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1
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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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2
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Gerussi A, Halliday N, Carbone M, Invernizzi P, Thorburn D. Open challenges in the management of autoimmune hepatitis. Minerva Gastroenterol (Torino) 2023; 69:61-83. [PMID: 33267568 DOI: 10.23736/s2724-5895.20.02805-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare autoimmune disease of the liver with many open questions as regards its etiopathogenesis, natural history and clinical management. The classical picture of AIH is chronic hepatitis with fluctuating elevation of serum transaminases and Immunoglobulin G levels, the presence of circulating autoantibodies and typical histological features. However, atypical presentations do occur and are not well captured by current diagnostic scores, with important consequences in terms of missed diagnoses and delayed treatments. AIH is treated with corticosteroids and immunosuppressive drugs but up to 40% of patients do not achieve full biochemical response and are at risk of progressing to cirrhosis and liver failure. Moreover, standard therapies are associated by significant side-effects which may impair the quality of life of patients living with AIH. However, advances in the understanding of the underlying immunology of AIH is raising the prospect of novel therapies and optimization of existing therapeutic approaches to reduce side-effect burdens and potentially restore immunological tolerance. In this review we outlined the clinical characteristics, etiopathogenesis and management of AIH and current challenges in the diagnosis and management of AIH and provided evidence underlying the evolution of diagnostic and clinical management protocols.
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Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy - .,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy - .,Ancient DNA Lab Dan David Center for Human Evolution and Biohistory Research, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel -
| | - Neil Halliday
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Marco Carbone
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy
| | - Douglas Thorburn
- Institute for Liver and Digestive Health, University College London, London, UK
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3
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Harsini S, Rezaei N. Autoimmune diseases. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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4
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Cancado ELR, Goldbaum-Crescente J, Terrabuio DRB. HLA-related genetic susceptibility in autoimmune hepatitis according to autoantibody profile. Front Immunol 2022; 13:1032591. [PMID: 36311739 PMCID: PMC9606223 DOI: 10.3389/fimmu.2022.1032591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
Although the prevalence of autoimmune hepatitis in first-degree relatives is small, the relationship between genetic markers, especially human leucocyte antigens (HLA), and susceptibility to this disease, has been studied for over three decades. The genetic susceptibility to AIH is believed to be different in the two subtypes of the disease, AIH type 1 and AIH type 2. Type 1 AIH has anti-smooth muscle and anti-nuclear antibodies as its main markers, while those of type 2 AIH are the anti-liver/kidney microsome type 1 and anti-liver cytosol type 1 antibodies. The anti-soluble liver antigen/liver-pancreas antibodies, which, in addition to being present in both subtypes, mark an important number of patients without serological markers. Therefore, a third type of disease is questionable. The vast majority of immunogenetic studies compare the differences between the two main types and make no difference between which antibodies are present to define the subtype. This review seeks to analyze what was most important published in the AIH in this context, trying to relate the HLA alleles according to the AIH marker autoantibodies.
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Affiliation(s)
- Eduardo Luiz Rachid Cancado
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Instituto de Medicina Tropical da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- *Correspondence: Eduardo Luiz Rachid Cancado,
| | - Juliana Goldbaum-Crescente
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Instituto de Medicina Tropical da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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5
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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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6
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Czaja AJ. Epigenetic Aspects and Prospects in Autoimmune Hepatitis. Front Immunol 2022; 13:921765. [PMID: 35844554 PMCID: PMC9281562 DOI: 10.3389/fimmu.2022.921765] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022] Open
Abstract
The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4+ and CD19+ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.
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Affiliation(s)
- Albert J. Czaja
- *Correspondence: Albert J. Czaja, ; orcid.org/0000-0002-5024-3065
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7
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Duclos-Vallée JC, Debray D, De Martin E, Beux EL, Louvet A. Best practice guidelines for France regarding the diagnosis and management of autoimmune hepatitis. Clin Res Hepatol Gastroenterol 2022; 46:101871. [PMID: 35108657 DOI: 10.1016/j.clinre.2022.101871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/04/2023]
Affiliation(s)
- Jean-Charles Duclos-Vallée
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Inserm Unité 1193, Université Paris-Saclay, FHU Hépatinov, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-Immunes, Villejuif, France.
| | - Dominique Debray
- Assistance Publique-Hôpitaux de Paris, University de Paris, Pediatric Liver Unit, Necker Hospital, Expert Center for Bile Duct Inflammatory Diseases and Autoimmune Hepatitis (FilFoie)
| | - Eleonora De Martin
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Inserm Unité 1193, Université Paris-Saclay, FHU Hépatinov, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-Immunes, Villejuif, France
| | - Emilie Le Beux
- Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-Immunes, Saint-Antoine Hospital, Paris, France
| | - Alexandre Louvet
- Service des Maladies de l'Appareil Digestif, Hôpital Claude-Huriez, Lille University Hospital, France, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-Immunes (FilFoie)
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8
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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: 55] [Impact Index Per Article: 13.8] [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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9
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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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10
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Li WW, Yang Y, Guo TZ, Sahbaie P, Shi XY, Guang Q, Kingery WS, Herzenberg LA, Clark JD. IL-6 signaling mediates the germinal center response, IgM production and nociceptive sensitization in male mice after tibia fracture. Brain Behav Immun 2021; 94:148-158. [PMID: 33636311 PMCID: PMC8058295 DOI: 10.1016/j.bbi.2021.02.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/14/2021] [Accepted: 02/18/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Up-regulated interleukin 6 (IL-6) signaling, immune system activation, and pronociceptive autoantibodies are characteristic of complex regional pain syndrome (CRPS). IL-6 is known to promote B cell differentiation, thus we hypothesized that IL-6 signaling plays a crucial role in the development of adaptive immune responses and nociceptive sensitization in a murine tibia fracture model of CRPS. METHODS Mice deficient in IL-6 expression (IL-6-/-) or B cell deficient (muMT) underwent tibia fracture and 3 weeks of cast immobilization or sham injury. The deposition of IgM in fractured limbs was followed using Western blotting, and passive serum transfer to muMT fracture mice was used to detect nociception-supporting autoantibodies. Lymph nodes were assessed for hypertrophy, IL-6 expression was measured using qPCR and ELISA, and germinal center formation was evaluated using FACS and immunohistochemistry. The therapeutic effects of exogenous neutralizing anti-IL-6 antibodies were also evaluated in the CRPS fracture model. RESULTS Functional IL-6 signaling was required for the post fracture development of nociceptive sensitization, vascular changes, and IgM immune complex deposition in the skin of injured limbs. Passive transfer of sera from wild-type, but not IL-6-/- fracture mice into muMT fracture mice caused enhanced allodynia and postural unweighting. IL-6-/- fracture mice displayed reduced popliteal lymphadenopathy after fracture. Germinal center responses were detected in the popliteal lymph nodes of wild-type, but not in IL-6-/- fracture mice. We observed that IL-6 expression was dramatically enhanced in popliteal lymph node tissue after fracture. Conversely, administration of anti-IL-6 antibodies reduced nociceptive and vascular changes after fracture and inhibited lymphadenopathy. CONCLUSIONS Collectively, these data support the hypothesis that IL-6 signaling in the fracture limb of mice is required for germinal center formation, IgM autoantibody production and nociceptive sensitization. Anti-IL-6 therapies might, therefore, reduce pain after limb fracture or in the setting of CRPS.
