Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease - 28/08/11
, Benjamin Terrier, MSc, MD a, , Michelle Rosenzwajg, MD, PhD a, Bertrand Wechsler, MD b, Maxime Touzot, MSc, MD c, Danielle Seilhean, MD, PhD d, Tu-Anh Tran, MD, PhD e, Bahram Bodaghi, MD, PhD f, Lucile Musset, MD g, Vassili Soumelis, MD, PhD c, David Klatzmann, MD, PhD a, Patrice Cacoub, MD a, b, ‡, David Saadoun, MD, PhD a, b, ‡, ⁎ 
Reprint requests: David Saadoun, MD, PhD, Department of Internal Medicine and Laboratory I3 “Immunology, Immunopathology, Immunotherapy,” UMR 7211 (CNRS/UPMC) INSERM U959, Hôpital Pitié-Salpétrière, 47-83 boulevard de l’Hôpital, 75013 Paris, France.Abstract |
Background |
Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown etiology.
Objective |
To determine the nature of T cells driving inflammatory lesions in BD.
Methods |
T cell homeostasis and cytokines production were analyzed in peripheral blood and brain inflammatory lesions from 45 adult patients with BD (active and untreated BD [n = 25] and patients in remission [n = 20]) and 20 healthy donors, using Luminex, flow cytometry, immunohistochemistry, and immunofluorescence analysis.
Results |
We found a marked increase in TH17 cells and a decrease in the frequency of CD4+ forkhead box P3+ regulatory T cells (Tregs) in peripheral blood that were induced by IL-21 production and that correlate with BD activity. The addition of serum from patients with active BD in a sorted CD4+ T cells culture of healthy donors induced a significant and dose-dependent production of IL-17A and a decrease in forkhead box P3 expression. We demonstrated the presence of IL-21– and IL-17A–producing T cells within the cerebrospinal fluid, brain parenchyma inflammatory infiltrates, and intracerebral blood vessels from patients with active BD and central nervous system involvement. The stimulation of CD4+ T cells with IL-21 increased TH17 and TH1 differentiation and decreased the frequency of Treg cells. Conversely, IL-21 blockade with an IL-21R-Fc restored the TH17 and Treg homeostasis in patients with BD.
Conclusion |
We provided here the first evidence of the critical role of IL-21 in driving inflammatory lesions in BD by promoting TH17 effectors and suppressing Treg cells. IL-21 represents a promising target for novel therapy in BD.
Le texte complet de cet article est disponible en PDF.Key words : Behçet disease, TH17, TH1, regulatory T cells, IL-21, vasculitis, autoimmunity
Abbreviations used : aBD, BD, CNS, CSF, Fc, FoxP3, HD, rBD, TCM, Treg
Plan
| Supported by the Direction Régionale des Affaires Sanitaires et Sociales (DRASS) (G.G.). B.T. was supported by the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale pour la Recherche sur le Sida et les Hépatites (ANRS). |
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| Disclosure of potential conflict of interest: P. Cacoub has received consultant fees, speaking fees, and/or honoraria from Bristol-Myers Squibb, Sanofi-Aventis, Pfizer, Vifor Pharma, Servier, and Roche. The rest of the authors have declared that they have no conflict of interest. |
Vol 128 - N° 3
P. 655-664 - septembre 2011 Retour au numéro
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