension to new joints, and identifies a rolling window of opportunity for altering the natural history of arthritis that extends well beyond the initiation phase of disease. This Review discusses joint-specific memory (the tendency of arthritis to recur in previously inflamed joints), explores the involvement of resident memory T cells and other contributors, and evaluates how arthritis might spread to new joints, emphasizing the important of sustained treatment. In rheumatoid arthritis and juvenile idiopathic arthritis, joints previously affected are more likely to flare than joints previously spared, a phenomenon termed joint-specific memory.One mechanism underlying joint-specific memory is the accumulation of synovial resident memory T (TRM) cells, long-lived resident lymphocytes that remain during remission and promote recurrent disease.Synovial TRM cells are predominantly CD8+ T cells and exhibit a restricted TCR repertoire; in animal models, TRM cells trigged by specific antigens induce arthritis flare by releasing chemokines, including CCL5.Mechanisms that predispose individual joints to greater disease activity include inflammation-induced fibroblast priming and an increase in the abundance of pro-inflammatory macrophages compared with that of regulatory macrophages.Recognition that both systemic factors and local factors drive arthritis suggests a new paradigm of chronicity, the joint accumulation model, implying a 'rolling window of opportunity' for therapy, even in established arthritis.