Background and Objectives IL-21 is a cytokine produced by activated CD4+ T cells and T follicular helper cells (TFh) that has been implicated in several autoimmune diseases. IL-21 regulates antibody production by B cells and induces osteoclastogenesis, mechanisms that contribute to rheumatoid arthritis (RA) pathology. Importantly, IL-21R blockade ameliorates arthritis in mice. Here we investigated the functional characteristics of CD4+IL-21+ T cells in RA.
Materials and Methods We evaluated the expression of surface markers and cytokine production in matched peripheral blood (PB) and synovial fluid (SF) from 13 RA and 6 psoriatic arthritis (PsA) patients, and PB of 17 healthy control (HC) subjects 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 = 6) patients and in synovial biopsy culture supernatants (6 days) of RA (n = 6) and ankylosing spondylitis (AS; n = 5) patients. The effects of IL-21 were evaluated on cytokine and matrix metalloproteinase (MMP) release by RA synovial biopsies.
Results The frequency of IL-21+CD4+ T cells in RA and PsA SF was significantly higher compared to PB (P < 0.0001 and P < 0.0001, respectively). Moreover, the frequency of both total IL-21+CD4+ (P = 0.0140) and IL-21+TNF+CD4+ T cells (P = 0.0038) in RA SF were significantly increased compared to PsA patients. The frequency 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 IgM-rheumatoid factor (IgM-RF; r = 0.691, P = 0.009). In addition, the percentage of IL-21+CD4+ T cells in anti-CCP+ or IgM-RF+ patients was significantly higher compared to anti-CCP- (P = 0.03) and IgM-RF- (P = 0.01) patients respectively. In addition to PB and SF, we found IL-21+CD4+ T cells present in RA synovial tissue. Significant higher levels of IL-21 in RA SF compared to OA SF (P = 0.04) were observed confirming previous observations. RA synovial biopsies released significantly higher levels of IL-21 compared to biopsies from AS patients. The levels of IL-21 in SF were associated with CRP and with the MMP-1 and MMP-3. Related to this, IL-21 selectively induced MMP-1 and MMP-3 secretion by RA synovial biopsies. Synovial IL-21+CD4+ T cells did not phenotypically fit the TFh cell paradigm in that they did not express CXCR5 and ICOS.
Conclusions The results of this study support the notion that IL-21-producing CD4 T cells are involved in promoting synovial inflammation (TNF) and joint destruction (MMP) in RA and might be a therapeutic target in this disease.
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