title: Autoimmune hepatitis in a murine autoimmune polyendocrine syndrome type 1 model is directed against multiple autoantigens.
abstract: Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations of the autoimmune regulator (AIRE) gene. Mouse studies have shown that this results in defective negative selection of T cells and defective early seeding of peripheral organs with regulatory T cells (Tregs). Aire deficiency in humans and mice manifests as spontaneous autoimmunity against multiple organs, and 20% of patients develop an autoimmune hepatitis (AIH). To study AIH in APS-1, we generated a murine model of human AIH on a BALB/c mouse background, in which Aire is truncated at exon 2. A subgroup of 24% of mice is affected by AIH, characterized by lymphoplasmacytic and periportal hepatic infiltrates, autoantibodies, elevated aminotransferases, and a chronic and progressive course of disease. Disease manifestation was dependent on specific Aire mutations and the genetic background of the mice. Though intrahepatic Treg numbers were increased and hyperproliferative, the intrahepatic CD4/CD8 ratio was decreased. The targets of the adaptive autoimmune response were polyspecific and not focussed on essential autoantigens, as described for other APS-1-related autoimmune diseases. The AIH could be treated with prednisolone or adoptive transfer of polyspecific Tregs.
  
  
  CONCLUSIONS
  Development of AIH in APS-1 is dependent on specific Aire mutations and genetic background genes. Autoimmune response is polyspecific and can be controlled by steroids or transfer with Tregs. This might enable new treatment options for patients with AIH.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hardtke-Wolenski
authors.forename: Richard
authors.initials: R
authors.lastname: Taubert
authors.forename: Fatih
authors.initials: F
authors.lastname: Noyan
authors.forename: Maren
authors.initials: M
authors.lastname: Sievers
authors.forename: Janine
authors.initials: J
authors.lastname: Dywicki
authors.forename: Jerome
authors.initials: J
authors.lastname: Schlue
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
authors.forename: Brita
authors.initials: B
authors.lastname: Ardesjö Lundgren
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: Andreas
authors.initials: A
authors.lastname: Pich
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Elmar
authors.initials: E
authors.lastname: Jaeckel
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D019693:Hepatitis, Autoimmune / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology*
chemical_list: D001324:Autoantigens