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Affiliation(s)
- Wen-Wu Li
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304, United States.,Department of Anesthesiology, Stanford University School of Medicine, 300 Pasture Drive, Stanford, CA 94305, United States
| | - Yang Yang
- Department of Genetics, Stanford University School of Medicine, 300 Pasture Drive, Stanford, CA 94305, USA.
| | - Tian-Zhi Guo
- Palo Alto Veterans Institute for Research, 3801 Miranda Ave, Palo Alto, CA 94304, United States
| | - Peyman Sahbaie
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304, USA; Palo Alto Veterans Institute for Research, 3801 Miranda Ave, Palo Alto, CA 94304, USA.
| | - Xiao-you Shi
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304, United States.,Department of Anesthesiology, Stanford University School of Medicine, 300 Pasture Drive, Stanford, CA 94305, United States
| | - Qin Guang
- Department of Genetics, Stanford University School of Medicine, 300 Pasture Drive, Stanford, CA 94305, United States
| | - Wade S. Kingery
- Palo Alto Veterans Institute for Research, 3801 Miranda Ave, Palo Alto, CA 94304, United States
| | - Leonore A. Herzenberg
- Department of Genetics, Stanford University School of Medicine, 300 Pasture Drive, Stanford, CA 94305, United States
| | - J. David Clark
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave, Palo Alto, CA 94304, United States.,Department of Anesthesiology, Stanford University School of Medicine, 300 Pasture Drive, Stanford, CA 94305, United States
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11
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Engel B, Laschtowitz A, Janik MK, Junge N, Baumann U, Milkiewicz P, Taubert R, Sebode M. Genetic aspects of adult and pediatric autoimmune hepatitis: A concise review. Eur J Med Genet 2021; 64:104214. [PMID: 33812046 DOI: 10.1016/j.ejmg.2021.104214] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/25/2021] [Accepted: 03/28/2021] [Indexed: 02/06/2023]
Abstract
Autoimmune Hepatitis (AIH) is a heterogenous, mostly chronic liver disease that affects people of all age groups, women more often than men. The aim of therapy is to prevent cirrhosis, as it mainly accounts for liver-related mortality in patients with AIH. Rates of remission are high in patients with AIH, but life-long immunosuppressive therapy is required. AIH is hypothesized to originate from immunologic reactivity targeted against mostly unknown self-antigens, potentially triggered by viral infections among other factors. While AIH does not follow a Mendelian inheritance pattern, part of the risk of developing AIH or worse disease course, is attributed to specific genetic risk factors. Major associations for the risk of development of AIH were found for HLA-DRB1*03:01 and HLA-DRB1*04:01 in adult AIH in the only genome-wide association study on AIH. However, other potential risk loci in SH2B3, CARD10 and KIR genes were described. This review covers the current knowledge on genetic risk factors in adult and pediatric AIH.
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Affiliation(s)
- Bastian Engel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany.
| | - Alena Laschtowitz
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Maciej K Janik
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Norman Junge
- Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Ulrich Baumann
- Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland; Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Marcial Sebode
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
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12
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Wang G, Tanaka A, Zhao H, Jia J, Ma X, Harada K, Wang FS, Wei L, Wang Q, Sun Y, Hong Y, Rao H, Efe C, Lau G, Payawal D, Gani R, Lindor K, Jafri W, Omata M, Sarin SK. The Asian Pacific Association for the Study of the Liver clinical practice guidance: the diagnosis and management of patients with autoimmune hepatitis. Hepatol Int 2021; 15:223-257. [PMID: 33942203 PMCID: PMC8144150 DOI: 10.1007/s12072-021-10170-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/27/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Guiqiang Wang
- Peking University First Hospital, Beijing, China.
- Peking University International Hospital, Beijing, China.
| | | | - Hong Zhao
- Peking University First Hospital, Beijing, China
- Peking University International Hospital, Beijing, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine Kanazawa, Kanazawa, Japan
| | - Fu-Sheng Wang
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Beijing, China
| | - Qixia Wang
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Sun
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuan Hong
- Peking University First Hospital, Beijing, China
| | - Huiying Rao
- Peking University People's Hospital, Beijing, China
| | - Cumali Efe
- Department of Gastroenterology, Harran University, Şanlıurfa, Turkey
| | - George Lau
- Humanity and Health Medical Group, Hong Kong Special Administrative Region, China
| | - Diana Payawal
- Department of Hepatology, Cardinal Santos Medical Center, Manila, Philippines
| | - Rino Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Keith Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | | | - Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu-City, Yamanashi, Japan
- The University of Tokyo, Tokyo, Japan
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13
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Higuchi T, Oka S, Furukawa H, Tohma S, Yatsuhashi H, Migita K. Genetic risk factors for autoimmune hepatitis: implications for phenotypic heterogeneity and biomarkers for drug response. Hum Genomics 2021; 15:6. [PMID: 33509297 PMCID: PMC7841991 DOI: 10.1186/s40246-020-00301-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/15/2020] [Indexed: 01/10/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a rare chronic progressive liver disease with autoimmune features. It mainly affects middle-aged women. AIH is occasionally complicated with liver cirrhosis that worsens the prognosis. Genetic and environmental factors are involved in the pathogenesis of AIH. Genetic studies of other diseases have been revealing of pathogenesis and drug efficacy. In this review, we summarize the genetic risk factors for AIH, including human leukocyte antigen (HLA) and non-HLA genes. A genome-wide association study (GWAS) on European AIH revealed the strongest associations to be with single nucleotide variants (SNVs) in HLA. Predisposing alleles for AIH were DRB1*03:01 and DRB1*04:01 in Europeans; DRB1*04:04, DRB1*04:05, and DRB1*13:01 in Latin Americans; and DRB1*04:01 and DRB1*04:05 in Japanese. Other risk SNVs in non-HLA genes for AIH were found by a candidate gene approach, but several SNVs were confirmed in replication studies. Some genetic factors of AIH overlapped with those of other autoimmune diseases. Larger-scale GWASs of other ethnic groups are required. The results of genetic studies might provide an explanation for the phenotypic heterogeneity of AIH and biomarkers for drug responses.
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Affiliation(s)
- Takashi Higuchi
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.,Department of Nephrology, Ushiku Aiwa General Hospital, 896 Shishiko-cho, Ushiku, 300-1296, Japan.,Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan
| | - Shomi Oka
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.,Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan.,Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan
| | - Hiroshi Furukawa
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan. .,Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan. .,Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan.
