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Yuming Z, Ruqi T, Gershwin ME, Xiong M. Autoimmune Hepatitis: Pathophysiology. Clin Liver Dis 2024; 28:15-35. [PMID: 37945156 DOI: 10.1016/j.cld.2023.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Genome-wide association analyses suggest that HLA genes including HLA-DRB*0301, HLA-DRB*0401, and HLA-B*3501 as well as non-HLA genes including CD28/CTLA4/ICOS and SYNPR increased AIH susceptibility. The destruction of hepatocytes is the result of the imbalance between proinflammatory cells and immunosuppressive cells, especially the imbalance between Tregs and Th17 cells. The microbiome in patients with AIH is decreased in diversity with a specific decline in Bifidobacterium and enrichment in Veillonella and Faecalibacterium. Recent evidence has demonstrated the pathogenic role of E. gallinarum and L.reuteri in inducing autoimmunity in the liver.
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Affiliation(s)
- Zhou Yuming
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Tang Ruqi
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Merrill Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
| | - Ma Xiong
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China; Institute of Aging & Tissue Regeneration, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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2
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Rojas M, Herrán M, Ramírez-Santana C, Leung PSC, Anaya JM, Ridgway WM, Gershwin ME. Molecular mimicry and autoimmunity in the time of COVID-19. J Autoimmun 2023; 139:103070. [PMID: 37390745 PMCID: PMC10258587 DOI: 10.1016/j.jaut.2023.103070] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/26/2023] [Accepted: 06/03/2023] [Indexed: 07/02/2023]
Abstract
Infectious diseases are commonly implicated as potential initiators of autoimmune diseases (ADs) and represent the most commonly known factor in the development of autoimmunity in susceptible individuals. Epidemiological data and animal studies on multiple ADs suggest that molecular mimicry is one of the likely mechanisms for the loss of peripheral tolerance and the development of clinical disease. Besides molecular mimicry, other mechanisms such as defects in central tolerance, nonspecific bystander activation, epitope-determinant spreading, and/or constant antigenic stimuli, may also contribute for breach of tolerance and to the development of ADs. Linear peptide homology is not the only mechanism by which molecular mimicry is established. Peptide modeling (i.e., 3D structure), molecular docking analyses, and affinity estimation for HLAs are emerging as critical strategies when studying the links of molecular mimicry in the development of autoimmunity. In the current pandemic, several reports have confirmed an influence of SARS-CoV-2 on subsequent autoimmunity. Bioinformatic and experimental evidence support the potential role of molecular mimicry. Peptide dimensional analysis requires more research and will be increasingly important for designing and distributing vaccines and better understanding the role of environmental factors related to autoimmunity.
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Affiliation(s)
- Manuel Rojas
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA; Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
| | - María Herrán
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Carolina Ramírez-Santana
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Juan-Manuel Anaya
- Health Research and Innovation Center at Coosalud, Cartagena, 130001, Colombia
| | - William M Ridgway
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
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Czaja AJ. Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis. Dig Dis Sci 2023:10.1007/s10620-023-07967-5. [PMID: 37160542 PMCID: PMC10169207 DOI: 10.1007/s10620-023-07967-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 05/01/2023] [Indexed: 05/11/2023]
Abstract
Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular mimicry as a cause of autoimmune hepatitis, indicates the limitations and uncertainties of this premise, and encourages investigations that assess diverse environmental antigens as sources of disease-relevant molecular mimics. Pertinent articles were identified in PubMed using multiple search phrases. Several pathogens have linear or conformational epitopes that mimic the self-antigens of autoimmune hepatitis. The occurrence of an acute immune-mediated hepatitis after vaccination for severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) has suggested that vaccine-induced peptides may mimic disease-relevant tissue antigens. The intestinal microbiome is an under-evaluated source of gut-derived antigens that could also engage in molecular mimicry. Chaperone molecules may enhance the pathogenicity of molecular mimics, and they warrant investigation. Molecular mimics of immune dominant epitopes within cytochrome P450 IID6, the autoantigen most closely associated with autoimmune hepatitis, should be sought in diverse environmental antigens and assessed for pathogenicity. Avoidance strategies, dietary adjustments, vaccine improvement, and targeted manipulation of the intestinal microbiota may emerge as therapeutic possibilities. In conclusion, molecular mimicry may be a missing causality of autoimmune hepatitis. Molecular mimics of key immune dominant epitopes of disease-specific antigens must be sought in diverse environmental antigens. The ubiquity of molecular mimicry compels rigorous assessments of peptide mimics for immunogenicity and pathogenicity in experimental models. Molecular mimicry may complement epigenetic modifications as causative mechanisms of autoimmune hepatitis.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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Lapierre P, Alvarez F. Type 2 autoimmune hepatitis: Genetic susceptibility. Front Immunol 2022; 13:1025343. [PMID: 36248826 PMCID: PMC9556705 DOI: 10.3389/fimmu.2022.1025343] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/14/2022] [Indexed: 11/13/2022] Open
