title: Thymic epithelium determines a spontaneous chronic neuritis in Icam1(tm1Jcgr)NOD mice.
abstract: The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4(+) T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1(tm1Jcgr)NOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17-producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1(tm1Jcgr)NOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1(tm1Jcgr)NOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases.
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany; gerd.mzh@uni-duesseldorf.de.
authors.forename: Gerd
authors.initials: G
authors.lastname: Meyer zu Horste
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
authors.forename: Anne K
authors.initials: AK
authors.lastname: Mausberg
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
authors.forename: Steffen
authors.initials: S
authors.lastname: Cordes
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
authors.forename: Houda
authors.initials: H
authors.lastname: El-Haddad
authors.affiliation: Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Partke
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
authors.forename: Verena I
authors.initials: VI
authors.lastname: Leussink
authors.affiliation: Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University, 40225 Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.affiliation: West-German Center of Diabetes and Health, Catholic Clinic Network of Düsseldorf, 40225 Düsseldorf, Germany; and.
authors.forename: Stephan
authors.initials: S
authors.lastname: Martin
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford, CA 94305.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
authors.forename: Bernd C
authors.initials: BC
authors.lastname: Kieseier
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004848:Epithelium; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D020381:Interleukin-17; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018993:Myelin P0 Protein / Q000276:immunology; D009186:Myelin Sheath / Q000276:immunology; D009444:Neuritis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology*; D010525:Peripheral Nerves / Q000276:immunology / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology
chemical_list: D020381:Interleukin-17; D018993:Myelin P0 Protein; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1