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Shao W, Huang W, Wang Y, Sima H, Ma K, Chen R, Han H, Yang Y, Bao Y, Pei X, Zhang L. Exosome-Modified AAV Gene Therapy Attenuates Autoimmune Hepatitis via Enhanced Regulatory T Cell Targeting and Immune Modulation. Microorganisms 2025; 13:823. [PMID: 40284659 PMCID: PMC12029567 DOI: 10.3390/microorganisms13040823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 03/27/2025] [Accepted: 04/02/2025] [Indexed: 04/29/2025] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disorder driven by immune dysregulation, marked by reduced regulatory T cells (Tregs) and unchecked inflammation. Current therapies lack specificity and efficacy, necessitating novel approaches. This study explores gene therapy using exosome-associated adeno-associated virus (exo-AAV) to deliver the Foxp3 gene, aiming to restore Treg-mediated immune tolerance in AIH. We engineered exosomes expressing the CD4-targeting antibody on their surface, encapsulating AAV6/Foxp3, to enhance lymphoid cell specificity. In a ConA-induced murine AIH model, engineered exo-AAV administration significantly increased hepatic Treg proportions while reducing Th17 cells and inflammatory cytokines (IFN-γ, TNF-α, IL-6), compared to control groups (unmodified exo-AAV or empty exosomes). Liver histopathology and serum ALT levels also improved in engineered exo-AAV treated mice. Mechanistically, engineered exo-AAV demonstrated superior targeting via CD4 binding, validated by immunofluorescence and nanoparticle tracking. Despite transient reductions in splenic Tregs, localized hepatic immune modulation underscored exo-AAV's efficacy. These findings highlight engineered exo-AAV as a promising strategy for precision gene therapy in AIH, overcoming limitations of traditional AAV delivery by enhancing lymphocyte-specific transduction and immune balance restoration. This approach presents a novel therapeutic avenue for systemic autoimmune diseases reliant on Treg reinforcement.
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Affiliation(s)
- Wenwei Shao
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China; (W.H.); (H.S.)
- Medical School, Tianjin University, Tianjin 300072, China; (K.M.); (R.C.); (H.H.); (Y.Y.); (Y.B.)
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin University, Tianjin 300072, China
| | - Weilin Huang
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China; (W.H.); (H.S.)
| | - Yixuan Wang
- State Key Laboratory of Experimental Hematology of China, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China; (Y.W.); (X.P.)
| | - Helin Sima
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China; (W.H.); (H.S.)
| | - Kai Ma
- Medical School, Tianjin University, Tianjin 300072, China; (K.M.); (R.C.); (H.H.); (Y.Y.); (Y.B.)
| | - Rongtao Chen
- Medical School, Tianjin University, Tianjin 300072, China; (K.M.); (R.C.); (H.H.); (Y.Y.); (Y.B.)
| | - Heqiao Han
- Medical School, Tianjin University, Tianjin 300072, China; (K.M.); (R.C.); (H.H.); (Y.Y.); (Y.B.)
| | - Yixuan Yang
- Medical School, Tianjin University, Tianjin 300072, China; (K.M.); (R.C.); (H.H.); (Y.Y.); (Y.B.)
| | - Yuchen Bao
- Medical School, Tianjin University, Tianjin 300072, China; (K.M.); (R.C.); (H.H.); (Y.Y.); (Y.B.)
| | - Xiaolei Pei
- State Key Laboratory of Experimental Hematology of China, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China; (Y.W.); (X.P.)
| | - Lei Zhang
- State Key Laboratory of Experimental Hematology of China, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China; (Y.W.); (X.P.)
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Cardon A, Guinebretière T, Dong C, Gil L, Ado S, Gavlovsky PJ, Braud M, Danger R, Schultheiß C, Doméné A, Paul-Gilloteaux P, Chevalier C, Bernier L, Judor JP, Fourgeux C, Imbert A, Khaldi M, Bardou-Jacquet E, Elkrief L, Lannes A, Silvain C, Schnee M, Tanne F, Vavasseur F, Brusselle L, Brouard S, Kwok WW, Mosnier JF, Lohse AW, Poschmann J, Binder M, Gournay J, Conchon S, Milpied P, Renand A. Single cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting. Nat Commun 2025; 16:1161. [PMID: 39880819 PMCID: PMC11779892 DOI: 10.1038/s41467-025-56363-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 01/15/2025] [Indexed: 01/31/2025] Open
Abstract
Autoimmune liver diseases (AILD) involve dysregulated CD4 T cell responses against liver self-antigens, but how these autoreactive T cells relate to liver tissue pathology remains unclear. Here we perform single-cell transcriptomic and T cell receptor analyses of circulating, self-antigen-specific CD4 T cells from patients with AILD and identify a subset of liver-autoreactive CD4 T cells with a distinct B-helper transcriptional profile characterized by PD-1, TIGIT and HLA-DR expression. These cells share clonal relationships with expanded intrahepatic T cells and exhibit transcriptional signatures overlapping with tissue-resident T cells in chronically inflamed environments. Using a mouse model, we demonstrate that, following antigen recognition in the liver, CD4 T cells acquire an exhausted phenotype, play a crucial role in liver damage, and are controlled by immune checkpoint pathways. Our findings thus suggest that circulating autoreactive CD4 T cells in AILD are imprinted by chronic antigen exposure to promote liver inflammation, thereby serving as a potential target for developing biomarkers and therapies for AILD.
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Affiliation(s)
- Anaïs Cardon
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Thomas Guinebretière
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Chuang Dong
- Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, CIML, Marseille, France
| | - Laurine Gil
- Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, CIML, Marseille, France
| | - Sakina Ado
- Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, CIML, Marseille, France
| | - Pierre-Jean Gavlovsky
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Martin Braud
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Richard Danger
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Christoph Schultheiß
- Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel, Division of Oncology, University Hospital Basel, Basel, Switzerland
| | - Aurélie Doméné
- Nantes Université, CHU Nantes, CNRS, Inserm, BioCore, US16, SFR Bonamy, Nantes, France
| | | | | | - Laura Bernier
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Jean-Paul Judor
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Cynthia Fourgeux
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Astrid Imbert
- Service Hepato-gastro-entérologie et Assistance Nutritionnelle, CHU Nantes, Nantes, France
| | - Marion Khaldi
- Service Hepato-gastro-entérologie et Assistance Nutritionnelle, CHU Nantes, Nantes, France
- Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Nantes, France
| | - Edouard Bardou-Jacquet
- CHU Rennes, Service des maladies du foie, Université Rennes, INSERM, INRAE, Institut NUMECAN, Rennes, France
| | - Laure Elkrief
- CHRU Tours, Service Hépato-Gastroentérologie, Tours, France
| | - Adrien Lannes
- CHU Angers, Service Hépato-Gastroentérologie et Oncologie Digestive, Université d'Angers, Laboratoire HIFIH, UPRES EA3859, SFR 4208, Angers, France
| | | | - Matthieu Schnee
- CHD Vendée-La Roche sur Yon, Service Hépato-Gastroentérologie, F- 85000, la Roche sur Yon, France
| | - Florence Tanne
- CHU Brest, Service Hépato-Gastroentérologie, Brest, France
| | | | - Lucas Brusselle
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Sophie Brouard
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - William W Kwok
- Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Jean-François Mosnier
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
- Service Anatomie et Cytologie Pathologiques, CHU Nantes, Nantes, France
| | - Ansgar W Lohse
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jeremie Poschmann
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Mascha Binder
- Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel, Division of Oncology, University Hospital Basel, Basel, Switzerland
| | - Jérôme Gournay
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
- Service Hepato-gastro-entérologie et Assistance Nutritionnelle, CHU Nantes, Nantes, France
- Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Nantes, France
| | - Sophie Conchon
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France.
| | - Pierre Milpied
- Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, CIML, Marseille, France.
| | - Amédée Renand
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France.
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Longhi MS, Zhang L, Mieli-Vergani G, Vergani D. B and T cells: (Still) the dominant orchestrators in autoimmune hepatitis. Autoimmun Rev 2024; 23:103591. [PMID: 39117005 PMCID: PMC11409799 DOI: 10.1016/j.autrev.2024.103591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 08/03/2024] [Accepted: 08/04/2024] [Indexed: 08/10/2024]
Abstract
Autoimmune hepatitis (AIH) is a severe hepatopathy characterized by hypergammaglobulinemia, presence of serum autoantibodies and histological appearance of interface hepatitis. Liver damage in AIH is initiated by the presentation of a liver autoantigen to uncommitted Th0 lymphocytes, followed by a cascade of effector immune responses culminating with the production of inflammatory cytokines, activation of cytotoxic cells and subsequent hepatocyte injury. B cells actively participate in AIH liver damage by presenting autoantigens to uncommitted T lymphocytes. B cells also undergo maturation into plasma cells that are responsible for production of immunoglobulin G and autoantibodies, which mediate antibody dependent cell cytotoxicity. Perpetuation of effector immunity with consequent progression of liver damage is permitted by impairment in regulatory T cells (Tregs), a lymphocyte subset central to the maintenance of immune homeostasis. Treg impairment in AIH is multifactorial, deriving from numerical decrease, reduced suppressive function, poor response to IL-2 and less stable phenotype. In this review, we discuss the role of B and T lymphocytes in the pathogenesis of AIH. Immunotherapeutic strategies that could limit inflammation and halt disease progression while reconstituting tolerance to liver autoantigens are also reviewed and discussed.
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Affiliation(s)
- Maria Serena Longhi
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
| | - Lina Zhang
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA; School of Arts and Sciences, Tufts University, Medford, MA, USA
| | - Giorgina Mieli-Vergani
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King's College London, London, United Kingdom.
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Liver Sciences and Medicine, King's College London, London, United Kingdom.
