Details

Autor(en) / Beteiligte

• Filer, Andrew
• Ward, Lewis S C
• Kemble, Samuel
• Davies, Christopher S
• Munir, Hafsa
• Rogers, Rebekah
• Raza, Karim
• Buckley, Christopher Dominic
• Nash, Gerard B
• McGettrick, Helen M

Titel

Identification of a transitional fibroblast function in very early rheumatoid arthritis

Ist Teil von

• Annals of the rheumatic diseases, 2017-12, Vol.76 (12), p.2105-2112

Ort / Verlag

England: BMJ Publishing Group LTD

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• ObjectivesSynovial fibroblasts actively regulate the inflammatory infiltrate by communicating with neighbouring endothelial cells (EC). Surprisingly, little is known about how the development of rheumatoid arthritis (RA) alters these immunomodulatory properties. We examined the effects of phase of RA and disease outcome (resolving vs persistence) on fibroblast crosstalk with EC and regulation of lymphocyte recruitment.MethodsFibroblasts were isolated from patients without synovitis, with resolving arthritis, very early RA (VeRA; symptom ≤12 weeks) and established RA undergoing joint replacement (JRep) surgery. Endothelial-fibroblast cocultures were formed on opposite sides of porous filters. Lymphocyte adhesion from flow, secretion of soluble mediators and interleukin 6 (IL-6) signalling were assessed.ResultsFibroblasts from non-inflamed and resolving arthritis were immunosuppressive, 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 transforming growth factor beta 1 (TGF-β1) signalling appeared critical for the loss of the immunosuppressive phenotype. In the absence of exogenous cytokines, JRep, but not VeRA, fibroblasts activated endothelium to support lymphocyte.ConclusionsIn RA, fibroblasts undergo two distinct changes in function: first 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 changes from immunosuppressive in resolving arthritis to stimulatory very early in the development of RA. Early interventions targeting ‘pathogenic’ fibroblasts may be required in order to restore protective regulatory processes.