title: T-helper 17 cell polarization in pulmonary arterial hypertension.
abstract: BACKGROUND
  Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the inflammation orchestrated by dendritic cells (DCs) and T cells, key driver and effector cells, respectively, of the immune system, may allow the identification of immunopathologic approaches to PAH management.
  
  
  METHODS
  Using flow cytometry, we performed immunophenotyping of monocyte-derived DCs (MoDCs) and circulating lymphocytes from patients with idiopathic PAH and control subjects. With the same technique, we performed cytokine profiling of both populations following stimulation, coculture, or both. We tested the immunomodulatory effects of a glucocorticoid (dexamethasone [Dex]) on this immunophenotype and cytokine profile. Using an epigenetic approach, we confirmed the immune polarization in blood DNA of patients with PAH.
  
  
  RESULTS
  The profile of membrane costimulatory molecules of PAH MoDCs was similar to that of control subjects. However, PAH MoDCs retained higher levels of the T-cell activating molecules CD86 and CD40 after Dex pretreatment than did control MoDCs. This was associated with an increased expression of IL-12p40 and a reduced migration toward chemokine (C-C motif) ligand 21. Moreover, both with and without Dex, PAH MoDCs induced a higher activation and proliferation of CD4+ T cells, associated with a reduced expression of IL-4 (T helper 2 response) and a higher expression of IL-17 (T helper 17 response). Purified PAH CD4+ T cells expressed a higher level of IL-17 after activation than did those of control subjects. Lastly, there was significant hypomethylation of the IL-17 promoter in the PAH blood DNA as compared with the control blood.
  
  
  CONCLUSIONS
  We have highlighted T helper 17 cell immune polarization in patients with PAH, as has been previously demonstrated in other chronic inflammatory and autoimmune conditions.
authors.affiliation: Faculté de médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hautefort
authors.affiliation: Faculté de médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Girerd
authors.affiliation: Faculté de médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.affiliation: Faculté de médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cohen-Kaminsky
authors.affiliation: Pulmonary Hypertension Service, Royal Brompton Hospital, London, England.
authors.forename: Laura
authors.initials: L
authors.lastname: Price
authors.affiliation: VIB Inflammation Research Center, University of Ghent, Gent, Belgium.
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.affiliation: Faculté de médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Faculté de médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France. Electronic address: frederic.perros@inserm.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Perros
mesh_terms: D000328:Adult; D051940:B7-2 Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D016764:Cell Polarity / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000276:immunology* / Q000473:pathology*; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*
chemical_list: D051940:B7-2 Antigen; D019013:CD40 Antigens; D005938:Glucocorticoids; D003907:Dexamethasone