| | - Shigeto Tohma
- Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan.,Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856-8562, Japan
| | - Kiyoshi Migita
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856-8562, Japan.,Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan
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14
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Zhang HP, Liu YM, Li Z, Ma YX, Li LJ, Zhao DT, Lou JL, Gao ZH, Yan HP. Clinical characteristics and HLA genotypes in Chinese patients with anti-SLA/LP-positive autoimmune hepatitis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:153. [PMID: 33569455 PMCID: PMC7867871 DOI: 10.21037/atm-20-8036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Anti-soluble liver antigen/liver pancreas (anti-SLA/LP) is a highly specific serological marker for the diagnosis of autoimmune hepatitis (AIH). The aim of the present study was to define the clinical characteristics and human leucocyte antigen (HLA) genotypes of Chinese patients with anti-SLA/LP positive AIH. Methods Ninety-one AIH patients who were anti-SLA/LP positive were enrolled in this case control study. Clinical information was obtained through reviewing patients’ clinical notes. High-resolution genotyping of HLA-A, B, C, DRB1, and DQB1 alleles was performed by sequence-based typing polymerase chain reaction on 62 of the 91 patients. Data from 500 healthy patients were used as baseline controls. Results Anti-SLA/LP-positive AIH patients were characterized as follows: adults (age 20–80 years), female (88%), and frequent anti-nuclear antibody positivity (91%). Genetically, compared with the controls, HLA-B*35:01 and C*08:01 were significantly more frequent in patients. The frequencies of HLA-B*08:01, B*40:02, DRB1*04:01, DRB1*04:05, DRB1*14:01, and DRB1*16:02 increased, and the frequency in DRB1*15:01 decreased in patients, but did not reach significance after Bonferroni’s correction. Patients with other autoimmune diseases had a higher DRB1*04:05 and DQB1*04:01 allele carrier frequency than those without. DRB1*04:05 and DQB1*04:01 alleles were found at increased frequency in patients with decompensated liver disease than those with compensated liver disease. Conclusions Chinese anti-SLA/LP-positive AIH patients have some distinct clinical characteristics than other populations reported in the literature. The presence of certain specific HLA alleles could potentially increase the risk of developing anti-SLA/LP-positive AIH or other autoimmune disease and decompensated liver disease in the Chinese population.
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Affiliation(s)
- Hai-Ping Zhang
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yan-Min Liu
- Department of Liver Disease Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zhao Li
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
| | - Yin-Xue Ma
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Li-Juan Li
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Dan-Tong Zhao
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jin-Li Lou
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zu-Hua Gao
- Department of Pathology, McGill University, Montreal, Canada
| | - Hui-Ping Yan
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
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15
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Zhao D, Hajiaghamohseni LM, Liu X, Szulc ZM, Bai A, Bielawska A, Norris JS, Reddy SV, Hannun YA, Haque A. Inhibition of acid ceramidase regulates MHC class II antigen presentation and suppression of autoimmune arthritis. Cytokine 2020; 135:155219. [PMID: 32738771 DOI: 10.1016/j.cyto.2020.155219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 07/04/2020] [Accepted: 07/20/2020] [Indexed: 12/30/2022]
Abstract
The bioactive sphingolipid ceramide affects immune responses although its effect on antigen (Ag) processing and delivery by HLA class II to CD4+T-cells remains unclear. Therefore, we examined the actions of a novel cell-permeable acid ceramidase (AC) inhibitor [(1R,2R) N myristoylamino-(4'-nitrophenyl)-propandiol-1,3] on antigen presentation and inflammatory cytokine production by Ag-presenting cells (APCs) such as B-cells, macrophages, and dendritic cells. We found that AC inhibition in APCs perturbed Ag-processing and presentation via HLA-DR4 (MHC class II) proteins as measured by coculture assay and T-cell production of IL-2. Mass spectral analyses showed that B13 treatment significantly raised levels of four types of ceramides in human B-cells. B13 treatment did not alter Ag internalization and class II protein expression, but significantly inhibited lysosomal cysteinyl cathepsins (B, S and L) and thiol-reductase (GILT), HLA class II Ag-processing, and generation of functional class II-peptide complexes. Ex vivo Ag presentation assays showed that inhibition of AC impaired primary and recall CD4+T-cell responses and cytokine production in response against type II collagen. Further, B13 delayed onset and reduced severity of inflamed joints and cytokine production in the collagen-induced arthritis mouse model in vivo. These findings suggest that inhibition of AC in APCs may dysregulate endolysosomal proteases and HLA class II-associated self-antigen presentation to CD4+T-cells, attenuating inflammatory cytokine production and suppressing host autoimmune responses.
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Affiliation(s)
- Dan Zhao
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States; Darby Children's Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States; Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States
| | - Laela M Hajiaghamohseni
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States; Darby Children's Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States; Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States
| | - Xiang Liu
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States; Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States
| | - Zdzislaw M Szulc
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States
| | - Aiping Bai
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States
| | - Alicja Bielawska
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States
| | - James S Norris
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States; Darby Children's Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States; Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States
| | - Sakamuri V Reddy
- Darby Children's Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States
| | - Yusuf A Hannun
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States
| | - Azizul Haque
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States; Darby Children's Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States; Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, United States.
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16
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 543] [Impact Index Per Article: 108.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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17
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Czaja AJ. Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions. World J Gastroenterol 2019; 25:6579-6606. [PMID: 31832000 PMCID: PMC6906207 DOI: 10.3748/wjg.v25.i45.6579] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/25/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple pathogenic mechanisms have been implicated in autoimmune hepatitis, but they have not fully explained susceptibility, triggering events, and maintenance or escalation of the disease. Furthermore, they have not identified a critical defect that can be targeted. The goals of this review are to examine the diverse pathogenic mechanisms that have been considered in autoimmune hepatitis, indicate investigational opportunities to validate their contribution, and suggest interventions that might evolve to modify their impact. English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Genetic and epigenetic factors can affect susceptibility by influencing the expression of immune regulatory genes. Thymic dysfunction, possibly related to deficient production of programmed cell death protein-1, can allow autoreactive T cells to escape deletion, and alterations in the intestinal microbiome may help overcome immune tolerance and affect gender bias. Environmental factors may trigger the disease or induce epigenetic changes in gene function. Molecular mimicry, epitope spread, bystander activation, neo-antigen production, lymphocytic polyspecificity, and disturbances in immune inhibitory mechanisms may maintain or escalate the disease. Interventions that modify epigenetic effects on gene expression, alter intestinal dysbiosis, eliminate deleterious environmental factors, and target critical pathogenic mechanisms are therapeutic possibilities that might reduce risk, individualize management, and improve outcome. In conclusion, diverse pathogenic mechanisms have been implicated in autoimmune hepatitis, and they may identify a critical factor or sequence that can be validated and used to direct future management and preventive strategies.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States
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18
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Autoimmune Hepatitis-Immunologically Triggered Liver Pathogenesis-Diagnostic and Therapeutic Strategies. J Immunol Res 2019; 2019:9437043. [PMID: 31886312 PMCID: PMC6899271 DOI: 10.1155/2019/9437043] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/15/2019] [Accepted: 09/21/2019] [Indexed: 12/20/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease that arises in genetically predisposed male and female individuals worldwide. Diagnosis of AIH is made clinically applying diagnostic scores; however, the heterotopic disease phenotype often makes a rapid determination of disease challenging. AIH responds favorably to steroids and pharmacologic immunosuppression, and liver transplantation is only necessary in cases with acute liver failure or end-stage liver cirrhosis. Recurrence or development of de novo AIH after transplantation is possible, and treatment is similar to standard AIH therapy. Current experimental investigations of T cell-mediated autoimmune pathways and analysis of changes within the intestinal microbiome might advance our knowledge on the pathogenesis of AIH and trigger a spark of hope for novel therapeutic strategies.
