| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Université Paris Descartes, Faculté de Médecine, EA1833,
Service de Médecine Interne, Centre National de Référence Sclérodermie-Vascularites, EA4058 Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris, France,
Faculté de Médecine de Reims, Service de Médecine Interne et Maladies Infectieuses, Hôpital Robert Debré, and
Faculté de Médecine de Reims, Laboratoire d’anatomopathologie Pol Bouin, Hôpital Maison Blanche, Reims, France
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 H2O2 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 H2O2 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a grant from "Fondation Philippe" (to F.B.), grants from Actelion and the "Association des Sclérodermiques de France" (to A.S.), and a grant from the "Fondation pour la Recherche Médicale" (to P.G. and N.K.).
2 A.S. and C.G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Frédéric Batteux, Faculté de Médecine, Laboratoire d’immunologie, EA 1833, Université Paris Descartes, Institut Fédératif de Recherche Alfred Jost, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, 75679 Paris cedex 14, France. E-mail address: frederic.batteux{at}cch.ap-hop-paris.fr
4 Abbreviations used in this paper: SSc, systemic sclerosis; AOPP, advanced oxidation protein product; NAC, N-acetylcysteine; O
2, superoxide anion; OH·, hydroxyl radical; ONOO–, peroxynitrite; ROS, reactive oxygen species; TLC, total lung capacity.
5 The online version of this article contains supplemental material.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