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Fujimori S, Chu PS, Teratani T, Harada Y, Suzuki T, Amiya T, Taniki N, Kasuga R, Mikami Y, Koda Y, Ichikawa M, Tabuchi T, Morikawa R, Yamataka K, Noguchi F, Tsujikawa H, Kurebayashi Y, Sakamoto M, Kanai T, Nakamoto N. IL-15-producing splenic B cells play pathogenic roles in the development of autoimmune hepatitis. JHEP Rep 2023; 5:100757. [PMID: 37305442 PMCID: PMC10251155 DOI: 10.1016/j.jhepr.2023.100757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 03/02/2023] [Accepted: 03/21/2023] [Indexed: 06/13/2023] Open
Abstract
Background & Aims B-cell depletion therapy with an anti-CD20 is an effective treatment strategy for patients with refractory autoimmune hepatitis (AIH). However, the mechanisms underlying B-cell action are unclear. Methods Herein, we used the adeno-associated virus IL-12 model, in which hepatic IL-12 expression triggers liver injuries characteristic of AIH. We also analysed the clinical samples of patients with AIH. Results B-cell depletion using anti-CD20 or splenectomy was found to improve liver functions and decrease the cytotoxic CD8+ T-cell (cytotoxic T lymphocyte [CTL]) count in the liver. This improvement was reversed by the adoptive transfer of splenic B cells derived from AAV IL-12-treated mice to splenectomised mice as it caused the hepatic CTL count to increase. RNA-sequencing analysis identified IL-15 as a key factor in pathogenic B cells, which promotes CTL expansion and subsequent migration to the liver via the CXCL9/CXCR3 axis. Indeed, IL-15 neutralisation ameliorated hepatitis by suppressing splenic and hepatic CTLs in vivo. The close distribution of B220+ B cells and CD8+ T cells in the spleen of AIH mice suggested mutual interactions. Mechanistically, IFNγ and CD40L/CD40 signalling were indispensable for the expression of IL-15 in B cells, and in vitro co-culture experiments revealed that splenic CD40L+CD8+ T cells promoted IL-15 production in B cells, which led to CTL expansion. In patients with AIH, high serum IL-15 concentration and IL-15+ B-cell counts, positively correlating with serum alanine aminotransferase levels, support translation and potential therapeutic targeting in human AIH. Conclusions This investigation elucidated the roles of IL-15-producing splenic B cells that occur in concert with pathogenic CD8+ T cells during the development of AIH. Impact and Implications IL-15-producing B cells were shown to exacerbate experimental AIH via cytotoxic T lymphocyte expansion. CD40L+CD8+ T cells promoted IL-15 expression in B cells, indicating the mutual interaction of both cells. High serum IL-15 concentrations, IL-15+ B-cell counts, and CD40L+IL-15Rα+CD8+ T-cell counts were confirmed in the blood of patients with AIH.
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Affiliation(s)
- Sota Fujimori
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yosuke Harada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takahiro Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takeru Amiya
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Ryosuke Kasuga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yuzo Koda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
| | - Masataka Ichikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takaya Tabuchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Rei Morikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Karin Yamataka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Fumie Noguchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hanako Tsujikawa
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yutaka Kurebayashi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
- Japan Agency for Medical Research and Development, AMED, Tokyo, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Czaja AJ. Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis. Dig Dis Sci 2023:10.1007/s10620-023-07967-5. [PMID: 37160542 PMCID: PMC10169207 DOI: 10.1007/s10620-023-07967-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 05/01/2023] [Indexed: 05/11/2023]
Abstract
Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular mimicry as a cause of autoimmune hepatitis, indicates the limitations and uncertainties of this premise, and encourages investigations that assess diverse environmental antigens as sources of disease-relevant molecular mimics. Pertinent articles were identified in PubMed using multiple search phrases. Several pathogens have linear or conformational epitopes that mimic the self-antigens of autoimmune hepatitis. The occurrence of an acute immune-mediated hepatitis after vaccination for severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) has suggested that vaccine-induced peptides may mimic disease-relevant tissue antigens. The intestinal microbiome is an under-evaluated source of gut-derived antigens that could also engage in molecular mimicry. Chaperone molecules may enhance the pathogenicity of molecular mimics, and they warrant investigation. Molecular mimics of immune dominant epitopes within cytochrome P450 IID6, the autoantigen most closely associated with autoimmune hepatitis, should be sought in diverse environmental antigens and assessed for pathogenicity. Avoidance strategies, dietary adjustments, vaccine improvement, and targeted manipulation of the intestinal microbiota may emerge as therapeutic possibilities. In conclusion, molecular mimicry may be a missing causality of autoimmune hepatitis. Molecular mimics of key immune dominant epitopes of disease-specific antigens must be sought in diverse environmental antigens. The ubiquity of molecular mimicry compels rigorous assessments of peptide mimics for immunogenicity and pathogenicity in experimental models. Molecular mimicry may complement epigenetic modifications as causative mechanisms of autoimmune hepatitis.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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Lapierre P, Alvarez F. Type 2 autoimmune hepatitis: Genetic susceptibility. Front Immunol 2022; 13:1025343. [PMID: 36248826 PMCID: PMC9556705 DOI: 10.3389/fimmu.2022.1025343] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/14/2022] [Indexed: 11/13/2022] Open
Abstract
Two types of autoimmune hepatitis (AIH) are recognized; AIH-1 is characterized by the presence of anti-nuclear and/or anti-smooth muscle autoantibodies, while AIH-2 is associated with the presence of anti-Liver kidney microsome and/or anti-Liver Cytosol antibodies. The autoantigens targeted by AIH-2 autoantibodies are the cytochrome P450 2D6 and Formiminotransferase-cyclodeaminase for anti-LKM1 and anti-LC1 respectively. Both autoantigens are expressed in hepatocytes at higher levels than in any other cell type. Therefore, compared to AIH-1, the autoantigens targeted in AIH-2 are predominantly tissue-specific. Distinct clinical features are specific to AIH-2 compared to AIH-1, including diagnosis in younger patients (mean age 6.6 years), onset as fulminant hepatitis in very young patients (3 years of age or less), higher frequency in children than in adults and is frequently associated with extrahepatic T cell-mediated autoimmune diseases. AIH-2 is also often diagnosed in patients with primary immunodeficiency. AIH-2 is associated with specific HLA class II susceptibility alleles; DQB1*0201 is considered the main determinant of susceptibility while DRB1*07/DRB1*03 is associated with the type of autoantibody present. HLA DQB1*0201 is in strong linkage disequilibrium with both HLA DRB1*03 and DRB1*07. Interestingly, as in humans, MHC and non-MHC genes strongly influence the development of the disease in an animal model of AIH-2. Altogether, these findings suggest that AIH-2 incidence is likely dependent on specific genetic susceptibility factors combined with distinct environmental triggers.
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Affiliation(s)
- Pascal Lapierre
- Laboratoire d’hépatologie cellulaire, Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Université de Montréal, Montréal, QC, Canada
| | - Fernando Alvarez
- Service de gastroentérologie, hépatologie et nutrition, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Montréal, QC, Canada
- Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada
- *Correspondence: Fernando Alvarez,
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Christen U, Hintermann E. Animal Models for Autoimmune Hepatitis: Are Current Models Good Enough? Front Immunol 2022; 13:898615. [PMID: 35903109 PMCID: PMC9315390 DOI: 10.3389/fimmu.2022.898615] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
Autoimmune liver diseases like autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related cholangitis are chronic inflammatory diseases of the liver with an autoimmune background. The therapy of autoimmune hepatitis targets the autoreactive immune system and is largely dependent on the use of glucocorticoids and cytostatic drugs. In contrast, the treatment of cholestatic autoimmune liver diseases is restricted to the use of secondary or semi-synthetic bile acids, like ursodeoxycholic acid or obeticholic acid. Although the management of the disease using such drugs works well for the majority of patients, many individuals do not respond to standard therapy. In addition, chronic treatment with glucocorticoids results in well-known side effects. Further, the use of bile acids is a symptomatic therapy that has no direct immunomodulatory effect. Thus, there is still a lot of room for improvement. The use of animal models has facilitated to elucidate the pathogenesis of autoimmune liver diseases and many potential target structures for immunomodulatory therapies have been identified. In this review, we will focus on autoimmune hepatitis for which the first animal models have been established five decades ago, but still a precise treatment for autoimmune hepatitis, as obtainable for other autoimmune diseases such as rheumatoid arthritis or multiple sclerosis has yet to be introduced. Thus, the question arises if our animal models are too far from the patient reality and thus findings from the models cannot be reliably translated to the patient. Several factors might be involved in this discrepancy. There is first and foremost the genetic background and the inbred status of the animals that is different from human patients. Here the use of humanized animals, such as transgenic mice, might reduce some of the differences. However, there are other factors, such as housing conditions, nutrition, and the microbiome that might also play an important role. This review will predominantly focus on the current status of animal models for autoimmune hepatitis and the possible ways to overcome discrepancies between model and patient.
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Du Y, Zhang W, Qiu H, Xiao C, Shi J, Reid LM, He Z. Mouse Models of Liver Parenchyma Injuries and Regeneration. Front Cell Dev Biol 2022; 10:903740. [PMID: 35721478 PMCID: PMC9198899 DOI: 10.3389/fcell.2022.903740] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/11/2022] [Indexed: 12/11/2022] Open
Abstract
Mice have genetic and physiological similarities with humans and a well-characterized genetic background that is easy to manipulate. Murine models have become the most favored, robust mammalian systems for experimental analyses of biological processes and disease conditions due to their low cost, rapid reproduction, a wealth of mouse strains with defined genetic conditions (both native ones as well as ones established experimentally), and high reproducibility with respect to that which can be done in experimental studies. In this review, we focus on murine models for liver, an organ with renown regenerative capacity and the organ most central to systemic, complex metabolic and physiological functions for mammalian hosts. Establishment of murine models has been achieved for all aspects of studies of normal liver, liver diseases, liver injuries, and regenerative repair mechanisms. We summarize key information on current mouse systems that partially model facets of clinical scenarios, particularly those associated with drug-induced acute or chronic liver injuries, dietary related, non-alcoholic liver disease (NAFLD), hepatitis virus infectious chronic liver diseases, and autoimmune hepatitis (AIH). In addition, we also include mouse models that are suitable for studying liver cancers (e.g., hepatocellular carcinomas), the aging process (senescence, apoptosis), and various types of liver injuries and regenerative processes associated with them.
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Affiliation(s)
- Yuan Du
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wencheng Zhang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
| | - Hua Qiu
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Canjun Xiao
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
| | - Jun Shi
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
| | - Lola M. Reid
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, United States
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
| | - Zhiying He
- Department of General Surgery, Ji’an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji’an, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- *Correspondence: Zhiying He, ; Lola M. Reid, , ; Jun Shi,
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9
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmmune hepatitis. Cell Mol Immunol 2022; 19:158-176. [PMID: 34580437 PMCID: PMC8475398 DOI: 10.1038/s41423-021-00768-8] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/29/2021] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino & Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Lugano, Switzerland.