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19
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Bovensiepen CS, Schakat M, Sebode M, Zenouzi R, Hartl J, Peiseler M, Li J, Henze L, Woestemeier A, Schramm C, Lohse AW, Herkel J, Weiler-Normann C. TNF-Producing Th1 Cells Are Selectively Expanded in Liver Infiltrates of Patients with Autoimmune Hepatitis. THE JOURNAL OF IMMUNOLOGY 2019; 203:3148-3156. [PMID: 31685647 DOI: 10.4049/jimmunol.1900124] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 10/03/2019] [Indexed: 12/23/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that is believed to be driven by a CD4+ T cell response to liver Ags. However, the pathogenic function of CD4+ effector T cells in AIH is not fully understood. To characterize liver-infiltrating lymphocytes in AIH, we determined the cytokine production of infiltrating cells obtained from biopsy material by quantitative RT-PCR and flow cytometry. A cytokine quantitiative RT-PCR array of AIH specimens revealed that TNF was the most strongly upregulated cytokine, as compared with control livers. To confirm this finding, we determined the frequencies of TNF-producing CD4+ T cells in peripheral blood and in liver biopsy specimens in comparison with those of CD4+ T cells producing IFN-γ or IL-17. In AIH, TNF-producing CD4+ T cells were significantly expanded, both in blood and liver, whereas IL-17-producing CD4+ T cells were not. However, the majority of the TNF-producing CD4+ T cells in AIH also produced IFN-γ, suggesting that TNF producers might represent a pathogenic activation state of Th1 cells. Ag-specific stimulation of PBMC from AIH patients with the AIH-associated autoantigen SEPSECS resulted in significant TNF production only in patients manifesting SLA/LP autoantibodies targeting SEPSEC but not in healthy individuals who do not manifest this reactivity. Taken together, our findings indicated that TNF-producing CD4+ T cells are expanded in AIH, both in blood and in liver. TNF-producing CD4+ T cells in AIH seem to be aberrantly activated Th1 cells. Our findings provide a rationale for therapeutic efforts using TNF blockade in AIH.
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Affiliation(s)
- Claudia S Bovensiepen
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Miriam Schakat
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Marcial Sebode
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Roman Zenouzi
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Johannes Hartl
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Moritz Peiseler
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Jun Li
- Department of Hepatobiliary Surgery and Transplantation, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.,Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; and
| | - Lara Henze
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Anna Woestemeier
- Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; and
| | - Christoph Schramm
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Johannes Herkel
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Christina Weiler-Normann
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany; .,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
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20
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Chen RL, Wang QX, Ma X. Precision medicine for autoimmune hepatitis. J Dig Dis 2019; 20:331-337. [PMID: 31099976 DOI: 10.1111/1751-2980.12786] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 05/07/2019] [Indexed: 01/10/2023]
Abstract
Autoimmune hepatitis (AIH) is an autoimmune liver disease induced by environmental factors in genetically susceptible individuals. AIH is characterized by hypergammaglobulinemia, elevation of serum autoantibodies and transaminases, and interface hepatitis. Personalized therapy is necessary in AIH because of its heterogeneity in clinical manifestations. Precision medicine is a recent and novel therapeutic pattern which ultimately aims to achieve personalized therapy. In this review we summarize the research progress of precision medicine to treat AIH by an exploration of the susceptible genes, precision diagnosis and prognosis of AIH, pharmacogenomics and precision medication, and the precision treatment for special types of AIH.
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Affiliation(s)
- Rui Ling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Xia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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21
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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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22
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Czaja AJ. Epigenetic changes and their implications in autoimmune hepatitis. Eur J Clin Invest 2018; 48. [PMID: 29383703 DOI: 10.1111/eci.12899] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 01/25/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND The genetic risk of autoimmune hepatitis is insufficient to explain the observed risk, and epigenetic changes may explain disparities in disease occurrence in different populations within and between countries. The goal of this review was to examine how epigenetic changes induced by the environment or inherited as a phenotypic trait may affect autoimmune hepatitis and be amenable to therapeutic intervention. MATERIALS AND METHODS Pertinent abstracts were identified in PubMed by multiple search terms. The number of abstracts reviewed was 1689, and the number of full-length articles reviewed exceeded 150. RESULTS Activation of pro-inflammatory genes in autoimmune disease is associated with hypomethylation of deoxyribonucleic acid and modification of histones within chromatin. Organ-specific microribonucleic acids can silence genes by marking messenger ribonucleic acids for degradation, and they can promote inflammatory activity or immunosuppression. High circulating levels of the microribonucleic acids 21 and 122 have been demonstrated in autoimmune hepatitis, and they may increase production of pro-inflammatory cytokines. Microribonucleic acids are also essential for maintaining regulatory T cells. Drugs, pollutants, infections, diet and ageing can induce inheritable epigenetic changes favouring autoimmunity. Reversal is feasible by manipulating enzymes, transcription factors, gene-silencing molecules and toxic exposures or by administering methyl donors and correcting vitamin D deficiency. Gene targets, site specificity, efficacy and consequences are uncertain. CONCLUSIONS Potentially reversible epigenetic changes may affect the occurrence and outcome of autoimmune hepatitis, and investigations are warranted to determine the nature of these changes, key genomic targets, and feasible interventions and their consequences.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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23
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Muratori P, Lenzi M, Cassani F, Lalanne C, Muratori L. Diagnostic approach to autoimmune hepatitis. Expert Rev Clin Immunol 2017; 13:769-779. [PMID: 28480763 DOI: 10.1080/1744666x.2017.1327355] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if left without treatment, can evolve into cirrhosis and possibly liver failure. The diagnosis of AIH is hampered by the lack of specific and reliable markers of the disease and a number of clinical, biochemical, immunological, histological and genetic factors should be considered to reach a confident diagnosis Areas covered: Clinical expression of AIH, histological features, serological and genetic profiles, differential diagnosis, overlap with other autoimmune liver diseases, assessed on the basis of personal experience and review of published literature in the last 10 years through a systematic Medline search (keywords: autoimmune hepatitis, diagnosis) Expert commentary: Notwithstanding numerous efforts to identify simple and reliable markers of the disease, the diagnosis of AIH is still based on the combination of histological, immunological and biochemical features and often can represent a real challenge for the hepatologist.
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Affiliation(s)
- Paolo Muratori
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Marco Lenzi
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Fabio Cassani
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Claudine Lalanne
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Luigi Muratori
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
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24
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Ylinen E, Salmela L, Peräsaari J, Jaatinen T, Tenca A, Vapalahti O, Färkkilä M, Jalanko H, Kolho K. Human leucocyte antigens B*08, DRB1*03 and DRB1*13 are significantly associated with autoimmune liver and biliary diseases in Finnish children. Acta Paediatr 2017; 106:322-326. [PMID: 27759901 DOI: 10.1111/apa.13641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 09/05/2016] [Accepted: 10/17/2016] [Indexed: 12/13/2022]
Abstract
AIM The human leucocyte antigen (HLA) allele and haplotype frequencies of the Finnish population are unique because of the restricted and homogenous gene population. There are no published data on HLA genotype associations in paediatric autoimmune liver diseases in Scandinavia. This study characterised the HLA genotypes of children with autoimmune liver or biliary disease in Finland. METHODS The study cohort comprised 19 paediatric patients (13 female) aged three years to 15 years treated for autoimmune liver or biliary disease at the Children's Hospital, Helsinki University Hospital, between 2000 and 2011, and followed up for four years and three months to 14.6 years. We genotyped HLA-B and HLA-DRB1 in the children, and the HLA antigen frequencies were compared with 19 807 records from the Finnish Bone Marrow Donor Registry. RESULTS All paediatric patients with autoimmune liver or biliary disease had either autoimmune HLA haplotype B*08;DRB1*03 or DRB1*13. These were significantly more common among patients with autoimmune hepatitis, primary sclerosing cholangitis and autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome than the Finnish control population. HLA RB1*04 was not found in the study cohort. CONCLUSION Our study found that B*08, DRB1*03 and DRB1*13 were significantly associated with autoimmune liver and biliary diseases in Finnish paediatric patients.
