Identification of a transitional fibroblast functional phenotype in very early rheumatoid arthritis

Objectives: Synovial fibroblasts actively regulate the inflammatory infiltrate by communicating with neighbouring endothelial cells (EC). Surprisingly little is known about how the development of RA alters these immunomodulatory properties. We examined the effects of phase of RA and disease outcome (resolving versus persistence) on fibroblast cross-talk with EC and regulation of lymphocyte recruitment.

Methods: Fibroblasts were isolated from patients without synovitis, with resolving arthritis, very early RA (VeRA; symptom ≤12weeks) and established RA undergoing replacement surgery (JRep). Endothelial-fibroblast co-cultures were formed on opposite sides of porous filters. Lymphocyte adhesion from flow, secretion of soluble mediators and IL-6 signalling were assessed.

Results: Fibroblasts from non-inflamed and resolving arthritis were immuno-suppressive, inhibiting lymphocyte recruitment to cytokine-treated endothelium. This effect was lost very early in the development of RA, such that fibroblasts no longer suppressed recruitment. Changes in IL-6 and TGFβ1 signalling appeared critical for the loss of the immuno-suppressive phenotype. In the absence of exogenous cytokines, JRep, but not VeRA, fibroblasts activated endothelium to support lymphocyte.

Conclusions: In RA, fibroblasts undergo two distinct changes in function: firstly a loss of immunosuppressive responses early in disease development, followed by the later acquisition of a stimulatory phenotype. Fibroblasts exhibit a transitional functional phenotype during the first 3 months of symptoms that contributes to the accumulation of persistent infiltrates. Finally, the role of IL-6 and TGF-β1 change from immuno-suppressive in resolving arthritis to stimulatory very early in the development of RA. Early interventions targeting “pathogenic” fibroblasts maybe required in order to restore protective regulatory processes.