- Institute for Research in Biomedicine, Bellinzona, Switzerland.
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK.
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK
| | - Diego Vergani
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK
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10
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Selected transgenic murine models of human autoimmune liver diseases. Pharmacol Rep 2022; 74:263-272. [PMID: 35032321 PMCID: PMC8964654 DOI: 10.1007/s43440-021-00351-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 12/19/2022]
Abstract
Murine models of human diseases are of outmost importance for both studying molecular mechanisms driving their development and testing new treatment strategies. In this review, we first discuss the etiology and risk factors for autoimmune liver disease, including primary biliary cholangitis, autoimmune hepatitis and primary sclerosing cholangitis. Second, we highlight important features of murine transgenic models that make them useful for basic scientists, drug developers and clinical researchers. Next, a brief description of each disease is followed by the characterization of selected animal models.
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11
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Thomas-Dupont P, Grube-Pagola P, Izaguirre-Hernández IY, Hernández-Flores KG, Sánchez-Marce EE, Cano-Contreras AD, Remes-Troche JM, Vivanco-Cid H. Development of a New Murine Model of Type 2 Autoimmune Hepatitis Using a Human Liver Protein. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:21-30. [PMID: 34717895 DOI: 10.1016/j.ajpath.2021.10.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 09/13/2021] [Accepted: 10/04/2021] [Indexed: 11/17/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver characterized by parenchymal destruction, hypergammaglobulinemia, specific autoantibody production, and hepatic fibrosis and necrosis. Murine models of AIH have been described; however, little is known about the immunologic mechanisms of tissue destruction. In this study, a new murine model of type 2 AIH was developed using recombinant human cytochrome P450 (CYP) 2D6 emulsified with complete Freund's adjuvant (CFA). BALB/c mice were immunized with 2 μg/mL i.p. of CYP2D6 in CFA. The control group received CFA or phosphate-buffered saline alone. Alanine aminotransferase activity, autoantibody production, IgG concentrations, histologic damage, and specific T-cell response were evaluated. Persistent AIH, characterized by cellular infiltration, hepatic fibrosis, elevated alanine aminotransferase, and the production of anti-liver kidney microsomal antibody type 1 developed in CFA/CYP2D6-immunized mice. These mice presented high levels of IgG and its subclasses IgG1, IgG2a, and IgG2b against liver self-proteins. Interestingly, IL-2+ and interferon γ-positive Cyp2d6-specific T cells were present in greater concentrations in mice immunized with CFA/CYP2D6 compared with control. Immunization with CFA, in combination with a natural human autoantigen like CYP2D6, was demonstrated to break tolerance, resulting in a chronic form of autoimmune-related liver damage. This murine model of type 2 AIH is expected to be instrumental in understanding the immunologic mechanisms of the pathogenesis of this autoimmune liver disease.
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Affiliation(s)
- Pablo Thomas-Dupont
- Instituto de Investigaciones Medico-Biológicas, Universidad Veracruzana, Veracruz, México
| | - Peter Grube-Pagola
- Instituto de Investigaciones Medico-Biológicas, Universidad Veracruzana, Veracruz, México
| | | | | | - Elvis E Sánchez-Marce
- Hospital Regional de Alta Especialidad de Veracruz, Servicios de Salud de Veracruz, Veracruz, México
| | - Ana D Cano-Contreras
- Instituto de Investigaciones Medico-Biológicas, Universidad Veracruzana, Veracruz, México
| | - José M Remes-Troche
- Instituto de Investigaciones Medico-Biológicas, Universidad Veracruzana, Veracruz, México
| | - Héctor Vivanco-Cid
- Instituto de Investigaciones Medico-Biológicas, Universidad Veracruzana, Veracruz, México.
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12
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Sirbe C, Simu G, Szabo I, Grama A, Pop TL. Pathogenesis of Autoimmune Hepatitis-Cellular and Molecular Mechanisms. Int J Mol Sci 2021; 22:13578. [PMID: 34948375 PMCID: PMC8703580 DOI: 10.3390/ijms222413578] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/09/2021] [Accepted: 12/14/2021] [Indexed: 02/05/2023] Open
Abstract
Pediatric autoimmune liver disorders include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is an idiopathic disease characterized by immune-mediated hepatocyte injury associated with the destruction of liver cells, causing inflammation, liver failure, and fibrosis, typically associated with autoantibodies. The etiology of AIH is not entirely unraveled, but evidence supports an intricate interaction among genetic variants, environmental factors, and epigenetic modifications. The pathogenesis of AIH comprises the interaction between specific genetic traits and molecular mimicry for disease development, impaired immunoregulatory mechanisms, including CD4+ T cell population and Treg cells, alongside other contributory roles played by CD8+ cytotoxicity and autoantibody production by B cells. These findings delineate an intricate pathway that includes gene to gene and gene to environment interactions with various drugs, viral infections, and the complex microbiome. Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. The current first-line therapy comprises prednisolone plus azathioprine to induce clinical and biochemical remission. Further understanding of the cellular and molecular mechanisms encountered in AIH may depict their impact on clinical aspects, detect biomarkers, and guide toward novel, effective, and better-targeted therapies with fewer side effects.
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Affiliation(s)
- Claudia Sirbe
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Gelu Simu
- Cardiology Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania
| | - Iulia Szabo
- Department of Rheumatology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Alina Grama
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Tudor Lucian Pop
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
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13
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Vuerich M, Wang N, Kalbasi A, Graham JJ, Longhi MS. Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies. Front Immunol 2021; 12:746436. [PMID: 34650567 PMCID: PMC8510512 DOI: 10.3389/fimmu.2021.746436] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/10/2021] [Indexed: 12/20/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory disorder characterized by hypergammaglobulinemia, presence of serum autoantibodies and histological features of interface hepatitis. AIH therapeutic management still relies on the administration of corticosteroids, azathioprine and other immunosuppressants like calcineurin inhibitors and mycophenolate mofetil. Withdrawal of immunosuppression often results in disease relapse, and, in some cases, therapy is ineffective or associated with serious side effects. Understanding the mechanisms underlying AIH pathogenesis is therefore of paramount importance to develop more effective and well tolerated agents capable of restoring immunotolerance to liver autoantigens. Imbalance between effector and regulatory cells permits liver damage perpetuation and progression in AIH. Impaired expression and regulation of CD39, an ectoenzyme key to immunotolerance maintenance, have been reported in Tregs and effector Th17-cells derived from AIH patients. Interference with these altered immunoregulatory pathways may open new therapeutic avenues that, in addition to limiting aberrant inflammatory responses, would also reconstitute immune homeostasis. In this review, we highlight the most recent findings in AIH immunopathogenesis and discuss how these could inform and direct the development of novel therapeutic tools.
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Affiliation(s)
- Marta Vuerich
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Na Wang
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.,Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,School of Medicine, Shandong University, Jinan, China
| | - Ahmadreza Kalbasi
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Jonathon J Graham
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Maria Serena Longhi
- Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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14
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Zachou K, Arvaniti P, Lyberopoulou A, Dalekos GN. Impact of genetic and environmental factors on autoimmune hepatitis. J Transl Autoimmun 2021; 4:100125. [PMID: 34622188 PMCID: PMC8479787 DOI: 10.1016/j.jtauto.2021.100125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic non-resolving liver disease characterized by diffuse hypergammaglobulinemia, the presence of autoantibodies and characteristic histological findings. The disease can have catastrophic outcome with the development of end-stage liver disease if misdiagnosed/undiagnosed and left untreated. AIH pathogenesis remains obscure and the main hypothesis supports its development in genetically predisposed individuals after being exposed to certain environmental triggers. Genetic predisposition is linked to the presence of certain HLA alleles, mainly HLA-DR3 and HLA-DR4. However, a wide number of non-HLA epitopes have also been associated with the disease although data vary significantly among different ethnic groups. Therefore, it is likely that epigenetic alterations may also play a crucial role in disease's pathogenesis, although not yet extensively studied. The aim of this review was to summarize the genetic and environmental factors that have been associated with AIH, but also to open new insights towards the role of epigenetic modifications in the etiology of the disease.
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Affiliation(s)
- Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
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15
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Sasaki Y, Yoshino N, Okuwa T, Odagiri T, Satoh T, Muraki Y. A mouse monoclonal antibody against influenza C virus attenuates acetaminophen-induced liver injury in mice. Sci Rep 2021; 11:11816. [PMID: 34083649 PMCID: PMC8175586 DOI: 10.1038/s41598-021-91251-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 05/24/2021] [Indexed: 11/09/2022] Open
Abstract
Molecular mimicry is one of the main processes for producing autoantibodies during infections. Although some autoantibodies are associated with autoimmune diseases, the functions of many autoantibodies remain unknown. Previously, we reported that S16, a mouse (BALB/c) monoclonal antibody against the hemagglutinin-esterase fusion glycoprotein of influenza C virus, recognizes host proteins in some species of animals, but we could not succeed in identifying the proteins. In the present study, we found that S16 cross-reacted with acetyl-CoA acyltransferase 2 (ACAA2), which is expressed in the livers of BALB/c mice. ACAA2 was released into the serum after acetaminophen (APAP) administration, and its serum level correlated with serum alanine aminotransferase (ALT) activity. Furthermore, we observed that S16 injected into mice with APAP-induced hepatic injury prompted the formation of an immune complex between S16 and ACAA2 in the serum. The levels of serum ALT (p < 0.01) and necrotic areas in the liver (p < 0.01) were reduced in the S16-injected mice. These results suggest that S16 may have a mitigation function in response to APAP-induced hepatotoxicity. This study shows the therapeutic function of an autoantibody and suggests that an antibody against extracellular ACAA2 might be a candidate for treating APAP-induced hepatic injury.
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Affiliation(s)
- Yutaka Sasaki
- Division of Infectious Diseases and Immunology, Department of Microbiology, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan
| | - Naoto Yoshino
- Division of Infectious Diseases and Immunology, Department of Microbiology, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan
| | - Takako Okuwa
- Department of Microbiology, Kanazawa Medical University School of Medicine, Ishikawa, Japan
| | - Takashi Odagiri
- Division of Infectious Diseases and Immunology, Department of Microbiology, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan
| | - Takashi Satoh
- Department of Pathology, School of Medicine, Iwate Medical University, Iwate, Japan
| | - Yasushi Muraki
- Division of Infectious Diseases and Immunology, Department of Microbiology, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan.