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Affiliation(s)
- E Ylinen
- Department of Paediatric Nephrology and Transplantation Children's Hospital University of Helsinki Helsinki University Hospital Helsinki Finland
- Department of Gastroenterology Children's Hospital University of Helsinki Helsinki University Hospital Helsinki Finland
| | - L Salmela
- Medical School University of Helsinki Helsinki Finland
| | - J Peräsaari
- Clinical Laboratory Finnish Red Cross Blood Service Helsinki Finland
| | - T Jaatinen
- Clinical Laboratory Finnish Red Cross Blood Service Helsinki Finland
| | - A Tenca
- Clinic of Gastroenterology University of Helsinki Helsinki University Hospital Helsinki Finland
| | - O Vapalahti
- Department of Virology and Immunology HUSLAB Hospital District of Helsinki and Uusimaa Helsinki Finland
| | - M Färkkilä
- Clinic of Gastroenterology University of Helsinki Helsinki University Hospital Helsinki Finland
| | - H Jalanko
- Department of Paediatric Nephrology and Transplantation Children's Hospital University of Helsinki Helsinki University Hospital Helsinki Finland
| | - K‐L Kolho
- Department of Gastroenterology Children's Hospital University of Helsinki Helsinki University Hospital Helsinki Finland
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Liver immunology: How to reconcile tolerance with autoimmunity. Clin Res Hepatol Gastroenterol 2017; 41:6-16. [PMID: 27526967 DOI: 10.1016/j.clinre.2016.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Accepted: 06/01/2016] [Indexed: 02/04/2023]
Abstract
There are several examples of liver tolerance: the relative ease by which liver allografts are accepted and the exploitation of the hepatic microenvironment by the malarial parasite and hepatotrophic viruses are notable examples. The vasculature of the liver supports a unique population of antigen presenting cells specialised to maintain immunological tolerance despite continuous exposure to gut-derived antigens. Liver sinusoidal endothelial cells and Kupffer cells appear to be key to the maintenance of immune tolerance, by promoting T cell anergy or deletion and the generation of regulatory cell subsets. Despite this, there are three liver diseases with likely autoimmune involvement: primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. How can we reconcile this with the inherent tolerogenicity of the liver? Genetic studies have uncovered several associations with genes involved in the activation of the innate and adaptive immune systems. There is also evidence pointing to pathogenic and xenobiotic triggers of autoimmune liver disease. Coupled to this, impaired immunoregulatory mechanisms potentially play a permissive role, allowing the autoimmune response to proceed.
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Abstract
Autoimmune hepatitis (AIH) is a chronic progressive liver disease characterized by high levels of aminotransferases and autoantibodies, hypergammaglobulinemia, and interface hepatitis. AIH affects all races and all ages worldwide, regardless of sex, although a preponderance of females is a constant finding. The etiology of AIH has not been completely elucidated, but immunogenetic background and environmental parameters may contribute to its development. The most important genetic factor is human leukocyte antigens (HLAs), especially HLA-DR, whereas the role of environmental factors is not completely understood. Immunologically, disruption of the immune tolerance to autologous liver antigens may be a trigger of AIH. The diagnosis of classical AIH is fairly easy, though not without pitfalls. In contrast, the diagnosis of atypical AIH poses great challenges. There is confusion as to the definition of the disease entity and its boundaries in the diagnosis of overlap syndrome, drug-induced autoimmune hepatitis, and AIH with concomitant nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C. Centrilobular zonal necrosis is now included in the histological spectrum of AIH. However, the definition and the significance of AIH presenting with centrilobular zonal necrosis have not been examined extensively. In ~20% of AIH patients who are treated for the first time with standard therapy, remission is not achieved. The development of more effective and better tolerated novel therapies is an urgent need. In this review, we discuss the current challenges and the future prospects in relation to the diagnosis and treatment of AIH, which have been attracting considerable recent attention.
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Affiliation(s)
- Yoshio Aizawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University Katsushika Medical Center, Katsushika-ku, Tokyo, Japan
| | - Atsushi Hokari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University Katsushika Medical Center, Katsushika-ku, Tokyo, Japan
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Czaja AJ. Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis. World J Gastroenterol 2016; 22:9257-9278. [PMID: 27895415 PMCID: PMC5107691 DOI: 10.3748/wjg.v22.i42.9257] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 10/07/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023] Open
Abstract
The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora (dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens (molecular mimicry). Activated gut-derived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.
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Liberal R, Grant CR. Cirrhosis and autoimmune liver disease: Current understanding. World J Hepatol 2016; 8:1157-1168. [PMID: 27729952 PMCID: PMC5055585 DOI: 10.4254/wjh.v8.i28.1157] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/14/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.
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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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Liberal R, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: From mechanisms to therapy. Rev Clin Esp 2016. [DOI: 10.1016/j.rceng.2016.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Woynarowski M, Woźniak M, Cukrowska B, Wierzbicka A, Lytton SD. Autoantibody Profile of Adult Patients With Childhood Onset Type 2 Autoimmune Hepatitis. J Clin Lab Anal 2016; 30:590-6. [PMID: 26676069 PMCID: PMC6807217 DOI: 10.1002/jcla.21907] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 10/05/2015] [Accepted: 10/12/2015] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Anti-liver kidney microsome (anti-LKM) autoantibodies are a distinguishing feature of type II autoimmune hepatitis (AIH-2). However, the levels of anti-LKM-1 in adult AIH-2 patients and their role in liver immunopathology remain equivocal. The aim of the study was to survey the autoantibody profile and the activity of liver disease in adult patients diagnosed with AIH-2 at childhood. METHODS The autoantibody profile of adults was compared with the autoantibodies of the pediatric period. Liver function test, Immunoglobulin G (IgG), and gamma globulins were evaluated at the AIH presentation, at the age of 18 years, and at the current adult visit. RESULTS All ten patients tested positive for LKM-1 at least once during the pediatric period. At the adult visit, four patients lost autoantibody positivity. LKM-1 was positive in four, liver cytosol antigen 1 (LC-1) in two, soluble liver antigen in one, and antinuclear antigen in one patient. Additionally three patients with LKM-1 and one patient without LKM-1 were positive for AMA-M2 (where AMA is antimitochondrial antibodies) Immunoglobulin M (IgM). Liver function markedly improved at 18 years and adult visit compared with initial diagnosis of AIH with only a mild decrease of IgG. The six adult patients positive for at least one autoantibody had statistically lower aspartate aminotransferase (AST) and gamma-glutamyltranspeptidase (GGTP) than the four patients autoantibody negative (AST: 52 vs. 88 IU/l, P < 0.05; GGTP 19 vs. 163 IU/l, P < 0.05). CONCLUSION LKM-1 positivity is not a stable condition in all patients with AIH-2. Patients who remained autoantibody positive had better liver function tests than those who lost their positivity. The presence of AMA-M2 autoantibodies suggest that development of AIH/Primary Biliary Cirrhosis (PBC) overlap syndrome should be considered.