Abstract
Two types of autoimmune hepatitis (AIH) are recognized; AIH-1 is characterized by the presence of anti-nuclear and/or anti-smooth muscle autoantibodies, while AIH-2 is associated with the presence of anti-Liver kidney microsome and/or anti-Liver Cytosol antibodies. The autoantigens targeted by AIH-2 autoantibodies are the cytochrome P450 2D6 and Formiminotransferase-cyclodeaminase for anti-LKM1 and anti-LC1 respectively. Both autoantigens are expressed in hepatocytes at higher levels than in any other cell type. Therefore, compared to AIH-1, the autoantigens targeted in AIH-2 are predominantly tissue-specific. Distinct clinical features are specific to AIH-2 compared to AIH-1, including diagnosis in younger patients (mean age 6.6 years), onset as fulminant hepatitis in very young patients (3 years of age or less), higher frequency in children than in adults and is frequently associated with extrahepatic T cell-mediated autoimmune diseases. AIH-2 is also often diagnosed in patients with primary immunodeficiency. AIH-2 is associated with specific HLA class II susceptibility alleles; DQB1*0201 is considered the main determinant of susceptibility while DRB1*07/DRB1*03 is associated with the type of autoantibody present. HLA DQB1*0201 is in strong linkage disequilibrium with both HLA DRB1*03 and DRB1*07. Interestingly, as in humans, MHC and non-MHC genes strongly influence the development of the disease in an animal model of AIH-2. Altogether, these findings suggest that AIH-2 incidence is likely dependent on specific genetic susceptibility factors combined with distinct environmental triggers.
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Affiliation(s)
- Pascal Lapierre
- Laboratoire d’hépatologie cellulaire, Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Université de Montréal, Montréal, QC, Canada
| | - Fernando Alvarez
- Service de gastroentérologie, hépatologie et nutrition, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Montréal, QC, Canada
- Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada
- *Correspondence: Fernando Alvarez,
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de Castro GLC, da Silva Graça Amoras E, Araújo MS, da Silva Conde SRS, Bichara CDA, Queiroz MAF, Vallinoto ACR. High prevalence of antinuclear antibodies in patients with chronic hepatitis C virus infection. Eur J Med Res 2022; 27:180. [PMID: 36114565 PMCID: PMC9479388 DOI: 10.1186/s40001-022-00809-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/06/2022] [Indexed: 11/24/2022] Open
Abstract
Background Hepatitis C virus (HCV) infection is a serious public health concern due to its high prevalence and mortality rate. In chronic infection, HCV may induce autoimmune responses through the production of autoantibodies, including antinuclear antibodies (ANA). Methods We assessed the presence of ANA by indirect immunofluorescence using HEp-2 cells in 89 patients with chronic hepatitis C. We also collected data on epidemiological variables; clinical characteristics; and biochemical, hematological, molecular, and histopathological information from the patients to assess the impact of the presence of ANA in those patients. Results The prevalence of ANA in the patients was 20.2%, which was significantly higher than that found in healthy controls (2%). However, there was no association of this marker with epidemiological, clinical-laboratory, molecular or histopathological characteristics of hepatitis C, although a slightly higher prevalence of ANA was detected in women and in patients infected with subgenotype 1a. In a specific analysis, chronic HCV patients with the “rods and rings” cytoplasmic pattern had higher degrees of hepatic fibrosis than did ANA-negative patients. Conclusions The results confirm a greater predisposition to the presence of ANA in patients with HCV, which may be associated with a worse prognosis, especially in the presence of the “rods and rings” cytoplasmic pattern.
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The intestinal and biliary microbiome in autoimmune liver disease-current evidence and concepts. Semin Immunopathol 2022; 44:485-507. [PMID: 35536431 PMCID: PMC9088151 DOI: 10.1007/s00281-022-00936-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 04/03/2022] [Indexed: 02/07/2023]
Abstract
Autoimmune liver diseases are a group of immune-mediated liver diseases with three distinct entities, including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. The interplay of genetic and environmental factors leads to the breakdown of self-tolerance, resulting in hyper-responsiveness, and auto-aggressive immune activation. Emerging evidence links autoimmune liver diseases with alterations of the commensal microbiome configuration and aberrant immune system activation by microbial signals, mainly via the gut-liver axis. Thus, the microbiome is a new frontier to deepen the pathogenetic understanding, uncover biomarkers, and inspire innovative treatments. Herein, we review the current evidence on the role of the microbiome in autoimmune liver diseases from both clinical and basic research. We highlight recent achievements and also bottlenecks and limitations. Moreover, we give an outlook on future developments and potential for clinical applications.
