title: Activation of TNF-α-AID axis and co-inhibitory signals in coordination with Th1-type immunity in a mouse model recapitulating hepatitis B.
abstract: Hepatitis B virus (HBV) infection evokes host immune responses that primarily determine the outcome of HBV infection and the clinical features of HBV-associated liver disease. The precise mechanisms by which host factors restrict HBV replication, however, are poorly understood due to the lack of useful animal models that recapitulate immune responses to HBV. Here, we performed comprehensive immunologic gene expression profiling of the liver of a mouse model recapitulating anti-HBV immune response using a high sensitivity direct digital counting system. Anti-HBV cellular immunity with liver inflammation was elicited in mice hydrodynamically injected with a CpG-depleted plasmid encoding hepatitis B surface antigen (HBsAg) gene after preimmunization with HBsAg vaccine. Comprehensive expression analyses revealed the upregulation of Th1-associated genes including tumor necrosis factor (Tnf) and negative regulators of T cell function in the inflamed liver. Interestingly, activation-induced cytidine deaminase (Aicda, termed AID in humans), which reportedly suppresses HBV infection in vitro, was upregulated in hepatocytes in the course of anti-HBV immunity. Hepatocytic expression of Aicda in a Tnf-dependent manner was confirmed by the administration of Tnf antagonist into Aicda-tdTomato mice with anti-HBV immunity. Our findings suggest that activation of Tnf-Aicda axis and co-inhibitory signals to T cells in coordination with Th1-type immunity has critical roles in the immune response against HBV infection.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inuzuka
authors.affiliation: Department of Gastroenterology, Kobe Asahi Hospital, Kobe, 653-0801, Japan.
authors.forename: Soo Ki
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, 852-8501, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: Department of Pharmaceutical Informatics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, 852-8501, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawakami
authors.affiliation: Graduate School of Advanced Integrated Studies in Human Survivability (Shishu-Kan), Kyoto University, Kyoto, 606-8306, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Seno
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan. Electronic address: maru@kuhp.kyoto-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Marusawa
mesh_terms: D000818:Animals; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006509:Hepatitis B / Q000276:immunology* / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D057446:Hydrodynamics; D008099:Liver / Q000276:immunology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D014409:Tumor Necrosis Factor-alpha; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: Activation-induced cytidine deaminase; Co-inhibitory signal; Hepatitis B virus; Hydrodynamic injection