title: Selective oxidation of DNA topoisomerase 1 induces systemic sclerosis in the mouse.
abstract: Systemic sclerosis (SSc) is a connective tissue disorder of great clinical heterogeneity. Its pathophysiology remains unclear. Our aim was to evaluate the relative roles of reactive oxygen species (ROS) and of the immune system using an original model of SSc. BALB/c and immunodeficient BALB/c SCID mice were injected s.c. with prooxidative agents (hydroxyl radicals, hypochlorous acid, peroxynitrites, superoxide anions), bleomycin, or PBS everyday for 6 wk. Skin and lung fibrosis were assessed by histological and biochemical methods. Autoantibodies were detected by ELISA. The effects of mouse sera on H(2)O(2) production by endothelial cells and on fibroblast proliferation, and serum concentrations in advanced oxidation protein products (AOPP) were compared with sera from patients with limited or diffuse SSc. We observed that s.c. peroxynitrites induced skin fibrosis and serum anti-CENP-B Abs that characterize limited SSc, whereas hypochlorite or hydroxyl radicals induced cutaneous and lung fibrosis and anti-DNA topoisomerase 1 autoantibodies that characterize human diffuse SSc. Sera from hypochlorite- or hydroxyl radical-treated mice and of patients with diffuse SSc contained high levels of AOPP that triggered endothelial production of H(2)O(2) and fibroblast hyperproliferation. Oxidized topoisomerase 1 recapitulated the effects of whole serum AOPP. SCID mice developed an attenuated form of SSc, demonstrating the synergistic role of the immune system with AOPP in disease propagation. We demonstrate a direct role for ROS in SSc and show that the nature of the ROS dictates the form of SSc. Moreover, this demonstration is the first that shows the specific oxidation of an autoantigen directly participates in the pathogenesis of an autoimmune disease.
authors.affiliation: Université Paris Descartes, Faculté de Médecine, EA1833, Paris, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Servettaz
authors.forename: Claire
authors.initials: C
authors.lastname: Goulvestre
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.forename: Philippe
authors.initials: P
authors.lastname: Guilpain
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.forename: Vincent
authors.initials: V
authors.lastname: Vuiblet
authors.forename: Loïc
authors.initials: L
authors.lastname: Guillevin
authors.forename: Luc
authors.initials: L
authors.lastname: Mouthon
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004264:DNA Topoisomerases, Type I / Q000378:metabolism* / Q000502:physiology / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008814:Mice, Inbred NZB; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000276:immunology*; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology
chemical_list: D017382:Reactive Oxygen Species; D004264:DNA Topoisomerases, Type I