title: B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.
authors.affiliation: ImmunoRhumatologie Moléculaire, INSERM UMR S1109, Université de Strasbourg; Fédération de Médecine Translationnelle de Strasbourg, Centre National de Référence pour les Maladies Auto-immunes Systémiques Rares, Service de Rhumatologie, CHU Strasbourg; Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: François
authors.affiliation: University of Orleans and CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Gombault
authors.affiliation: University of Orleans and CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Villeret
authors.affiliation: ImmunoRhumatologie Moléculaire, INSERM UMR S1109, Université de Strasbourg; Fédération de Médecine Translationnelle de Strasbourg, Centre National de Référence pour les Maladies Auto-immunes Systémiques Rares, Service de Rhumatologie, CHU Strasbourg; Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France.
authors.forename: Ghada
authors.initials: G
authors.lastname: Alsaleh
authors.affiliation: University of Orleans and CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Manoussa
authors.initials: M
authors.lastname: Fanny
authors.affiliation: University of Orleans and CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Paméla
authors.initials: P
authors.lastname: Gasse
authors.affiliation: University François Rabelais, CEPR UMR-INSERM U1100/E.A. 6305, Faculté de Médecine; CHU de Tours, Service de Pneumologie, Tours, France.
authors.forename: Sylvain Marchand
authors.initials: SM
authors.lastname: Adam
authors.affiliation: Service de Pneumologie, Hôpital Bichat, Assistance Publique - Hôpitaux de Paris; Université Paris Diderot - Paris 7; INSERM Unité 700, Faculté de Médecine Bichat, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
authors.affiliation: ImmunoRhumatologie Moléculaire, INSERM UMR S1109, Université de Strasbourg; Fédération de Médecine Translationnelle de Strasbourg, Centre National de Référence pour les Maladies Auto-immunes Systémiques Rares, Service de Rhumatologie, CHU Strasbourg; Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Sibilia
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.affiliation: ImmunoRhumatologie Moléculaire, INSERM UMR S1109, Université de Strasbourg; Fédération de Médecine Translationnelle de Strasbourg, Centre National de Référence pour les Maladies Auto-immunes Systémiques Rares, Service de Rhumatologie, CHU Strasbourg; Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France.
authors.forename: Seiamak
authors.initials: S
authors.lastname: Bahram
authors.affiliation: University of Orleans and CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Quesniaux
authors.affiliation: University of Orleans and CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: ImmunoRhumatologie Moléculaire, INSERM UMR S1109, Université de Strasbourg; Fédération de Médecine Translationnelle de Strasbourg, Centre National de Référence pour les Maladies Auto-immunes Systémiques Rares, Service de Rhumatologie, CHU Strasbourg; Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Wachsmann
authors.affiliation: ImmunoRhumatologie Moléculaire, INSERM UMR S1109, Université de Strasbourg; Fédération de Médecine Translationnelle de Strasbourg, Centre National de Référence pour les Maladies Auto-immunes Systémiques Rares, Service de Rhumatologie, CHU Strasbourg; Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France. Electronic address: jacques-eric.gottenberg@chru-strasbourg.fr.
authors.forename: Jacques-Eric
authors.initials: JE
authors.lastname: Gottenberg
authors.affiliation: University of Orleans and CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, Orleans, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Couillin
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression; D054990:Idiopathic Pulmonary Fibrosis / Q000209:etiology* / Q000473:pathology; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D053264:B-Cell Activating Factor; D020381:Interleukin-17; D053583:Interleukin-1beta; D001761:Bleomycin
keywords: Autoimmunity; BAFF; IL-17; IL-1β; Pulmonary fibrosis; Systemic sclerosis