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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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Karakoyun M, Ecevit CO, Kilicoglu E, Aydogdu S, Yagci RV, Ozgenc F. Autoimmune hepatitis and long-term disease course in children in Turkey, a single-center experience. Eur J Gastroenterol Hepatol 2016; 28:927-30. [PMID: 27254777 DOI: 10.1097/meg.0000000000000648] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION The aim of this study is to determine clinic and laboratory features, treatment protocols, treatment responses, and long term follow-up of children with autoimmune hepatitis (AIH) in a region of Turkey followed at Ege University. MATERIALS AND METHODS The records of 47 children with AIH between 1998 and 2012 were retrospectively analyzed for clinical profiles, treatment response, relapse rate, and long-term side effects. RESULTS The median age of the children was 10±4.1 years (55.3% females). A total of 29 patients presented with chronic hepatitis (61.7%). According to the autoantibody profiles, 40 (85.1%) and seven (14.9%) cases were classified as type 1 and type 2, respectively. Presentation with acute hepatitis and chronic hepatitis was significantly higher in type 1 disease. Laboratory findings at presentation was found similar among races as well as AIH types (P>0.05). The prednisolone was used for remission induction in 37 patients; 86.4% (n: 32) achieved a complete response, 2.7% (n: 1) achieved a partial response, and four patients (10.8%) showed no response. Maintenance was attained by low-dose steroid plus thiopurine and relapse in steroid responders (n: 32) was 9.4% (n: 3) at 8, 12, and 48 months. A total of 36% (n: 24) had neither acute nor chronic treatment side effects. Bone marrow suppression was observed in five patients and hyperglycemia was observed in one patient (10.6 and 2.1%), respectively. CONCLUSION AIH type 1 prevails in children in a region of Turkey during the second decade of life. Low-dose corticosteroids combined with azathioprine are found.
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Affiliation(s)
- Miray Karakoyun
- aDepartment of Pediatric Gastroenterology, Hepatalogy and Nutrition, Gaziantep Children's Hospital, Gaziantep bDepartment of Pediatric Gastroenterology, Hepatology and Nutrition cDepartment of Pediatrics, Dr. Behcet Uz Children's Hospital dDepartment of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University, Izmir, Turkey
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van Gerven NMF, de Boer YS, Mulder CJJ, van Nieuwkerk CMJ, Bouma G. Auto immune hepatitis. World J Gastroenterol 2016; 22:4651-4661. [PMID: 27217697 PMCID: PMC4870072 DOI: 10.3748/wjg.v22.i19.4651] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/29/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023] Open
Abstract
To provide an update of the latest trends in epidemiology, clinical course, diagnostics, complications and treatment of auto immune hepatitis (AIH). A search of the MEDLINE database was performed using the search terms: “auto immune hepatitis”, “clinical presentation”, “symptoms”, “signs”, “diagnosis”, “auto antibodies”, “laboratory values”, “serology”, “histopathology”, “histology”, “genetics”, “HLA genes”, “non-HLA genes”, “environment”, “epidemiology”, “prevalence”, “incidence”, “demographics”, “complications”, “HCC”, “PBC”, “PSC”, “corticosteroid”, “therapy”, “treatment”, “alternative treatment”. English-language full-text articles and abstracts were considered. Articles included reviews, meta-analysis, prospective retrospective studies. No publication date restrictions were applied. AIH is an immune meditated progressive inflammatory liver disease that predominantly affects middle-aged females but may affect people of all ages. The clinical spectrum of AIH is wide, ranging from absent or mild symptoms to fulminant hepatic failure. The aetiology of AIH is still unknown, but is believed to occur as the consequence of an aberrant immune response towards an un-known trigger in a genetically susceptible host. In the absence of a gold standard, diagnosis is based on the combination of clinical, biochemical and histopathological criteria. Immunosuppressive treatment has been the cornerstone of treatment since the earliest description of the disease in 1950 by Waldenström. Such treatment is often successful at inducing remission and generally leads to normal life expectancy. Nevertheless, there remain significant areas of unmet aetiological a clinical needs including fundamental insight in disease pathogenesis, optimal therapy, duration of treatment and treatment alternatives in those patients unresponsive to standard treatment regimens.
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Liberal R, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: From mechanisms to therapy. Rev Clin Esp 2016; 216:372-383. [PMID: 27161382 DOI: 10.1016/j.rce.2016.04.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 04/02/2016] [Indexed: 12/13/2022]
Abstract
Autoimmune hepatitis (AIH) is a progressive inflammatory hepatopathy and an important cause of end-stage liver disease. Its aetiology remains unknown, though both genetic and environmental factors are involved in its development. The major mechanism of autoimmune liver damage involves immune reactions against host liver antigens. Numerical and functional defects of regulatory T-cells play a permissive role enabling autoimmune liver injury to occur and persist. The most typical features of AIH are female preponderance, hypergammaglobulinaemia, seropositivity for circulating autoantibodies and a picture of interface hepatitis on histology. Two types of AIH are distinguished according to serological profile: AIH type 1 patients are positive for anti-nuclear and/or anti-smooth muscle antibodies, whereas AIH type 2 patients are defined by the positivity for anti-liver kidney microsomal type 1 antibody and/or for anti-liver cytosol type 1 antibody. Clinical manifestations are variable, and AIH onset is often ill-defined, frequently mimicking acute hepatitis; its course may be fluctuating. AIH responds to immunosuppressive treatment in the majority of cases. Steroids with or without azathioprine should be instituted promptly upon diagnosis. Remission is achieved in some 80% of patients. For the remaining 20% of patients, alternative immunosuppressive agents such as mycophenolate mofetil and calcineurin inhibitors are an option. Liver transplantation should be considered for those patients who progress to cirrhosis and develop complications of end-stage liver disease, as well as for those presenting with acute liver failure; outcomes are excellent, although the disease may recur in the allograft.
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Affiliation(s)
- R Liberal
- Institute of Liver Studies, King's College London, Faculty of Life Sciences & Medicine, London, UK; Department of Gastroenterology, Centro Hospitalar São João and Faculty of Medicine, University of Porto, Porto, Portugal
| | - G Mieli-Vergani
- Institute of Liver Studies, King's College London, Faculty of Life Sciences & Medicine, London, UK; Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - D Vergani
- Institute of Liver Studies, King's College London, Faculty of Life Sciences & Medicine, London, UK.