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16
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Preti M, Schlott L, Lübbering D, Krzikalla D, Müller AL, Schuran FA, Poch T, Schakat M, Weidemann S, Lohse AW, Weiler-Normann C, Sebode M, Schwinge D, Schramm C, Carambia A, Herkel J. Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver. JCI Insight 2021; 6:141462. [PMID: 33600378 PMCID: PMC8026180 DOI: 10.1172/jci.insight.141462] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 02/17/2021] [Indexed: 12/11/2022] Open
Abstract
The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II–restricted model peptide in hepatocytes by autoreactive CD4+ T cells. We found that the hepatic peptide was not expressed in the thymus, leading to deficient thymic deletion and resulting in peripheral abundance of autoreactive CD4+ T cells. In the liver, autoreactive CD4+ effector T cells accumulated within portal ectopic lymphoid structures and maturated toward pathogenic IFN-γ and TNF coproducing cells. Expansion and pathogenic maturation of autoreactive effector T cells was enabled by a selective increase of plasticity and instability of autoantigen-specific Tregs but not of nonspecific Tregs. Indeed, antigen-specific Tregs were reduced in frequency and manifested increased IL-17 production, reduced epigenetic demethylation, and reduced expression of Foxp3. As a consequence, autoantigen-specific Tregs had a reduced suppressive capacity, as compared with that of nonspecific Tregs. In conclusion, loss of tolerance and the pathogenesis of AIH were enabled by combined failure of thymic deletion and peripheral regulation.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Christoph Schramm
- Department of Medicine I.,Martin Zeitz Center for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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17
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Abstract
PURPOSE OF REVIEW Autoimmune hepatitis (AIH) is a chronic disease characterized by a lymphocyte infiltrate in the liver. For decades, nonspecific immunosuppression has been used to limit chronic liver inflammation. The high risk of relapse, the treatments side effects, and the significant number of refractory patients are the main clinical issues that require efforts to understand AIH immune mechanisms. RECENT FINDINGS The balance between regulatory CD4 T cells, known to control autoimmunity, and effector CD4 T cells, that recognize liver self-antigens and mediate the liver inflammation, appears central in AIH immune mechanisms. Recent advances in the identification of pathogenic auto-reactive CD4 T cells, and of new mechanisms of immune regulatory defects in AIH patients, give new insights into the pathophysiology of this disease. SUMMARY In this review, we propose an overview of the central role of CD4 T cells (both regulatory and pathogenic) in mechanisms of AIH, with a focus on recent advances regarding defective regulatory mechanisms and immune profile of auto-reactive CD4 T cells. These findings may have implication for the orientation of new therapeutic strategies to treat AIH, such as regulatory T-cell infusion or targeting B cells and cytokines released by pathogenic CD4 T cells.
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Affiliation(s)
- Anaïs Cardon
- Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France
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18
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Splenectomy Prior to Experimental Induction of Autoimmune Hepatitis Promotes More Severe Hepatic Inflammation, Production of IL-17 and Apoptosis. Biomedicines 2021; 9:biomedicines9010058. [PMID: 33435354 PMCID: PMC7827897 DOI: 10.3390/biomedicines9010058] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/05/2021] [Accepted: 01/07/2021] [Indexed: 01/25/2023] Open
Abstract
Autoimmune hepatitis (AIH) is detected at a late stage in the course of the disease. Therefore, induction and etiology are largely unclear. It is controversial if the induction of autoimmunity occurs in the liver or in the spleen. In our experimental murine AIH model, the induction of autoimmunity did not occur in the spleen. Instead, a protective role of the spleen could be more likely. Therefore, we splenectomized mice followed by induction of experimental murine AIH. Splenectomized mice presented more severe portal inflammation. Furthermore, these mice had more IL-17, IL-23 receptor (IL-23R) and caspase 3 (casp3) and a decreased amount of erythropoietin in serum, while intrahepatic T cell compartments were unaffected. These results indicate that the spleen is not necessary for induction of AIH, and splenectomy disrupts the ability to immune regulate the intensity of hepatic inflammation, production of IL-17 and apoptosis.
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19
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Liu SP, Bian ZH, Zhao ZB, Wang J, Zhang W, Leung PSC, Li L, Lian ZX. Animal Models of Autoimmune Liver Diseases: a Comprehensive Review. Clin Rev Allergy Immunol 2020; 58:252-271. [PMID: 32076943 DOI: 10.1007/s12016-020-08778-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Autoimmune liver diseases (AILDs) are potentially life-threatening chronic liver diseases which include autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and recently characterized IgG4-related sclerosing cholangitis. They are caused by immune attack on hepatocytes or bile ducts, with different mechanisms and clinical manifestations. The etiologies of AILDs include a susceptible genetic background, environment insults, infections, and changes of commensal microbiota, but remain complicated. Understanding of the underlying mechanisms of AILDs is mandatory for early diagnosis and intervention, which is of great importance for better prognosis. Thus, animal models are developed to mimic the pathogenesis, find biomarkers for early diagnosis, and for therapeutic attempts of AILDs. However, no animal models can fully recapitulate features of certain AILD, especially the late stages of diseases. Certain limitations include different living condition, cell composition, and time frame of disease development and resolution. Moreover, there is no IgG4 in rodents which exists in human. Nevertheless, the understanding and therapy of AILDs have been greatly advanced by the development and mechanistic investigation of animal models. This review will provide a comprehensive overview of traditional and new animal models that recapitulate different features and etiologies of distinct AILDs.
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Affiliation(s)
- Shou-Pei Liu
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Zhen-Hua Bian
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.,School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Zhi-Bin Zhao
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Jinjun Wang
- College of Environmental Science and Engineering, Yangzhou University, Yangzhou, 225127, Jiangsu, China
| | - Weici Zhang
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Patrick S C Leung
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Liang Li
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China. .,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.
| | - Zhe-Xiong Lian
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China. .,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.
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20
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Wang H, Feng X, Yan W, Tian D. Regulatory T Cells in Autoimmune Hepatitis: Unveiling Their Roles in Mouse Models and Patients. Front Immunol 2020; 11:575572. [PMID: 33117375 PMCID: PMC7575771 DOI: 10.3389/fimmu.2020.575572] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe and chronic liver disease, and its incidence has increased worldwide in recent years. Research into the pathogenesis of AIH remains limited largely owing to the lack of suitable mouse models. The concanavalin A (ConA) mouse model is a typical and well-established model used to investigate T cell-dependent liver injury. However, ConA-induced hepatitis is acute and usually disappears after 48 h; thus, it does not mimic the pathogenesis of AIH in the human body. Several studies have explored various AIH mouse models, but as yet there is no widely accepted and valid mouse model for AIH. Immunosuppression is the standard clinical therapy for AIH, but patient side effects and recurrence limit its use. Regulatory T cells (Tregs) play critical roles in the maintenance of immune homeostasis and in the prevention of autoimmune diseases, which may provide a potential therapeutic target for AIH therapy. However, the role of Tregs in AIH has not yet been clarified, partly because of difficulties in diagnosing AIH and in collecting patient samples. In this review, we discuss the studies related to Treg in various AIH mouse models and patients with AIH and provide some novel insights for this research area.
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Affiliation(s)
- Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinxia Feng
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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21
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Henze L, Schwinge D, Schramm C. The Effects of Androgens on T Cells: Clues to Female Predominance in Autoimmune Liver Diseases? Front Immunol 2020; 11:1567. [PMID: 32849531 PMCID: PMC7403493 DOI: 10.3389/fimmu.2020.01567] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 06/15/2020] [Indexed: 12/16/2022] Open
Abstract
The immune system responds differently in women and in men. Generally speaking, adult females show stronger innate and adaptive immune responses than males. This results in lower risk of developing most of the infectious diseases and a better ability to clear viral infection in women (1–5). On the other hand, women are at increased risk of developing autoimmune diseases (AID) such as rheumatoid arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjögren's syndrome, and the autoimmune liver diseases autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) (6). Factors contributing to the female sex bias in autoimmune diseases include environmental exposure, e.g., microbiome, behavior, and genetics including X chromosomal inactivation of genes. Several lines of evidence and clinical observations clearly indicate that sex hormones contribute significantly to disease pathogenesis, and the role of estrogen in autoimmune diseases has been extensively studied. In many of these diseases, including the autoimmune liver diseases, T cells are thought to play an important pathogenetic role. We will use this mini-review to focus on the effects of androgens on T cells and how the two major androgens, testosterone and dihydrotestosterone, potentially contribute to the pathogenesis of autoimmune liver diseases (AILD).
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Affiliation(s)
- Lara Henze
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dorothee Schwinge
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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22
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Bellan M, Andreoli L, Mele C, Sainaghi PP, Rigamonti C, Piantoni S, De Benedittis C, Aimaretti G, Pirisi M, Marzullo P. Pathophysiological Role and Therapeutic Implications of Vitamin D in Autoimmunity: Focus on Chronic Autoimmune Diseases. Nutrients 2020; 12:E789. [PMID: 32192175 PMCID: PMC7146294 DOI: 10.3390/nu12030789] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 03/13/2020] [Indexed: 02/07/2023] Open
Abstract
Vitamin D is a pleiotropic secosteroid yielding multiple actions in human physiology. Besides the canonical regulatory activity on bone metabolism, several non-classical actions have been described and the ability of vitamin D to partake in the regulation of the immune system is particularly interesting, though far stronger and convincing evidence has been collected in in vitro as compared to in vivo studies. Whether vitamin D is able to regulate at physiological concentrations the human immune system remains unproven to date. Consequently, it is not established if vitamin D status is a factor involved in the pathogenesis of immune-mediated diseases and if cholecalciferol supplementation acts as an adjuvant for autoimmune diseases. The development of autoimmunity is a heterogeneous process, which may involve different organs and systems with a wide range of clinical implications. In the present paper, we reviewed the current evidences regarding vitamin D role in the pathogenesis and management of different autoimmune diseases.
