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

Abstract

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.

Fig. 1 |. Joint-specific memory.

a, Synovial fibroblasts (also known as fibroblast-like synoviocytes (FLSs)) and synovial tissue macrophages (STMs) reside in a quiescent joint naive to inflammation. b, Inflammation recruits immune cells, including lymphocytes, monocyte-derived macrophages and neutrophils. c, After resolution of acute joint inflammation, tissue-resident memory T (T_RM) cells remain in the tissue, FLSs are primed to become proinflammatory and STMs have been reprogrammed, whereas new inflammation-imprinted monocytederived macrophages remain in the joint as part of the new STM population. With each arthritis flare, the joint cycles between the inflamed (b) and remission (c) states, accumulating more T_RM cells and pro-inflammatory features.

Fig. 2 |. Multilineage interactions in the joint.

Fibroblasts (also known as fibroblast-like synoviocytes (FLSs)), synovial tissue macrophages (STMs)) and tissue-resident memory T (T_RM) cells interact with each other within the synovial microenvironment. T_RM cells are anchored to the stroma through interactions with FLSs (red). FLSs and STMs provide cytokines and other factors to promote T_RM cell maintenance and persistence (green). STMs function as antigen-presenting cells to activate T_RM cells through antigen recognition, whereas T_RM cells secrete cytokines and soluble factors to activate FLSs and STMs during inflammation.

Fig. 3 |. The joint accumulation model and the rolling window of opportunity.

Arthritis chronicity is driven by a persistent systemic drive that enables disease spread to new joints, as well as by local memory mechanisms, such as T_RM cell accumulation. The blue line depicts the number of joints currently inflamed in an individual patient; this number falls to zero during remission but might increase with flares. The red line depicts the number of joints ever involved, and increases progressively in a stepwise manner, reflecting the accumulation of joints that have acquired durable changes that place them at a higher risk of subsequent flare. Effective treatment arrests this stepwise escalation of risk, providing a rolling window of opportunity to prevent further joint accumulation. Figure 3 adapted with permission from ref. 4, Wiley.

Fig. 4 |. Candidate mechanisms through which arthritis extends into new joints.

a, In the systemic driver model, new joints become inflamed through the same processes that originally initiated arthritis, for example, the recruitment of arthritogenic T cells from the circulation. b, In the cell spread model, new joints become inflamed when cells originating from an arthritic joint (such as resident memory T (T_RM) cells or fibroblasts) enter the circulation and deposit in new joints. c, In the founder model, new joints become inflamed when pathogenic cells seeded during an index event expand past a threshold that renders the joint symptomatic; joints cross this threshold at different times, depending on local factors, including the size of the initial inoculum. These three models are not mutually exclusive.