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Human leucocyte antigens and pediatric autoimmune liver disease: diagnosis and prognosis. Eur J Pediatr 2016; 175:527-37. [PMID: 26567543 DOI: 10.1007/s00431-015-2662-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 10/20/2015] [Accepted: 11/03/2015] [Indexed: 02/07/2023]
Abstract
UNLABELLED An association of human leukocyte antigen (HLA) class II alleles with autoimmune conditions is increasingly being used for diagnostic purposes. The aim of our study was to examine whether HLA class II alleles in pediatric-onset autoimmune liver disease (pAILD) may serve as diagnostic markers and if they correlate with clinical outcome parameters. HLA-DRB1 alleles of 76 children with pAILD (autoimmune hepatitis [AIH], autoimmune sclerosing cholangitis [AISC], primary sclerosing cholangitis [PSC]) and of 50 healthy blood donors as control group were analyzed retrospectively. Diagnosis of these patients was confirmed by the autoimmune hepatitis score including liver histology, which has been re-evaluated by a blinded liver pathologist, and by bile duct imaging, as appropriate. Our results showed significant association of HLA-DRB1*03 with AIH1 and AISC with 82 % specificity for AIH. For pAILD (excluding AIH2), HLA-DRB1*03 homozygosity had specificity of 98 %, whereas sensitivity is low. Remission in HLA-DRB1*03-positive patients appears to be less likely. HLA-DRB1*13 is significantly associated with PSC and also with AIH1. CONCLUSION HLA-DRB1 alleles provide supportive information for diagnostic workup in patients with liver disease, but they were not suitable for differentiation within pAILD. Their prognostic value could be helpful but needs to be evaluated further. WHAT IS KNOWN • HLA-DRB1*03 is NOT associated with pediatric AIH in a previous national study. • In other studies, HLA-DRB1*03 is associated with AIH1. • HLA-DRB1*13 is associated with PSC. • HLA-DRB1*04 is described as protective for AILD. What is New: • HLA-DRB1 four-digit typing for all alleles and for all subgroups of pAILD combined with re-assessment of liver histology • HLA-DRB1*03:01 is associated with pediatric AIH1 and AISC. • HLA-DRB1*03:01 appears to be a prognostic marker. • HLA-DRB1*13:01 is associated with pediatric AIH1 in mixed ethnicity cohort. • HLA-DRB1*04 does not show any protective effect for pAILD.
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Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions. Gut Liver 2016; 10:177-203. [PMID: 26934884 PMCID: PMC4780448 DOI: 10.5009/gnl15352] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is characterized by autoantibodies, hypergammaglobulinemia, and interface hepatitis on histological examination. The features lack diagnostic specificity, and other diseases that may resemble autoimmune hepatitis must be excluded. The clinical presentation may be acute, acute severe (fulminant), or asymptomatic; conventional autoantibodies may be absent; centrilobular necrosis and bile duct changes may be present; and the disease may occur after liver transplantation or with features that suggest overlapping disorders. The diagnostic criteria have been codified, and diagnostic scoring systems can support clinical judgment. Nonstandard autoantibodies, including antibodies to actin, α-actinin, soluble liver antigen, perinuclear antineutrophil antigen, asialoglycoprotein receptor, and liver cytosol type 1, are tools that can support the diagnosis, especially in patients with atypical features. Prednisone or prednisolone in combination with azathioprine is the preferred treatment, and strategies using these medications in various doses can ameliorate treatment failure, incomplete response, drug intolerance, and relapse after drug withdrawal. Budesonide, mycophenolate mofetil, and calcineurin inhibitors can be considered in selected patients as frontline or salvage therapies. Molecular (recombinant proteins and monoclonal antibodies), cellular (adoptive transfer and antigenic manipulation), and pharmacological (antioxidants, antifibrotics, and antiapoptotic agents) interventions constitute future directions in management. The evolving knowledge of the pathogenic pathways and the advances in technology promise new management algorithms.
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Affiliation(s)
- Albert J. Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN,
USA
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Genetic factors affect the etiology, clinical characteristics and outcome of autoimmune hepatitis. Clin J Gastroenterol 2015; 8:360-6. [DOI: 10.1007/s12328-015-0620-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023]
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Bittencourt PL, Cançado ELR, Couto CA, Levy C, Porta G, Silva AEB, Terrabuio DRB, Carvalho Filho RJD, Chaves DM, Miura IK, Codes L, Faria LC, Evangelista AS, Farias AQ, Gonçalves LL, Harriz M, Lopes Neto EPA, Luz GO, Oliveira P, Oliveira EMGD, Schiavon JLN, Seva-Pereira T, Parise ER, Parise ER. Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver. ARQUIVOS DE GASTROENTEROLOGIA 2015; 52 Suppl 1:15-46. [DOI: 10.1590/s0004-28032015000500002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
ABSTRACT In order to draw evidence-based recommendations concerning the management of autoimmune diseases of the liver, the Brazilian Society of Hepatology has sponsored a single-topic meeting in October 18th, 2014 at São Paulo. An organizing committee comprised of seven investigators was previously elected by the Governing Board to organize the scientific agenda as well as to select twenty panelists to make a systematic review of the literature and to present topics related to the diagnosis and treatment of autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and their overlap syndromes. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript organized in topics, followed by the recommendations of the Brazilian Society of Hepatology.
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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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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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Liberal R, Vergani D, Mieli-Vergani G. Update on Autoimmune Hepatitis. J Clin Transl Hepatol 2015; 3:42-52. [PMID: 26357634 PMCID: PMC4542083 DOI: 10.14218/jcth.2014.00032] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 12/08/2014] [Accepted: 12/08/2014] [Indexed: 12/17/2022] Open
Abstract
Autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, is characterized by inflammatory liver histology, elevated transaminase levels, circulating nonorganspecific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels. AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine, with symptom free long-term survival for the majority of patients. For those who do not respond to standard treatment, or who are difficult-to-treat, mycophenolate mofetil and, in the absence of a response, calcineurin inhibitors should be tried in addition to steroids. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.
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Affiliation(s)
- Rodrigo Liberal
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Diego Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
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Maggiore G, Nastasio S, Sciveres M. Juvenile autoimmune hepatitis: Spectrum of the disease. World J Hepatol 2014; 6:464-476. [PMID: 25067998 PMCID: PMC4110538 DOI: 10.4254/wjh.v6.i7.464] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 03/19/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Juvenile autoimmune hepatitis (JAIH) is a progressive inflammatory liver disease, affecting mainly young girls, from infancy to late adolescence, characterized by active liver damage, as shown by high serum activity of aminotransferases, by elevated immunoglobulin G levels, high titers of serum non organ-specific and organ-specific autoantibodies, and by interface hepatitis on liver biopsy. It is a multifactorial disease of unknown etiology in which environmental factors act as a trigger in genetically predisposed individuals. Two types of JAIH are identified according to the autoantibody panel detected at diagnosis: AIH-1, characterized by the presence of anti-smooth muscle antibody and/or antinuclear antibody and AIH-2, by anti-liver-kidney microsomal antibody type 1 and/or by the presence of anti-liver cytosol type 1 antibody. Epidemiological distribution, genetic markers, clinical presentation and pattern of serum cytokines differentiate the two types of AIH suggesting possible pathogenetic mechanisms. The most effective therapy for AIH is pharmacological suppression of the immune response. Treatment should be started as soon as the diagnosis is made to avoid severe liver damage and progression of fibrosis. The aim of this review is to outline the most significant and peculiar features of JAIH, based largely on our own personal database and on a review of current literature.
