title: Synovial IL-21/TNF-producing CD4+T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast-like synoviocytes.
abstract: 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.
authors.affiliation: Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, The Netherlands.|Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Lebre
authors.affiliation: Department of Immunology, Imperial College London, Hammersmith Campus, London, United Kingdom.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Vieira
authors.affiliation: Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, The Netherlands.|Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Man Wai
authors.initials: MW
authors.lastname: Tang
authors.affiliation: Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, The Netherlands.|Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Saïda
authors.initials: S
authors.lastname: Aarrass
authors.affiliation: Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, The Netherlands.|Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Boy
authors.initials: B
authors.lastname: Helder
authors.affiliation: Department of Immunology, Imperial College London, Hammersmith Campus, London, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Newsom-Davis
authors.affiliation: Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.affiliation: Department of Immunology, Imperial College London, Hammersmith Campus, London, United Kingdom.
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Screaton
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D007596:Joints / Q000473:pathology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism; D011565:Psoriasis / Q000276:immunology / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism; D012217:Rheumatoid Factor / Q000378:metabolism; D013582:Synovial Fluid / Q000378:metabolism; D000070918:Synoviocytes / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000097043:Interleukin-22; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
chemical_list: D007075:Immunoglobulin M; D007371:Interferon-gamma; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D020781:Matrix Metalloproteinase 1; D019278:Matrix Metalloproteinase 3; D010456:Peptides, Cyclic; D051560:Proto-Oncogene Proteins c-bcl-6; D053245:RANK Ligand; D012217:Rheumatoid Factor; D020825:T-Box Domain Proteins; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21; C084103:BCL6 protein, human; C487763:cyclic citrullinated peptide; C511768:MMP3 protein, human; C522360:MMP1 protein, human
keywords: autoimmune; inflammation; peripheral blood; synovial fluid