Synovial IL-21/TNF-producing CD4+ T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast-like synoviocytes

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

Tak, Paul P.²  da²  Newsom-Davis, Thomas³  Aarrass, Saï³  Tang, Man Wai⁴  Screaton, Gavin R.⁴  Helder, Boy⁴  Vieira, Pedro L.⁵ 

[1] and;..Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, The Netherlands;Department of Immunology, Imperial College London, Hammersmith Campus, London, United Kingdom

关键词: synovial fluid;    peripheral blood;    autoimmune;    inflammation;   

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Bone and cartilage destruction is one of the key manifestations of rheumatoid arthritis (RA). Although the role of T helper (Th)17 cells in these processes is clear, the role of IL-21–producing cells T cells has been neglected. We sought to investigate the role of IL-21 in RA by focusing on the functional characteristics of the main producers of this cytokine, synovial CD4⁺IL-21⁺ T cells. We show that the frequency of both synovial fluid (SF) CD4⁺IL-21⁺ or CD4⁺IL-21⁺TNF⁺ T cells in patients with RA was significantly higher compared with patients with psoriatic arthritis (PsA). The frequency of peripheral blood (PB) IL-21⁺CD4⁺ T cells in patients with RA positively correlated with disease activity score 28 (DAS28), serum anticyclic citrullinated peptide (anti-CCP) antibodies and IgM-rheumatoid factor (IgM-RF). IL-21 levels in RA SF were associated with matrix metalloproteinase (MMP)-1 and MMP-3. Related to this, IL-21 induced significantly the secretion of MMP-1 and MMP-3 in RA synovial biopsies. Sorted SF CD4⁺IL-21⁺ T cells significantly induced the release of MMP-1 and MMP-3 by fibroblast-like synoviocytes (FLS) compared with medium or CD4⁺IL-21⁻ T cells in a coculture system. Neutralization of both IL-21 and TNF resulted in significantly less production of MMP by FLS. The results of this study indicate a new role for synovial CD4⁺IL-21⁺TNF⁺ T cells in promoting synovial inflammation/joint destruction in patients with RA. Importantly, IL-21 blockade in combination with anti-TNF might be an effective therapy in patients with RA by inhibiting MMP-induced inflammation/joint destruction.

【 授权许可】

CC BY