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Kaur N, Minz RW, Anand S, Saikia B, Aggarwal R, Das A, Thapa BR, Chawla YK. HLA DRB1 Alleles Discriminate the Manifestation of Autoimmune Hepatitis as Type 1 or Type 2 in North Indian Population. J Clin Exp Hepatol 2014; 4:14-8. [PMID: 25755530 PMCID: PMC4017209 DOI: 10.1016/j.jceh.2013.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 12/02/2013] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Autoimmune hepatitis is a polygenic disorder of unknown etiology, where genetic factors affect the occurrence and clinical phenotype of the disease. It has been reported as a rare disease entity in the Indian subcontinent. This study was undertaken to investigate the association of HLA alleles with autoimmune hepatitis type 1 and type 2 in north Indian population and to analyze if distinct human leukocyte antigen (HLA) alleles help in characterization of the subtypes of autoimmune hepatitis. METHODS Sixty-eight patients with autoimmune hepatitis and 128 healthy controls were recruited in the study. Out of 68 patients, 55 were diagnosed with autoimmune hepatitis type 1 and 13 with autoimmune hepatitis type 2. The patients and the controls were typed for HLA class II alleles by PCR-SSP method. RESULTS HLA DRB1*04 and DRB1*08 were found to be significantly associated with autoimmune hepatitis type 1 in north Indian population. It was also observed that DRB1*04, DRB1*13 were significantly associated with pediatric autoimmune hepatitis type 1 and DRB1*08 was significantly associated with adult autoimmune hepatitis type 1. DRB1*14 was significantly associated with autoimmune hepatitis type 2. CONCLUSION The study indicates that autoimmune hepatitis in north Indian population is associated with HLA alleles that may help to discriminate the subtypes as autoimmune hepatitis type 1 and type 2. The study also highlights the ethnic variations in the Indian subcontinent in context to the genetic association of HLA with autoimmune diseases.
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Key Words
- AASLD, American Association for the Study of the Liver
- AIH, autoimmune hepatitis
- ANA, antinuclear antibody
- ASMA, anti smooth muscle antibody
- CI, confidence interval
- HLA, human leukocyte antigen
- IAHG, International Autoimmune Hepatitis Group
- IIF, indirect immuno florescence
- LKM, liver kidney microsomal
- MHC, major histocompatibility complex
- Mb, megabase
- OR, odds ratio
- PCR-SSP, polymerase chain reaction-sequence specific primers
- RR, relative risk
- autoimmune hepatitis
- ethnic variations
- human leukocyte antigen
- north India
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Affiliation(s)
- Navchetan Kaur
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Ranjana W. Minz
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Shashi Anand
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Biman Saikia
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Ritu Aggarwal
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Ashim Das
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Babu R. Thapa
- Department of Paediatric Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Yogesh K. Chawla
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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Abstract
Autoimmune hepatitis is a disease of the hepatic parenchyma that can present in acute or chronic forms. In common with many autoimmune diseases, autoimmune hepatitis is associated with non-organ-specific antibodies in the context of hepatic autoimmunity. This dichotomy has made definition of a unifying hypothesis in the pathophysiology of the disease difficult, although data from the past 8 years have drawn attention to the role of regulatory T cells. Several triggers have been identified, and the disease arises in genetically susceptible individuals. Clinical and biochemical remission is achievable in up to 85% of cases. For the remaining patients, alternative immunosuppression strategies are an option. Liver transplantation provides an excellent outcome for patients with acute liver failure or complications of end-stage liver disease, including hepatocellular carcinoma. Variant or overlapping syndromes are worthy of consideration when unexpected disease features arise.
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Affiliation(s)
- Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.
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Czaja AJ. Autoimmune hepatitis in diverse ethnic populations and geographical regions. Expert Rev Gastroenterol Hepatol 2013; 7:365-85. [PMID: 23639095 DOI: 10.1586/egh.13.21] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis has diverse clinical phenotypes and outcomes in ethnic groups within a country and between countries, and these differences may reflect genetic predispositions, indigenous etiological agents, pharmacogenomic mechanisms and socioeconomic reasons. In the USA, African-American patients have cirrhosis more commonly, treatment failure more frequently and higher mortality than white American patients. Survival is poorest in Asian-American patients. Autoimmune hepatitis in other countries is frequently associated with genetic predispositions that may favor susceptibility to indigenous etiological agents. Cholestatic features influence treatment response; acute-on-chronic liver disease increases mortality and socioeconomic and cultural factors affect prognosis. Ethnic-based deviations from classical phenotypes and the frequency of late-stage disease can complicate the diagnosis and management of autoimmune hepatitis in non-white populations.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Liberal R, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: A comprehensive review. J Autoimmun 2013; 41:126-39. [DOI: 10.1016/j.jaut.2012.11.002] [Citation(s) in RCA: 147] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2012] [Accepted: 11/05/2012] [Indexed: 12/12/2022]
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Czaja AJ. Diagnosis, pathogenesis, and treatment of autoimmune hepatitis after liver transplantation. Dig Dis Sci 2012; 57:2248-66. [PMID: 22562533 DOI: 10.1007/s10620-012-2179-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 04/12/2012] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis can recur or appear de novo after liver transplantation, and it can result in hepatic fibrosis, graft loss, and re-transplantation. The goals of this review are to describe the prevalence, manifestations, putative pathogenic mechanisms, outcomes, and management of these occurrences. Autoimmune hepatitis recurs in 8-12 % of transplanted patients at 1 year and 36-68 % at 5 years. Recurrence may be asymptomatic and detected only by surveillance liver test abnormalities or protocol liver tissue examination. Autoantibodies that characterized the original disease, hypergammaglobulinemia, increased serum immunoglobulin G level, and histological findings of interface hepatitis, lymphoplasmacytic infiltration, perivenular hepatocyte necrosis, pseudo-rosetting, and acidophil bodies typify recurrence. Premature corticosteroid withdrawal and pre-transplant severity of the original disease are possible risk factors. De novo autoimmune hepatitis occurs in 1-7 % of patients 0.1-9 years after transplantation, especially in children. The appearance of autoantibodies may herald its emergence, and antibodies to glutathione-S-transferase T1 have been predictive of the disease. Recurrent disease may reflect recruitment of residual memory T lymphocytes and host-specific genetic predispositions, whereas de novo disease may reflect an allo-antigenic immune response and molecular mimicries that override self-tolerance. Treatment should be appropriate for autoimmune hepatitis and not based on anti-rejection drugs. Corticosteroid therapy alone or combined with azathioprine is the essential treatment. The substitution of mycophenolate mofetil for azathioprine and switch of the calcineurin inhibitor or its replacement with rapamycin have also been used for refractory disease. Re-transplantation has been necessary in 8-23 %.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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Abstract
Autoimmune hepatitis has a variable clinical phenotype, and the absence of conventional autoantibodies does not preclude its diagnosis or need for treatment. The goals of this review are to describe the frequency and nature of autoantibody-negative autoimmune hepatitis, indicate its outcome after corticosteroid treatment, and increase awareness of the diagnosis in patients with unexplained acute and chronic hepatitis. The frequency of presumed autoantibody-negative autoimmune hepatitis in patients with acute and acute severe presentations is ≤7%, and its frequency in patients with chronic presentations is 1-34%. Patients with acute presentations can have normal serum γ-globulin levels, centrilobular zone 3 necrosis, and low pre-treatment international diagnostic scores. Liver tissue examination is essential for the diagnosis, and hepatic steatosis can be a co-morbid feature. The comprehensive international scoring system can support but never override the clinical diagnosis pre-treatment, and non-standard serological markers should be sought if the clinical diagnosis is uncertain or the diagnostic score is low. A 3-month treatment trial with corticosteroids should be considered in all patients, regardless of the serological findings, and improvements have occurred in 67-87% of cases. Autoantibody-negative autoimmune hepatitis may be associated with an autoantibody outside the conventional battery; it may have a signature autoantibody that is still undiscovered, or its characteristic autoantibodies may have been suppressed or have a delayed expression. The pathogenic mechanisms are presumed to be identical to those of classical disease. Autoantibody-negative autoimmune hepatitis is an infrequent but treatable disease that must be considered in unexplained acute and chronic hepatitis.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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