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Affiliation(s)
- Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of Internal Medicine, “AOU Maggiore della Carità”, 28100 Novara, Italy
- CAAD, Centre for Autoimmune and Allergic Diseases, 28100 Novara, Italy
| | - Laura Andreoli
- Rheumatology and Clinical Immunology Unit and Department of Clinical and Experimental Sciences, Spedali Civili and University of Brescia, 25128 Brescia, Italy; (L.A.); (S.P.)
| | - Chiara Mele
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
| | - Pier Paolo Sainaghi
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of Internal Medicine, “AOU Maggiore della Carità”, 28100 Novara, Italy
- CAAD, Centre for Autoimmune and Allergic Diseases, 28100 Novara, Italy
| | - Cristina Rigamonti
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of Internal Medicine, “AOU Maggiore della Carità”, 28100 Novara, Italy
- CAAD, Centre for Autoimmune and Allergic Diseases, 28100 Novara, Italy
| | - Silvia Piantoni
- Rheumatology and Clinical Immunology Unit and Department of Clinical and Experimental Sciences, Spedali Civili and University of Brescia, 25128 Brescia, Italy; (L.A.); (S.P.)
| | - Carla De Benedittis
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of Internal Medicine, “AOU Maggiore della Carità”, 28100 Novara, Italy
- CAAD, Centre for Autoimmune and Allergic Diseases, 28100 Novara, Italy
| | - Gianluca Aimaretti
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of Internal Medicine, “AOU Maggiore della Carità”, 28100 Novara, Italy
- CAAD, Centre for Autoimmune and Allergic Diseases, 28100 Novara, Italy
| | - Paolo Marzullo
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of General Medicine, Ospedale S. Giuseppe, I.R.C.C.S. Istituto Auxologico Italiano, 28921 Verbania, Italy
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23
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Christen U. Breakdown of tolerance in autoimmune hepatitis: This time toxin beats virus. Immunol Lett 2020; 218:51-53. [DOI: 10.1016/j.imlet.2019.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 10/25/2022]
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24
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Dywicki J, Buitrago-Molina LE, Pietrek J, Lieber M, Broering R, Khera T, Schlue J, Manns MP, Wedemeyer H, Jaeckel E, Hardtke-Wolenski M. Autoimmune hepatitis induction can occur in the liver. Liver Int 2020; 40:377-381. [PMID: 31724273 DOI: 10.1111/liv.14296] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 10/16/2019] [Accepted: 10/17/2019] [Indexed: 12/11/2022]
Abstract
The priming of T cells in the liver is widely accepted. Nonetheless, it is controversial whether immune activation in autoimmune hepatitis (AIH) occurs in the liver or in the spleen. To address this issue, we splenectomized mice and induced experimental murine AIH (emAIH) with an adenovirus (Ad)-expressing formiminotransferase cyclodeaminase (FTCD). Post-splenectomy, the experimental mice developed emAIH to a higher extent than the control mice. In addition, splenectomized mice harboured more intrahepatic B cells and a disproportionately small number of regulatory T cells (Tregs) within a reduced T cell population at the site of inflammation. These results imply that the spleen is not the site of AIH induction. In contrast, the spleen seems to have a protective function since the pathological score was more severe in splenectomized animals. These findings have important implications for the aetiology of AIH.
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Affiliation(s)
- Janine Dywicki
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Laura Elisa Buitrago-Molina
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Julia Pietrek
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Maren Lieber
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Tanvi Khera
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Jerome Schlue
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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25
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Chi G, Pei JH, Ma QY, Ru YX, Feng ZH. Chemical induced inflammation of the liver breaks tolerance and results in autoimmune hepatitis in Balb/c mice. Immunol Lett 2019; 218:44-50. [PMID: 31794800 DOI: 10.1016/j.imlet.2019.11.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 11/10/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease mediated by immunity, and could lead to liver fibrosis and hepatocellular carcinoma. However, the mechanisms for breaking hepatic tolerance and driving AIH still remain elusive. We herein reported that the non-specific liver inflammation triggered by carbon tetrachloride (CCl4) recruited high numbers of CD4+T, CD8+T and B cells, and elevated the expression of proinflammaitory cytokines in Balb/c mice, further breaking liver tolerance and inducing autoimmune response, AIH inflammation and liver fibrosis in the presence of CYP2D6 antigen mimicry. In contrast, adenovirus infection could not break liver tolerance and induce AIH in Balb/c mice even in the presence of CYP2D6 antigen mimicry. These results suggested that genetic predisposition could determine liver tolerance in Balb/c mice. The chemical induced inflammation in the liver breaks tolerance and might be considered important for the initiation and development of AIH in Balb/c mice.
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Affiliation(s)
- Gang Chi
- Department of Biochemistry, Changzhi Medical College, Changzhi, Shanxi 046000, China.
| | - Jin-Hong Pei
- Department of Biochemistry, Changzhi Medical College, Changzhi, Shanxi 046000, China
| | - Qin-Ya Ma
- DNA Laboratory, Changzhi Public Security Bureau, Changzhi, Shanxi 046000, China
| | - Ying-Xia Ru
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China
| | - Zuo-Hua Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China.
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26
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Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME. Cellular and Molecular Mechanisms of Autoimmune Hepatitis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:247-292. [PMID: 29140756 DOI: 10.1146/annurev-pathol-020117-043534] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.
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Affiliation(s)
- G J Webb
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - G M Hirschfield
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - E L Krawitt
- Department of Medicine, University of Vermont, Burlington, Vermont 05405, USA; .,Department of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA
| | - M E Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, California 95817, USA;
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27
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Sciveres M, Nastasio S, Maggiore G. Novel Diagnostic and Therapeutic Strategies in Juvenile Autoimmune Hepatitis. Front Pediatr 2019; 7:382. [PMID: 31616649 PMCID: PMC6763601 DOI: 10.3389/fped.2019.00382] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022] Open
Abstract
Juvenile autoimmune hepatitis (JAIH) is a rare, chronic, inflammatory disease of the liver characterized by a complex interaction between genetic, immunological, and environmental factors leading to loss of immunotolerance to hepatic antigens. It affects both children and adolescents, most commonly females, and its clinical manifestations are quite variable. JAIH is progressive in nature and if left untreated may lead to cirrhosis and terminal liver failure. Although JAIH was first described almost 50 years ago, there have been few significant advances in the clinical management of these patients, both in terms of available diagnostic tools and therapeutic options. Aminotransferase activity, class G immunoglobulins and autoantibodies are the biomarkers used to diagnose AIH and monitor treatment response alongside clinical and histological findings. Despite their utility and cost-effectiveness, these biomarkers are neither an accurate expression of AIH pathogenic mechanism nor a precise measure of treatment response. Current standard of care is mainly based on the administration of steroids and azathioprine. This combination of drugs has been proven effective in inducing remission of disease in the majority of patients dramatically improving their survival; however, it not only fails to restore tolerance to hepatic autoantigens, but it also does not halt disease progression in some patients, it is often needed life-long and finally, it has deleterious side-effects. The ideal therapy should be enough selective to contrast immune-mediated live damage while preserving or potentiating the ability to develop permanent tolerance vs. pathogenic autoantigens. By reviewing the state of the art literature, this article highlights novel diagnostic and therapeutic strategies for managing pediatric AIH with a special focus on new strategies of immunotherapy. These promising tools could improve the diagnostic algorithm, more accurately predict disease prognosis, and provide targeted, individualized treatment.
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Affiliation(s)
- Marco Sciveres
- Pediatric Hepatology and Liver Transplantation, ISMETT-University of Pittsburgh Medical Center Italy, Palermo, Italy
| | - Silvia Nastasio
- Division of Gastroenterology, Hepatology, and Nutrition, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Giuseppe Maggiore
- Pediatric Hepatology and Liver Transplantation, ISMETT-University of Pittsburgh Medical Center Italy, Palermo, Italy.,Section of Pediatrics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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28
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Floreani A, Restrepo-Jiménez P, Secchi MF, De Martin S, Leung PS, Krawitt E, Bowlus CL, Gershwin ME, Anaya JM. Etiopathogenesis of autoimmune hepatitis. J Autoimmun 2018; 95:133-143. [DOI: 10.1016/j.jaut.2018.10.020] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/18/2018] [Accepted: 10/22/2018] [Indexed: 12/13/2022]
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29
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Taubert R, Diestelhorst J, Junge N, Kirstein MM, Pischke S, Vogel A, Bantel H, Baumann U, Manns MP, Wedemeyer H, Jaeckel E. Increased seroprevalence of HAV and parvovirus B19 in children and of HEV in adults at diagnosis of autoimmune hepatitis. Sci Rep 2018; 8:17452. [PMID: 30487523 PMCID: PMC6261942 DOI: 10.1038/s41598-018-35882-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 11/13/2018] [Indexed: 12/13/2022] Open
Abstract
Preceding viral infections have mostly been described in autoimmune hepatitis (AIH) in single cases. We aimed to identify viral infections that potentially trigger AIH, as suggested for hepatitis E virus (HEV) infections. Therefore, antibodies against hepatitis A (HAV), B, C and E viruses; hepatotropic herpesviruses; and parvovirus B19 (PVB19) were analyzed retrospectively in 219 AIH patients at diagnosis, 356 patients with other liver diseases and 89 children from our center. Untreated adult AIH (aAIH) patients showed higher anti-HEV seroprevalences at diagnosis than patients with other liver diseases. Untreated aAIH patients had no increased incidence of previous hepatitis A, B or C. Antibodies against hepatotropic herpesviruses in untreated AIH were in the range published for the normal population. Untreated pediatric AIH (pAIH) patients had evidence of more previous HAV and PVB19 infections than local age-matched controls. The genetic AIH risk factor HLA DRB1*03:01 was more frequent in younger patients, and DRB1*04:01 was more frequent in middle-aged patients without an obvious link to virus seropositivities. Pediatric and adult AIH seem to be distinct in terms of genetic risk factors and preceding viral infections. While associations cannot prove causal relations, the results suggest that hepatotropic virus infections could be involved in AIH pathogenesis.
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Affiliation(s)
- Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Jana Diestelhorst
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Norman Junge
- Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Martha M Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Sven Pischke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heike Bantel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ulrich Baumann
- Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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30
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Christen U. Animal models of autoimmune hepatitis. Biochim Biophys Acta Mol Basis Dis 2018; 1865:970-981. [PMID: 29857050 DOI: 10.1016/j.bbadis.2018.05.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 05/14/2018] [Accepted: 05/22/2018] [Indexed: 02/06/2023]
Abstract
Many animal models for autoimmune hepatitis (AIH) have been described in the past. Most models had to deal with the relative immunosuppressive environment of the liver. Therefore, some models used a combination of several triggering factors often on a susceptible background to generate an aggressive immune response that targets the liver. In addition, in order to be able to track the immune response the models used specific model autoantigens as targets that are either not present or have not been identified as a natural autoantigen in AIH patients. Thereby the feasibility of such models is somewhat questionable. Although many historic approaches included challenges of experimental animals with liver homogenates it was only in the last decade that natural occurring liver autoantigens have been used in animal models. This article reflects on the requirements for breaking liver tolerance and on how an ideal experimental model for AIH would look like. In addition, it discusses historic as well as recent animal models in the context of feasibility of induction, similarity of the clinical outcome to human AIH, and gain of knowledge for possible future therapies.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany.
