title: A novel "humanized mouse" model for autoimmune hepatitis and the association of gut microbiota with liver inflammation.
abstract: Autoimmune hepatitis (AIH) in humans is a severe inflammatory liver disease characterized by interface hepatitis, the presence of circulating autoantibodies, and hyper-gammaglobulinemia. There are two types of AIH, type 1 (AIH-1) and type 2 (AIH-2), characterized by distinct autoimmune serology. Patients with AIH-1 are positive for anti-smooth muscle and/or antinuclear autoantibodies, whereas patients with AIH-2 have anti-liver kidney microsomal type 1 and/or anti-liver cytosol type 1 autoantibodies. Cytochrome P4502D6 is the antigenic target of anti-liver kidney microsomal type 1, and formiminotransferase cyclodeaminase is the antigenic target of anti-liver cytosol type 1. It is known that AIH, both types 1 and 2, is strongly linked to the human leukocyte antigen (HLA) alleles -DR3, -DR4, and -DR7. However, direct evidence of the association of HLA with AIH is lacking. We developed a novel mouse model of AIH using the HLA-DR3 transgenic mouse on the nonobese-diabetic background by immunization of HLA-DR3- and HLA-DR3+ nonobese-diabetic mice with a DNA plasmid, coding for human cytochrome P4502D6/formiminotransferase cyclodeaminase fusion protein. Immunization with cytochrome P4502D6/formiminotransferase cyclodeaminase leads to a sustained elevation of alanine aminotransferase, development of antinuclear autoantibodies and anti-liver kidney microsomal type 1/anti-liver cytosol type 1 autoantibodies, chronic immune cell infiltration, and parenchymal fibrosis on liver histology in HLA-DR3+ mice. Immunized mice also showed an enhanced T helper 1 immune response and paucity of the frequency of regulatory T cells in the liver. Moreover, HLA-DR3+ mice with exacerbated AIH showed reduced diversity and total load of gut bacteria.
  
  
  CONCLUSIONS
  Our humanized animal model has provided a novel experimental tool to further elucidate the pathogenesis of AIH and to evaluate the efficacy and safety of immunoregulatory therapeutic interventions in vivo.
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, CT.|Laboratory of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.|Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College Hospital, King's College London, London, UK.
authors.forename: Muhammed
authors.initials: M
authors.lastname: Yuksel
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, CT.|Clinical Research Centre for Autoimmune Liver Disease, Beijing You-an Hospital, Capital Medical University, Beijing, China.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, CT.
authors.forename: Ningwen
authors.initials: N
authors.lastname: Tai
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, CT.
authors.forename: Jian
authors.initials: J
authors.lastname: Peng
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, CT.|Department of Rheumatology, PLA General Hospital, Beijing, China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Guo
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada.
authors.forename: Kathie
authors.initials: K
authors.lastname: Beland
authors.affiliation: Immunovirology Laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Québec, Canada.
authors.forename: Pascal
authors.initials: P
authors.lastname: Lapierre
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN.
authors.forename: Chella
authors.initials: C
authors.lastname: David
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada.
authors.forename: Fernando
authors.initials: F
authors.lastname: Alvarez
authors.affiliation: Laboratory of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Colle
authors.affiliation: Clinical Research Centre for Autoimmune Liver Disease, Beijing You-an Hospital, Capital Medical University, Beijing, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Yan
authors.affiliation: Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College Hospital, King's College London, London, UK.
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mieli-Vergani
authors.affiliation: Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College Hospital, King's College London, London, UK.
authors.forename: Diego
authors.initials: D
authors.lastname: Vergani
authors.affiliation: Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College Hospital, King's College London, London, UK.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, CT.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001483:Base Sequence; D019389:Cytochrome P-450 CYP2D6 / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D015803:HLA-DR3 Antigen / Q000276:immunology; D019693:Hepatitis, Autoimmune / Q000209:etiology*; D006801:Humans; D007114:Immunization; D007422:Intestines / Q000382:microbiology*; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D064307:Microbiota; D008969:Molecular Sequence Data; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D015803:HLA-DR3 Antigen; C060729:anti-liver kidney microsome antibody; D019389:Cytochrome P-450 CYP2D6