56: Circulating fibrocytes contribute to the pathogenesis of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in joint inflammation and bone and cartilage destruction. We have identified a circulating cell population – fibrocytes – that is activated early in RA patients and mice with arthritis. As RA is characterized by autoreactive T cells, our objective was to characterize fibrocyte activation in the context of T cell activation. Using multiparameter phosphoflow FACS, we show increased numbers of activated circulating fibrocytes in the blood of RA patients, with increased TLR expression, in agreement with increased levels of phosphorylation of NFkB and IRF3. Pathogen/ligand activation of TLRs may be associated with fibrocyte activation. We observe a direct correlation between the number of circulating fibrocytes and CD4 + T cells in RA patients, with higher numbers of pro-inflammatory, activated Th17 cells in the circulation of RA patients compared with healthy individuals: increased phosphorylation of ZAP70, STAT3 and CD40L. Notably, activated fibrocytes in RA patients exhibit increased expression of CD40. Co-culture of naive murine CD4 + T cells with activated fibrocytes enhances fibrocyte and T cell proliferation and polarizes the T cells to Th17 cells. Inclusion of anti-IL-6 antibodies reverses Th17 polarization and enhances Treg numbers. We infer that fibrocyte-T cell CD40-CD40L interactions result in IL-6 production that drives Th17 lineage commitment. Additionally, activated T cells secrete cytokines that enhance fibrocyte proliferation, in vitro. Gene expression analysis of activated fibrocytes and RA joint T cells reveals factors associated with a potential paracrine activation loop between fibrocytes and T cells. Altogether our data suggest that activated fibrocytes interact with T cells to promote RA pathogenesis.