title: The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model.
abstract: Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti-smooth muscle actin and/or anti-nuclear, anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)-DR3, -DR7 and -DR13. HLA-DR4 has the second strongest association with adult AIH, after HLA-DR3. We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti-LKM1/anti-LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (Tregs), which had decreased programmed death (PD)-1 expression. Splenic Tregsfrom these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8+T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild-type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of Tregsand reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8+T effectors, facilitating the induction of AIH and persistent liver damage.
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, USA.|Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium.|Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Yuksel
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, USA.|Department of Nephrology, Qilu Hospital, Shandong University, China.
authors.forename: X
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, USA.
authors.forename: N
authors.initials: N
authors.lastname: Tai
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, USA.|Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK.
authors.forename: Manakkat
authors.initials: M
authors.lastname: Vijay
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, USA.
authors.forename: E
authors.initials: E
authors.lastname: Gülden
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada.
authors.forename: K
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: P
authors.initials: P
authors.lastname: Lapierre
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Alvarez
authors.affiliation: Department of Nephrology, Qilu Hospital, Shandong University, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Colle
authors.affiliation: Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Section of Endocrinology, Yale University School of Medicine, New Haven, USA. li.wen@yale.edu.
authors.forename: L
authors.initials: L
authors.lastname: Wen
mesh_terms: D000642:Ammonia-Lyases; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D051042:Glutamate Formimidoyltransferase; D015804:HLA-DR4 Antigen / Q000235:genetics* / Q000276:immunology*; D019693:Hepatitis, Autoimmune / Q000209:etiology* / Q000473:pathology*; D006801:Humans; D006942:Hypergammaglobulinemia / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000235:genetics / Q000276:immunology; D064251:Multifunctional Enzymes; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D015804:HLA-DR4 Antigen; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D009097:Multienzyme Complexes; D064251:Multifunctional Enzymes; C094307:anti-liver cytosolic protein 1; C060729:anti-liver kidney microsome antibody; D019389:Cytochrome P-450 CYP2D6; C494850:Ftcd protein, mouse; D051042:Glutamate Formimidoyltransferase; D000642:Ammonia-Lyases
keywords: Tregs; autoantigen; transgenic-HLA-mouse model