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31
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Abstract
Autoimmune disorders are characterized by a loss of immune tolerance and consequent autoimmunity-mediated disease manifestation. Experimental models are invaluable research tools helping us to understand disease pathogenesis and to search for novel therapeutics. Animal models of autoimmune diseases consist of two groups, spontaneous and induced models. In this review article, we focus on the induced models of autoimmune diseases. Due to the complex nature of autoimmune disorders, many strategies have been applied for the induction of corresponding experimental models in animals like monkeys, rabbits, rats, and mice. Methodologically, these strategies can be categorized into three categories, namely immunization with autoantigen, transfer of autoimmunity, and induction by environmental factors. In this review article, we aim to provide a comprehensive overview of the field of induced experimental autoimmune diseases. On the one hand, we describe and summarize the different strategies used for induction of experimental autoimmune disease. On the other hand, we discuss how to select a strategy for modeling human disease, including the choice of an appropriate species and method for such an approach.
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Affiliation(s)
- Xinhua Yu
- Research Center Borstel, Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), 23845 Borstel, Germany; Xiamen-Borstel Joint Laboratory of Autoimmunity, Medical College of Xiamen University, Xiamen, 361102, China.
| | - Frank Petersen
- Research Center Borstel, Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), 23845 Borstel, Germany
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32
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Czaja AJ. Review article: next-generation transformative advances in the pathogenesis and management of autoimmune hepatitis. Aliment Pharmacol Ther 2017; 46:920-937. [PMID: 28901565 DOI: 10.1111/apt.14324] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 08/01/2017] [Accepted: 08/25/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Advances in autoimmune hepatitis that transform current concepts of pathogenesis and management can be anticipated as products of ongoing investigations driven by unmet clinical needs and an evolving biotechnology. AIM To describe the advances that are likely to become transformative in autoimmune hepatitis, based on the direction of current investigations. METHODS Pertinent abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and a secondary bibliography was developed. The discovery process was repeated, and a tertiary bibliography was identified. The number of abstracts reviewed was 2830, and the number of full-length articles reviewed exceeded 150. RESULTS Risk-laden allelic variants outside the major histocompatibility complex (rs3184504, r36000782) are being identified by genome-wide association studies, and their gene products are potential therapeutic targets. Epigenetic changes associated with environmental cues can enhance the transcriptional activity of genes, and chromatin re-structuring and antagonists of noncoding molecules of ribonucleic acid are feasible interventions. The intestinal microbiome is a discovery field for microbial products and activated immune cells that may translocate to the periphery and respond to manipulation. Epidemiological studies and controlled interview-based surveys may implicate environmental and xenobiotic factors that warrant evidence-based changes in lifestyle, and site-directed molecular and cellular interventions promise to change the paradigm of treatment from one of blanket immunosuppression. CONCLUSIONS Advances in genetics, epigenetics, pathophysiology, epidemiology, and site-directed molecular and cellular interventions constitute the next generation of transformative advances in autoimmune hepatitis.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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33
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The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development. J Autoimmun 2017; 78:39-45. [DOI: 10.1016/j.jaut.2016.12.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 11/07/2016] [Accepted: 12/04/2016] [Indexed: 12/31/2022]
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34
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Cassim S, Bilodeau M, Vincent C, Lapierre P. Novel Immunotherapies for Autoimmune Hepatitis. Front Pediatr 2017; 5:8. [PMID: 28184367 PMCID: PMC5266689 DOI: 10.3389/fped.2017.00008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 01/10/2017] [Indexed: 12/23/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a multifactorial autoimmune disease of unknown pathogenesis, characterized by a loss of immunological tolerance against liver autoantigens resulting in the progressive destruction of the hepatic parenchyma. Current treatments are based on non-specific immunosuppressive drugs. Although tremendous progress has been made using specific biological agents in other inflammatory diseases, progress has been slow to come for AIH patients. While current treatments are successful in the majority of patients, treatment discontinuation is difficult to achieve, and relapses are frequent. Lifelong immunosuppression is not without risks, especially in the pediatric population; 4% of patient with type 1 AIH will eventually develop hepatocellular carcinoma with a 2.9% probability after 10 years of treatment. Therefore, future treatments should aim to restore tolerance to hepatic autoantigens and induce long-term remission. Promising new immunotherapies have been tested in experimental models of AIH including T and B cell depletion and regulatory CD4+ T cells infusion. Clinical studies on limited numbers of patients have also shown encouraging results using B-cell-depleting (rituximab) and anti-TNF-α (infliximab) antibodies. A better understanding of key molecular targets in AIH combined with effective site-specific immunotherapies could lead to long-term remission without blanket immunosuppression and with minimal deleterious side effects.
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Affiliation(s)
- Shamir Cassim
- Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada
| | - Marc Bilodeau
- Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada; Département de médecine, Université de Montréal, Montréal, QC, Canada
| | - Catherine Vincent
- Département de médecine, Université de Montréal , Montréal, QC , Canada
| | - Pascal Lapierre
- Laboratoire d'hépatologie cellulaire, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada; Département de médecine, Université de Montréal, Montréal, QC, Canada
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35
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Christen U, Hintermann E. Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models? Int J Mol Sci 2016; 17:ijms17122007. [PMID: 27916939 PMCID: PMC5187807 DOI: 10.3390/ijms17122007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/22/2016] [Accepted: 11/23/2016] [Indexed: 12/14/2022] Open
Abstract
Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel therapeutic strategies has been hampered by a lack of understanding the basic immunopathogenic mechanisms of AIH and the absence of valid animal models. However, in the past decade, knowledge from clinical observations in AIH patients and the development of innovative animal models have led to a situation where critical factors driving the disease have been identified and alternative treatments are being evaluated. Here we will review the insight on the immunopathogenesis of AIH as gained from clinical observation and from animal models.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
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36
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Montano-Loza AJ, Thandassery RB, Czaja AJ. Targeting Hepatic Fibrosis in Autoimmune Hepatitis. Dig Dis Sci 2016; 61:3118-3139. [PMID: 27435327 DOI: 10.1007/s10620-016-4254-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 07/11/2016] [Indexed: 02/06/2023]
Abstract
Hepatic fibrosis develops or progresses in 25 % of patients with autoimmune hepatitis despite corticosteroid therapy. Current management regimens lack reliable noninvasive methods to assess changes in hepatic fibrosis and interventions that disrupt fibrotic pathways. The goals of this review are to indicate promising noninvasive methods to monitor hepatic fibrosis in autoimmune hepatitis and identify anti-fibrotic interventions that warrant evaluation. Laboratory methods can differentiate cirrhosis from non-cirrhosis, but their accuracy in distinguishing changes in histological stage is uncertain. Radiological methods include transient elastography, acoustic radiation force impulse imaging, and magnetic resonance elastography. Methods based on ultrasonography are comparable in detecting advanced fibrosis and cirrhosis, but their performances may be compromised by hepatic inflammation and obesity. Magnetic resonance elastography has excellent performance parameters for all histological stages in diverse liver diseases, is uninfluenced by inflammatory activity or body habitus, has been superior to other radiological methods in nonalcoholic fatty liver disease, and may emerge as the preferred instrument to evaluate fibrosis in autoimmune hepatitis. Promising anti-fibrotic interventions are site- and organelle-specific agents, especially inhibitors of nicotinamide adenine dinucleotide phosphate oxidases, transforming growth factor beta, inducible nitric oxide synthase, lysyl oxidases, and C-C chemokine receptors types 2 and 5. Autoimmune hepatitis has a pro-fibrotic propensity, and noninvasive radiological methods, especially magnetic resonance elastography, and site- and organelle-specific interventions, especially selective antioxidants and inhibitors of collagen cross-linkage, may emerge to strengthen current management strategies.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - Ragesh B Thandassery
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
| | - Albert J Czaja
- Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN, 55905, USA.
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Liberal R, Mieli-Vergani G, Vergani D. Contemporary issues and future directions in autoimmune hepatitis. Expert Rev Gastroenterol Hepatol 2016; 10:1163-1174. [PMID: 27215278 DOI: 10.1080/17474124.2016.1193004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Autoimmune hepatitis (AIH) is a severe life-threatening hepatopathy of unknown etiology, affecting both pediatric and adult populations, and characterised by inflammatory liver histology, circulating non-organ-specific autoantibodies, and hypergammaglobulinaemia. AIH is a very heterogeneous disease with a variety of clinical presentations, ranging from asymptomatic liver test abnormalities to acute severe hepatitis or even acute liver failure. It responds very well to immunosuppressive treatment with prednisolone with or without azathioprine. Patients who are intolerant or fail to respond to standard therapy are candidates for alternative immunosuppressive regimens, the combination of steroids with mycophenolate mofetil or calcineurin inhibitors being the most frequently reported. The pathogenesis of AIH remains not completely understood, although there is evidence that genetic predisposition, molecular mimicry and defective immunoregulatory mechanisms contribute to the autoimmune liver damage. Areas covered: A literature search was conducted using the key-words 'autoimmune hepatitis', 'immunogenetics', 'regulatory T-cells' and 'immunosuppression'. The aim of this review is to discuss recent breakthroughs in the understanding AIH pathogenesis, diagnosis and treatment. Expert commentary: Progress in the understanding of AIH pathogenesis is likely to contribute to the development of novel therapeutic strategies, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells.
