Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Expansions of Interleukin-21-Secreting CD4 T Helper Cells in Inflammatory Arthritides.
Vieira1, Pedro L., Lebre2, Maria C., Aarrass2, Saïda, Newsom-Davis1, Thomas, Tak2, PP., Screaton1, Gavin R.
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 DCs but also by activated antigen-specific CD4+ T helper (Th) cells. IL-21 is a pleiotropic type 1 cytokine that shares the common cytokine receptor g-chain, g(c), with IL-2, IL-4, IL-7, IL-9, and IL-15. IL-21 is most homologous to IL-2. Whereas IL-2 promotes development of regulatory T cells and confers protection from autoimmune disease, IL-21 promotes differentiation of Th17 cells and is implicated in several autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus and rheumatoid arthritis. IL-21, an inflammatory cytokine that belongs to the common g-chain receptor binding family is secreted by several cell types including Th17 and T follicular helper cells (TFh). An increasing number of inflammatory molecules are being identified that may contribute to RA pathology. Therefore we investigated the expression of interleukin-17A (IL-17A), IL-21 and IL-22 in RA, psoriatic arthritis (PsA) and undifferentiated arthritis (UA). In addition we dissected the in vitro requirements for the differentiation of human IL-21-secreting CD4+ T helper (Th) cells.
Expression of surface markers and cytokine production at the single cell level in peripheral blood (PB) and matched synovial fluid (SF) from RA (n=8), PsA (n=4) and UA (n=5) patients, as compared to PB of healthy control subjects (n=25), was evaluated by flow cytometry following polyclonal stimulation ex-vivo. IL-21 concentrations were assessed by ELISA in cell-free SF samples of RA (n=15), PsA (n=14) and UA (n=9) patients and in 6 days supernatants of RA (n=6) and spondyloarthropathy (SpA, n=5) synovial biopsy cultures. Immunohistochemistry analysis were performed on synovial tissues (STs) of healthy donors (HD), RA, PsA, OA, and gout patients and sections were evaluated by digital image analysis.
We observed significant expansions of IL-21-secreting cells, which represented up to 47% of total CD4+ Th cells in SF. While the expression of IL-21 in STs and SF did not differ between the different arthritides, in ST IL-21 was significantly higher in inflammatory arthritis compared to HD. Interestingly, RA synovial biopsies released significantly higher levels of IL-21 compared to SpA. CD4+IL-21+ could be detected in RA ST that do not co-localized with IL-17 neither IL-22. Synovial IL-21-secreting cells did not phenotypically fit the TFh cell paradigm in that they did not express CXCR5. In humans, differentiation of naïve 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-b.
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.
To cite this abstract, please use the following information:
Vieira, Pedro L., Lebre, Maria C., Aarrass, Saïda, Newsom-Davis, Thomas, Tak, PP., Screaton, Gavin R.; Expansions of Interleukin-21-Secreting CD4 T Helper Cells in Inflammatory Arthritides. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2356