title: Imbalance of the Vanin-1 Pathway in Systemic Sclerosis.
abstract: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs and vascular alterations. SSc pathophysiology involves systemic inflammation and oxidative stress. Because the vanin-1 gene (vnn1) encodes an enzyme with pantetheinase activity that converts vasculoprotective pantethine into profibrotic pantothenic acid and pro-oxidant cystamine, we tested this pathway in the pathophysiology of SSc. Activation of the vanin-1/pantetheinase pathway was investigated in wild-type BALB/c mice with hypochlorous acid (HOCl)-induced SSc by ELISA and Western blotting. We then evaluated the effects of the inactivation of vnn1 on the development of fibrosis, endothelial alterations, and immunological activation in mice with HOCl- and bleomycin-induced SSc. We then explored the vanin-1/pantetheinase pathway in a cohort of patients with SSc and in controls. In wild-type mice with HOCl-induced SSc, the vanin-1/pantetheinase pathway was dysregulated, with elevation of vanin-1 activity in skin and high levels of serum pantothenic acid. Inactivation of the vnn1 gene in vnn1-/-mice with HOCl-induced SSc prevented the development of characteristic features of the disease, including fibrosis, immunologic abnormalities, and endothelial dysfunction. Remarkably, patients with diffuse SSc also had increased expression of vanin-1 in skin and blood and elevated levels of serum pantothenic acid that correlated with the severity of the disease. Our data demonstrate that vanin-1/pantetheinase controls fibrosis, vasculopathy, autoimmunity, and oxidative stress in SSc. The levels of vanin-1 expression and pantothenic acid determine SSc severity and can be used as markers of disease severity. More importantly, inhibition of vanin-1 can open new therapeutic approaches in SSc.
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'Immunologie Biologique, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France; niloufar.kavian@cch.aphp.fr.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'Immunologie Biologique, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Souad
authors.initials: S
authors.lastname: Mehlal
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'Immunologie Biologique, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Wioleta
authors.identifier: 0000-0002-4080-1676
authors.initials: W
authors.lastname: Marut
authors.affiliation: Faculté de Médecine de Reims, Service de Médecine Interne, Maladies Infectieuses, Immunologie Clinique, Hôpital Robert Debré, 51092 Reims Cedex, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Servettaz
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Université d'Aix-Marseille, INSERM U1104, CNRS UMR7280, 13288 Marseille, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Giessner
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Université d'Aix-Marseille, INSERM U1104, CNRS UMR7280, 13288 Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Bourges
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'Immunologie Biologique, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'Immunologie Biologique, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.affiliation: Service de Diagnostic Biologique Automatisé, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Hervé
authors.identifier: 0000-0001-8675-8784
authors.initials: H
authors.lastname: Lemaréchal
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'Immunologie Biologique, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Marie-Flore
authors.identifier: 0000-0003-3297-964X
authors.initials: MF
authors.lastname: Dutilh
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'Immunologie Biologique, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cerles
authors.affiliation: Université Montpellier 1, Service de Médecine Interne A, Hôpital Saint-Eloi, 34295 Montpellier Cedex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Guilpain
authors.affiliation: Faculté de Médecine de Reims, Laboratoire d'Anatomopathologie, Hôpital Robert Debré, 51092 Reims Cedex, France; and.
authors.forename: Vincent
authors.initials: V
authors.lastname: Vuiblet
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'Immunologie Biologique, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chouzenoux
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Université d'Aix-Marseille, INSERM U1104, CNRS UMR7280, 13288 Marseille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Galland
authors.affiliation: Service de Médecine Interne et des Maladies Vasculaires, Hôpital Saint-Eloi, 34295 Montpellier Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Quere
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'Immunologie Biologique, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Bernard
authors.identifier: 0000-0002-5528-8799
authors.initials: B
authors.lastname: Weill
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Université d'Aix-Marseille, INSERM U1104, CNRS UMR7280, 13288 Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Naquet
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine, Institut Cochin INSERM U1016 et Laboratoire d'Immunologie Biologique, Assistance Publique Hôpitaux de Paris Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010205:Pantothenic Acid / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism*
chemical_list: D058851:GPI-Linked Proteins; D010205:Pantothenic Acid; D000581:Amidohydrolases; C022314:pantetheinase