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Affiliation(s)
- Rodrigo Liberal
- a Institute of Liver Studies and Paediatric Liver, GI & Nutrition Centre , King's College Hospital , London , UK
| | - Giorgina Mieli-Vergani
- a Institute of Liver Studies and Paediatric Liver, GI & Nutrition Centre , King's College Hospital , London , UK
| | - Diego Vergani
- a Institute of Liver Studies and Paediatric Liver, GI & Nutrition Centre , King's College Hospital , London , UK
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Gil-Farina I, Di Scala M, Salido E, López-Franco E, Rodríguez-García E, Blasi M, Merino J, Aldabe R, Prieto J, Gonzalez-Aseguinolaza G. Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis. THE JOURNAL OF IMMUNOLOGY 2016; 197:2145-2156. [DOI: 10.4049/jimmunol.1600228] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Abstract
The etiopathogenesis of autoimmune hepatitis (AIH) remains poorly understood. In this study, we sought to develop an animal model of human AIH to gain insight into the immunological mechanisms driving this condition. C57BL/6 mice were i.v. injected with adeno-associated viral vectors encoding murine IL-12 or luciferase under the control of a liver-specific promoter. Organ histology, response to immunosuppressive therapy, and biochemical and immunological parameters, including Ag-specific humoral and cellular response, were analyzed. Mechanistic studies were carried out using genetically modified mice and depletion of lymphocyte subpopulations. Adeno-associated virus IL-12–treated mice developed histological, biochemical, and immunological changes resembling type 1 AIH, including marked and persistent liver mononuclear cell infiltration, hepatic fibrosis, hypergammaglobulinemia, anti-nuclear and anti–smooth muscle actin Abs, and disease remission with immunosuppressive drugs. Interestingly, transgenic IL-12 was short-lived, but endogenous IL-12 expression was induced, and both IL-12 and IFN-γ remained elevated during the entire study period. IFN-γ was identified as an essential mediator of liver damage, and CD4 and CD8 T cells but not NK, NKT, or B cells were essential executors of hepatic injury. Furthermore, both MHC class I and MHC class II expression was upregulated at the hepatocellular membrane, and induction of autoreactive liver-specific T cells was detected. Remarkably, although immunoregulatory mechanisms were activated, they only partially mitigated liver damage. Thus, low and transient expression of transgenic IL-12 in hepatocytes causes loss of tolerance to hepatocellular Ags, leading to chronic hepatitis resembling human AIH type 1. This model provides a practical tool to explore AIH pathogenesis and novel therapies.
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Affiliation(s)
- Irene Gil-Farina
- *Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain
| | - Marianna Di Scala
- *Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain
| | - Eduardo Salido
- †Unidad de Investigación Mixta Hospital Universitario de Canarias–Universidad de La Laguna, Facultad de Medicina, Universidad de La Laguna, 38071 Santa Cruz de Tenerife, Spain; and
| | - Esperanza López-Franco
- *Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain
| | - Estefania Rodríguez-García
- *Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain
| | - Mercedes Blasi
- *Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain
| | - Juana Merino
- ‡University Clinic of Navarra, University of Navarra, 31008 Pamplona, Spain
| | - Rafael Aldabe
- *Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain
| | - Jesús Prieto
- *Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain
- ‡University Clinic of Navarra, University of Navarra, 31008 Pamplona, Spain
| | - Gloria Gonzalez-Aseguinolaza
- *Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra, 31008 Pamplona, Spain
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Yuksel M, Xiao X, Tai N, Vijay M, Gülden E, Beland K, Lapierre P, Alvarez F, Hu Z, Colle I, Ma Y, Wen L. The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model. Clin Exp Immunol 2016; 186:164-176. [PMID: 27414259 DOI: 10.1111/cei.12843] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2016] [Indexed: 12/17/2022] Open
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 Tregs from 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 Tregs and 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.
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Affiliation(s)
- M Yuksel
- 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
| | - X Xiao
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.,Department of Nephrology, Qilu Hospital, Shandong University, China
| | - N Tai
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
| | - Manakkat Vijay
- 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
| | - E Gülden
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
| | - K Beland
- Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada
| | - P Lapierre
- Immunovirology Laboratory, Institut National De La Recherche Scientifique, INRS-Institut Armand-Frappier, Laval, Québec, Canada
| | - F Alvarez
- Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada
| | - Z Hu
- Department of Nephrology, Qilu Hospital, Shandong University, China
| | - I Colle
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium
| | - Y Ma
- Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK
| | - L Wen
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.
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40
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Liberal R, Krawitt EL, Vierling JM, Manns MP, Mieli-Vergani G, Vergani D. Cutting edge issues in autoimmune hepatitis. J Autoimmun 2016; 75:6-19. [PMID: 27502148 DOI: 10.1016/j.jaut.2016.07.005] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 07/06/2016] [Accepted: 07/10/2016] [Indexed: 12/14/2022]
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease affecting all age groups worldwide. Novel basic and clinical aspects of AIH, addressed at a Monothematic Conference in London in September 2015, are highlighted in this review. The diagnosis of AIH relies upon detection of characteristic autoantibodies, hypergammaglobulinemia, and interface hepatitis on liver histology. The International Autoimmune Hepatitis Group (IAIHG) has devised diagnostic scoring systems to help in comparative studies and clinical practice. AIH arises in a genetically predisposed host, when yet unknown triggers - such an encounter with a pathogen - lead to a T cell-mediated immune response targeting liver autoantigens. This immune response is inadequately controlled because regulatory mechanisms are impaired. The mainstay of treatment for AIH is immunosuppression, which should be instituted as soon as the diagnosis is made. Standard treatment regimens include relatively high doses of predniso(lo)ne, which are tapered gradually as azathioprine is introduced. Recent guidelines have described newer treatment regimens and have tightened the goal of therapy to complete normalization of biochemical, serological and histological parameters. Mycophenolate mofetil, calcineurin inhibitors, mTOR inhibitors and biological agents are potential salvage therapies, but should be reserved for selected non-responsive patients and administered only in experienced centers. Liver transplantation is a life-saving option for those patients who progress to end-stage liver disease. Further dissection of cellular and molecular pathways involved in AIH pathogenesis is likely to lead to the discovery of novel, tailored and better tolerated therapies.
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Affiliation(s)
- Rodrigo Liberal
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Edward L Krawitt
- Department of Medicine, Dartmouth College, Hanover, NH, USA; Department of Medicine, University of Vermont, Burlington, VT, USA
| | - John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, TX, USA
| | | | - Giorgina Mieli-Vergani
- Institute of Liver Studies, King's College Hospital, London, UK; Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - Diego Vergani
- Institute of Liver Studies, King's College Hospital, London, UK.
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41
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Shumyak S, Yang LJ, Han S, Zhuang H, Reeves WH. "Lupoid hepatitis" in SLE patients and mice with experimental lupus. Clin Immunol 2016; 172:65-71. [PMID: 27430519 DOI: 10.1016/j.clim.2016.07.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 07/10/2016] [Indexed: 12/17/2022]
Abstract
The unusual subset of patients with severe hepatitis, hypergammaglobulinemia, arthritis, and LE cells in the blood reported by Henry Kunkel and others suggested to these investigators that "lupoid" hepatitis might share pathogenic mechanisms with SLE. More than half a century later, the etiology of autoimmune hepatitis remains unclear. The occurrence of autoimmune hepatitis in a small fraction (about 3%) of SLE patients in our lupus cohort and in two mouse models of SLE supports their conclusion that lupoid hepatitis may be share pathogenic mechanisms with SLE. The development of autoimmune hepatitis in mice with pristane-induced lupus provides an opportunity to further explore the potential link between these two autoimmune disorders.
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Affiliation(s)
- Stepan Shumyak
- Division of Rheumatology & Clinical Immunology, University of Florida, Gainesville, FL 32610. United States
| | - Li-Jun Yang
- Department of Pathology, Immunology, & Laboratory Medicine, University of Florida, Gainesville, FL 32610. United States
| | - Shuhong Han
- Division of Rheumatology & Clinical Immunology, University of Florida, Gainesville, FL 32610. United States
| | - Haoyang Zhuang
- Division of Rheumatology & Clinical Immunology, University of Florida, Gainesville, FL 32610. United States
| | - Westley H Reeves
- Division of Rheumatology & Clinical Immunology, University of Florida, Gainesville, FL 32610. United States.
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Yuksel M, Wang Y, Tai N, Peng J, Guo J, Beland K, Lapierre P, David C, Alvarez F, Colle I, Yan H, Mieli-Vergani G, Vergani D, Ma Y, Wen L. A novel "humanized mouse" model for autoimmune hepatitis and the association of gut microbiota with liver inflammation. Hepatology 2015; 62:1536-50. [PMID: 26185095 PMCID: PMC4763614 DOI: 10.1002/hep.27998] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 07/15/2015] [Indexed: 12/24/2022]
Abstract
UNLABELLED 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. CONCLUSION 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.
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Affiliation(s)
- Muhammed Yuksel
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
- Laboratory of Hepatology and Gastroenterology, Ghent University, Belgium
- Institute of Liver Studies, King’s College London Faculty of Life Sciences and Medicine at King’s College Hospital, London, UK
| | - Yipeng Wang
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
- Clinical Research Centre for Autoimmune Liver Disease, Beijing You-an Hospital, Capital Medical University, Beijing, China
| | - Ningwen Tai
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
| | - Jian Peng
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
| | - Junhua Guo
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
- Department of Rheumatology, PLA General Hospital, Beijing, China
| | - Kathie Beland
- Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada
| | - Pascal Lapierre
- Immunovirology Laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Québec, Canada
| | - Chella David
- Department of Immunology, Mayo Clinic, Minnesota, USA
| | - Fernando Alvarez
- Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada
| | - Isabelle Colle
- Laboratory of Hepatology and Gastroenterology, Ghent University, Belgium
| | - Huiping Yan
- Clinical Research Centre for Autoimmune Liver Disease, Beijing You-an Hospital, Capital Medical University, Beijing, China
| | - Giorgina Mieli-Vergani
- Institute of Liver Studies, King’s College London Faculty of Life Sciences and Medicine at King’s College Hospital, London, UK
| | - Diego Vergani
- Institute of Liver Studies, King’s College London Faculty of Life Sciences and Medicine at King’s College Hospital, London, UK
| | - Yun Ma
- Institute of Liver Studies, King’s College London Faculty of Life Sciences and Medicine at King’s College Hospital, London, UK
| | - Li Wen
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
- Corresponding author: Li Wen, Section of Endocrinology, Yale University School of Medicine, Mail Box-208020, New Haven, CT-06520, USA, Tel: 203-785-7186, Fax: 203-737-5558,
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43
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Béland K, Marceau G, Labardy A, Bourbonnais S, Alvarez F. Depletion of B cells induces remission of autoimmune hepatitis in mice through reduced antigen presentation and help to T cells. Hepatology 2015; 62:1511-23. [PMID: 26175263 DOI: 10.1002/hep.27991] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 07/13/2015] [Indexed: 12/25/2022]
Abstract
UNLABELLED Autoimmune hepatitis (AIH) is known as a T cell-mediated disease. However, AIH patients refractory to conventional treatment have been successfully treated with anti-CD20-mediated B-cell depletion. The aim of this project was to understand the immunological changes underlying the AIH remission caused by B-cell depletion in an experimental model of AIH. C57BL/6 AIH mice, xenoimmunized with DNA coding for human liver antigens, were treated with a single dose of depleting mouse anti-CD20 antibody at the peak of liver inflammation. Liver inflammation, alanine aminotransferase levels, chemokine (C-X-C) ligand 10 expression, and circulating B-cell, autoantibody, and total immunoglobulin G levels were monitored following depletion. T-cell and B-cell phenotype and function were characterized. Administration of a single dose of anti-CD20 resulted in a drastic reduction of liver inflammation accompanied by a significant reduction of alanine aminotransferase levels and of proinflammatory chemokine (C-X-C) ligand 10 expression. The treatment did not result in significant changes in total immunoglobulin G levels or autoantibodies. There were significantly more naive and less antigen-experienced CD4+ and CD8+ T cells, and T-cell proliferation was significantly reduced following anti-CD20 treatment. B cells served as antigen-presenting cells to CD4+ T cells. Anti-CD20 treatment also led to a profound reduction of T follicular helper cells. CONCLUSION B cells play an active role in the pathogenesis of AIH in antigen presentation processes and the modulation of T-cell functions and influence the T follicular helper-cell population; this active role of B cells could explain the success of B-cell depletion for remission of AIH despite its classification as a T cell-mediated autoimmune liver disease.
