title: The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development.
abstract: Autoimmune hepatitis (AIH) is defined as a chronic liver inflammation with loss of tolerance against hepatocytes. The etiology and pathophysiology of AIH are still poorly understood because reliable animal models are limited. Therefore, we recently introduced a model of experimental murine AIH by a self-limited adenoviral infection with the AIH type 2 antigen formiminotransferase cyclodeaminase (FTCD). We could demonstrate that break of humoral tolerance towards liver specific autoantigens like FTCD and cytochrome P450 2D6 (CYP2D6) is not dependent on the genetic background. However, the development of AIH in autoantibody positive animals is determined by genetic background genes. We could also show that the break of humoral tolerance is necessary but not sufficient for the development of AIH. In contrast the break of tolerance against the ubiquitously expressed nuclear antigens (ANAs) is strictly dependent on genetic predisposition. Priming with the UGA suppressor tRNA-associated protein (soluble liver antigen; SLA) is a strong inducer of ANA reactivity, but not sufficient to cause AIH development thereby questioning the importance of anti-SLA immune response as an important driver in AIH. Monogenetic mutations such as Aire-deficiency can cause AIH in otherwise genetically resistant strains.
  
  
  
  The results have important implications for our understanding of the pathophysiology of AIH development and for the interpretation of humoral antibody responses in AIH.
authors.affiliation: Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany. Electronic address: Wolenski.Matthias@mh-hannover.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hardtke-Wolenski
authors.affiliation: Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Dywicki
authors.affiliation: Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hapke
authors.affiliation: Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Sievers
authors.affiliation: Inst. of Pathology, Hannover Medical School, Germany.
authors.forename: Jerome
authors.initials: J
authors.lastname: Schlue
authors.affiliation: Diabetes Center, University of California-San Francisco, San Francisco, United States.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
authors.affiliation: Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany; Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Taubert
authors.affiliation: Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany; Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Germany.
authors.forename: Fatih
authors.initials: F
authors.lastname: Noyan
authors.affiliation: Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany; Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Jaeckel
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004195:Disease Models, Animal; D004777:Environment; D020022:Genetic Predisposition to Disease; D019693:Hepatitis, Autoimmune / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D007108:Immune Tolerance; D056724:Immunity, Humoral; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation
chemical_list: D001324:Autoantigens; D007106:Immune Sera; D019389:Cytochrome P-450 CYP2D6
keywords: Autoantibodies; Autoimmune hepatitis; Cytochrome P450 2D6; Experimental murine autoimmune hepatitis; Formiminotransferase cyclodeaminase; Genetic predisposition; Soluble liver antigen