Background/Purpose:

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting synovial tissue in multiple joints. The inflammatory process in RA is regulated by several cytokines, especially TNF, which is produced not only by macrophages and dendritic cells (DC) but also by activated antigen-specific CD4⁺ T helper cells. IL-21 is a T cell-derived cytokine that has been implicated in several autoimmune diseases, including RA. Both activated CD4⁺ T cells and T follicular helper cells (TFh) secrete this inflammatory cytokine. IL-21 regulates T helper 17 cells and antibody production by B cells and induces osteoclastogenesis, mechanisms that contribute to RA pathology. In addition IL-21R blockade ameliorates arthritis in mice. Taking into account the recent literature we investigated whether IL-21 might play a role in RA.

Methods:

Expression of surface markers and cytokine production at the single cell level in peripheral blood (PB) and matched synovial fluid (SF) from RA (n=13) and psoriatic arthritis (PsA, n=6) patients, as compared to PB of healthy control (HC) subjects (n=17), was evaluated by flow cytometry following PMA/ionomycin stimulation ex-vivo. IL-21 concentrations were assessed by ELISA in cell-free SF samples of RA (n=15), PsA (n=14) and OA (n=5) patients and in 6 days supernatants of RA (n=6) and spondyloarthropathy (SpA, n=5) synovial biopsy cultures. In addition we dissected the in vitro requirements for the differentiation of human IL-21-secreting CD4+ T cells from naive T cells.

Results: We observed significant expansions of CD4⁺ T cells secreting IL-21 in RA SF compared to matched PB (p<0.0001). Interestingly, while the % of IL-21⁺ CD4⁺ T cells in PB did not differ between RA, PsA and HC, the % of both total IL-21⁺ and IL-21⁺TNF-a⁺ CD4⁺ T cells in RA SF were significantly increased compared to PsA (p=0.0140 and p=0.0038, respectively). The % of IL-21⁺ CD4⁺ T cells in RA PB was positively correlated with DAS28 (r=0.592, p=0.033), serum anti-cyclic citrullinated peptide (anti-CCP) antibodies (r=0.788, p=0.001) and rheumatoid factor (RF; r=0.691, p=0.009). In addition, the % of IL-21⁺ CD4⁺ T cells in anti-anti-CCP⁺ or RF⁺ patients was significantly higher compared to anti-CCP^– (p=0.03) and RF^– (p=0.01) patients respectively. The levels of IL-21 present in SF did not differ between RA and PsA but there was trend towards elevated levels of this cytokine in RA SF compared to OA SF (p=0.06). RA synovial biopsies released significantly higher levels of IL-21 compared to SpA (p=0.03). Synovial IL-21-secreting CD4⁺ T cells did not phenotypically fit the TFh cell paradigm in that they did not express CXCR5. In humans, differentiation of naive CD4⁺ T cells into IL-21-secreting cells in vitro was preferentially driven by IL-21 and/or IL-6 in the additional presence of transforming growth factor-β.

Conclusion: IL-21 and IL-21 blocking therapy is now being tested in a number of diseases. The results of this study enhance the rationale for a trial of IL-21 blockade in RA where it may provide a useful adjunct in those patients refractory to or unable to tolerate anti-TNF therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elevated-frequency-of-synovial-interleukin-21-cd4-t-cells-co-expressing-tumor-necrosis-factor-a-in-rheumatoid-arthritis/