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Affiliation(s)
- Kathie Béland
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, QC, Canada
| | - Gabriel Marceau
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, QC, Canada
| | - Agathe Labardy
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, QC, Canada
| | - Sara Bourbonnais
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, QC, Canada
| | - Fernando Alvarez
- Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, QC, Canada.,Microbiology and Immunology Department.,Department of Pediatrics, University of Montreal, Montreal, QC, Canada
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44
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Hua Y, Lu P, Ji JL, Shao JG, Wang LJ. Transgenic animal models of type 2 autoimmune hepatitis. Shijie Huaren Xiaohua Zazhi 2015; 23:4652-4657. [DOI: 10.11569/wcjd.v23.i29.4652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease putatively caused by loss of tolerance to hepatocyte specific autoantigens. It is currently divided into types 1 and 2, based on the expression of autoantibodies. Autoantigenic epitopes have been identified only for the less frequent type 2 AIH. Many type 2 AIH mouse models have been well developed in recent years. This review focuses on some kinds of well-established type 2 AIH mouse models.
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Czaja AJ. Transitioning from Idiopathic to Explainable Autoimmune Hepatitis. Dig Dis Sci 2015; 60:2881-900. [PMID: 25999246 DOI: 10.1007/s10620-015-3708-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 05/06/2015] [Indexed: 02/08/2023]
Abstract
Autoimmune hepatitis lacks an identifiable cause, and its diagnosis requires the exclusion of etiologically defined diseases that resemble it. Insights into its pathogenesis are moving autoimmune hepatitis from an idiopathic to explainable disease, and the goal of this review is to describe the insights that are hastening this transition. Two types of autoimmune hepatitis are justified by serological markers, but they also have distinctive genetic associations (DRB1 and DQB1 genes) and autoantigens. DRB1 alleles are the principal susceptibility factors in white adults, and a six amino acid sequence encoded in the antigen-binding groove of class II molecules of the major histocompatibility complex can influence the selection of autoantigens. Polymorphisms, including variants of SH2B3 and CARD10 genes, may affect immune reactivity and disease severity. The cytochrome mono-oxygenase, CYP2D6, is the autoantigen associated with type 2 autoimmune hepatitis, and it shares homologies with multiple viruses that might promote self-intolerance by molecular mimicry. Chemokines, especially CXCL9 and CXCL10, orchestrate the migration of effector cells to sites of injury and are associated with disease severity. Cells of the innate and adaptive immune responses promote tissue damage, and possible deficiencies in the number and function of regulatory T cells may facilitate the injurious process. Receptor-mediated apoptosis is the principal mechanism of hepatocyte loss, and cell-mediated and antibody-dependent mechanisms of cytotoxicity also contribute. Insights that explain autoimmune hepatitis will allow triggering exogenous antigens to be characterized, risk management to be improved, prognostic indices to be refined, and site-specific therapeutic interventions to emerge.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN, 55905, USA.
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Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis. J Immunol Res 2015; 2015:479703. [PMID: 26106627 PMCID: PMC4464004 DOI: 10.1155/2015/479703] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 05/21/2015] [Indexed: 12/26/2022] Open
Abstract
In both autoimmune liver disease and chronic viral hepatitis, the injury results from an immune-mediated cytotoxic T cell response to liver cells. As such, it is not surprising that CD4(+) regulatory T cells, a key regulatory population of T cells able to curb immune responses, could be involved in both autoimmune hepatitis and chronic viral hepatitis. The liver can induce the conversion of naïve CD4(+) T cells to CD4(+) regulatory T cells and induce tolerance to locally expressed antigens. This tolerance mechanism is carefully regulated in physiological conditions but any imbalance could be pathological. An overly tolerant immune response can lead to chronic infections while an overreactive and unbridled immune response can lead to autoimmune hepatitis. With the recent advent of monoclonal antibodies able to target regulatory T cells (daclizumab) and improve immune responses and several ongoing clinical trials analysing the impact of regulatory T cell infusion on autoimmune liver disease or liver transplant tolerance, modulation of immunological tolerance through CD4(+) regulatory T cells could be a key element of future immunotherapies for several liver diseases allowing restoring the balance between proper immune responses and tolerance. .
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Hardtke-Wolenski M, Taubert R, Noyan F, Sievers M, Dywicki J, Schlue J, Falk CS, Ardesjö Lundgren B, Scott HS, Pich A, Anderson MS, Manns MP, Jaeckel E. Autoimmune hepatitis in a murine autoimmune polyendocrine syndrome type 1 model is directed against multiple autoantigens. Hepatology 2015; 61:1295-305. [PMID: 25475693 DOI: 10.1002/hep.27639] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Accepted: 12/02/2014] [Indexed: 12/16/2022]
Abstract
UNLABELLED 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. CONCLUSION 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.
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Affiliation(s)
- Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Alexandropoulos K, Bonito AJ, Weinstein EG, Herbin O. Medullary thymic epithelial cells and central tolerance in autoimmune hepatitis development: novel perspective from a new mouse model. Int J Mol Sci 2015; 16:1980-2000. [PMID: 25603179 PMCID: PMC4307344 DOI: 10.3390/ijms16011980] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 01/07/2015] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease.
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Affiliation(s)
- Konstantina Alexandropoulos
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA.
| | - Anthony J Bonito
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA.
| | - Erica G Weinstein
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA
| | - Olivier Herbin
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA.
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Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN. Autoimmune hepatitis, one disease with many faces: Etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol 2015; 21:60-83. [PMID: 25574080 PMCID: PMC4284362 DOI: 10.3748/wjg.v21.i1.60] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 10/30/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is an unresolving progressive liver disease of unknown etiology characterized by hypergammaglobulinemia, autoantibodies detection and interface hepatitis. Due to the absence of specific diagnostic markers and the large heterogeneity of its clinical, laboratory and histological features, AIH diagnosis may be potentially difficult. Therefore, in this in-depth review we summarize the substantial progress on etiopathogenesis, clinical, serological and histological phenotypes of AIH. AIH has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations vary from asymptomatic to severe or rarely fulminant hepatitis. Hypergammaglobulinemia with selective elevation of IgG is found in most cases. Autoimmune attack is perpetuated, possibly via molecular mimicry, and favored by the impaired control of T-regulatory cells. Histology (interface hepatitis, emperipolesis and hepatic rosette formation) and autoantibodies detection although not pathognomonic, are still the hallmark for a timely diagnosis. AIH remains a major diagnostic challenge. AIH should be considered in every case in the absence of viral, metabolic, genetic and toxic etiology of chronic or acute hepatitis. Laboratory personnel, hepato-pathologists and clinicians need to become more familiar with disease expressions and the interpretation of liver histology and autoimmune serology to derive maximum benefit for the patient.
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Marceau G, Yang R, Lapierre P, Béland K, Alvarez F. Low-dose anti-CD3 antibody induces remission of active autoimmune hepatitis in xenoimmunized mice. Liver Int 2015; 35:275-84. [PMID: 24517723 DOI: 10.1111/liv.12498] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 02/04/2014] [Indexed: 12/27/2022]
Abstract
BACKGROUND Some patients with autoimmune hepatitis (AIH), despite appropriate treatment, progress towards cirrhosis and liver failure, requiring transplantation. New biological agents targeting immune cell subtypes have been developed, with better specificity and longer-lasting effects than conventional wide-spectrum immunosuppressive drugs. AIMS The goal of this study was to evaluate the effectiveness of low dose of αCD3 targeting therapy in a model of type 2 AIH. METHODS This experimental model is based on xenoimmunization of C57BL/6 mice with DNA coding for human liver autoantigens. Mice with AIH were treated with five daily injections of low dose of αCD3 monoclonal antibody, before disease onset (5.5 months post-xenoimmunization) or during AIH (7 months post-xenoimmunization). Along with serum aminotransferases, autoantibody levels and end-point liver histology, spleen and liver-infiltrating lymphocytes were phenotyped by flow cytometry and immune response measured by lymphoproliferative assays. RESULTS Before onset of AIH, treatment prevented the development of liver inflammation and tissue injury. During active AIH, low dose of αCD3 antibody therapy resulted in a resorption of liver inflammatory infiltrates, normalization of serum aminotransferas levels, reduced autoantibody titres, increased regulatory T cells and lowered proliferation of autoreactive liver lymphocytes. CONCLUSIONS We report that low dose αCD3 antibody administration is an effective treatment for AIH in an experimental model of type 2 AIH. These data suggest that αCD3 antibody therapy could be tested in clinical trials as a rescue therapy for patients with uncontrolled AIH.
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Affiliation(s)
- Gabriel Marceau
- Division of Gastroenterology, Hepatology & Nutrition, CHU Sainte-Justine, Montréal, QC, Canada
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