Background/Purpose: Effective treatment of Rheumatoid arthritis (RA) patients is achievable within a short window of opportunity following diagnosis. Identification of pathogenic immune mechanisms at a pre-RA stage would greatly benefit our understating of the early events that govern disease progression and help identify new therapeutic targets and early points for therapeutic intervention. Recent studies illustrate the pathogenic effect of increased T cell polyreactivity in autoimmunity, such studies in pre-RA arthralgia subjects have been hindered by the rare availability of synovial biopsy samples and minimal synovial cell recovery. In this study, we describe for the first time, polyreactive T cell responses in the synovial tissue of Arthralgia subjects and RA patients.

Methods: Synovial biopsies of RA patients and arthralgia subjects were obtained by key-hole arthsoscopic surgery. Following enzymatic and mechanical digestion of the tissue, a single cell suspension was obtained. Synovial cells and paired PBMC were stimulated in vitro and analysed by 15-colour flow cytometric analysis for the identification of T cell pro-inflammatory cytokine responses. Following multiparametric flow-cytometric analysis, SPICE algorithm and Flowsome unsupervised clustering were utilised to examine peripheral blood and synovial tissue T-cell cytokine polyreactivity of arthralgia subject and RA patients and peripheral blood and synovial fluid Tfh responses.

Results: Higher T cell pro-inflammatory cytokine polyreactivity was identified in arthralgia subjects compared to RA patients. Compared to the periphery, synovial tissue T cell polyreactivity is significantly higher with comparable pro-inflammatory cytokine profiles between arthralgia and RA synovial tissue T cells. Flowsome clustering analysis resulted in the identification of novel T cell clusters that exhibit high polyreactivity and an accumulation of DP (CD4⁺CD8⁺) in the synovial tissue of arthralgia subjects and RA patients. Peripheral blood Tfh cell frequency is significantly higher in arthralgia subjects compared to RA patients, with an accumulation of germinal centre like-Tfh T cells in the synovial fluid of established RA.

Conclusion: Polyreactive pro-inflammatory T cell responses pre-date disease onset as demonstrated by the accumulation of polyreactive T cells in the synovial tissue of pre-RA arthralgia subjects. These data highlight a key early pathogenic role for T cell plasticity and the newly, in autoimmunity, described T cell cluster of DP T cells in RA. We are currently investigating transcription factor profiles that govern polyreactivity of these T cell clusters.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-t-cell-polyreactivity-with-marked-accumulation-of-tnf-%ce%b1-dp-cd4cd8-in-the-synovial-tissue-of-pre-ra-arthralgia-subjects/