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S-Are V, Yoder L, Samala N, Nephew L, Lammert C, Vuppalanchi R. An Outbreak Presents An Opportunity to Learn About A Rare Phenotype: Autoimmune Hepatitis After Acute Hepatitis A. Ann Hepatol 2021; 19:694-696. [PMID: 32927125 DOI: 10.1016/j.aohep.2020.08.069] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/18/2020] [Accepted: 08/21/2020] [Indexed: 02/04/2023]
Abstract
There are rare instances where patients with acute hepatitis A virus infection subsequently developed autoimmune hepatitis. The diagnosis of autoimmune hepatitis in this setting is challenging. Furthermore, information on treatment with steroids or other immune suppressants, duration of therapy and possibility of treatment discontinuation is currently unclear. Here we report a case series of four patients with histology proven autoimmune hepatitis after hepatitis A virus infection. We describe the presenting features, diagnosis, treatment and long-term outcomes of these cases. This case series provides a insight into the clinical presentation and treatment of autoimmune hepatitis after hepatitis A infection with interesting take home points for clinical hepatologists.
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Affiliation(s)
- Vijay S-Are
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis IN, USA
| | - Lindsay Yoder
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis IN, USA
| | - Niharika Samala
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis IN, USA
| | - Lauren Nephew
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis IN, USA
| | - Craig Lammert
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis IN, USA
| | - Raj Vuppalanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis IN, USA.
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Decrocq-Rudler MA, Chan Kwong AHXP, Meunier L, Fraisse J, Ursic-Bedoya J, Khier S. Can We Predict Individual Concentrations of Tacrolimus After Liver Transplantation? Application and Tweaking of a Published Population Pharmacokinetic Model in Clinical Practice. Ther Drug Monit 2021; 43:490-498. [PMID: 33560099 DOI: 10.1097/ftd.0000000000000867] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 01/04/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Various population pharmacokinetic models have been developed to describe the pharmacokinetics of tacrolimus in adult liver transplantation. However, their extrapolated predictive performance remains unclear in clinical practice. The purpose of this study was to predict concentrations using a selected literature model and to improve these predictions by tweaking the model with a subset of the target population. METHODS A literature review was conducted to select an adequate population pharmacokinetic model (L). Pharmacokinetic data from therapeutic drug monitoring of tacrolimus in liver-transplanted adults were retrospectively collected. A subset of these data (70%) was exploited to tweak the L-model using the $PRIOR subroutine of the NONMEM software, with 2 strategies to weight the prior information: full informative (F) and optimized (O). An external evaluation was performed on the remaining data; bias and imprecision were evaluated for predictions a priori and Bayesian forecasting. RESULTS Seventy-nine patients (851 concentrations) were enrolled in the study. The predictive performance of L-model was insufficient for a priori predictions, whereas it was acceptable with Bayesian forecasting, from the third prediction (ie, with ≥2 previously observed concentrations), corresponding to 1 week after transplantation. Overall, the tweaked models showed a better predictive ability than the L-model. The bias of a priori predictions was -41% with the literature model versus -28.5% and -8.73% with tweaked F and O models, respectively. The imprecision was 45.4% with the literature model versus 38.0% and 39.2% with tweaked F and O models, respectively. For Bayesian predictions, whatever the forecasting state, the tweaked models tend to obtain better results. CONCLUSIONS A pharmacokinetic model can be used, and to improve the predictive performance, tweaking the literature model with the $PRIOR approach allows to obtain better predictions.
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Affiliation(s)
- Marie-Astrid Decrocq-Rudler
- Pharmacokinetic and Modeling Department, School of Pharmacy, Montpellier University, Montpellier, France
- Probabilities and Statistics Department, Institut Montpellierain Alexander Grothendieck (IMAG), Montpellier University, Montpellier, France
| | - Anna H-X P Chan Kwong
- Pharmacokinetic and Modeling Department, School of Pharmacy, Montpellier University, Montpellier, France
- Probabilities and Statistics Department, Institut Montpellierain Alexander Grothendieck (IMAG), Montpellier University, Montpellier, France
- SMARTc Group, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Aix-Marseille University, Marseille, France
| | - Lucy Meunier
- Department of Hepato-Gastroenterology and Liver Transplantation, Montpellier University Hospital (Saint Eloi), Montpellier, France ; and
| | | | - José Ursic-Bedoya
- Department of Hepato-Gastroenterology and Liver Transplantation, Montpellier University Hospital (Saint Eloi), Montpellier, France ; and
| | - Sonia Khier
- Pharmacokinetic and Modeling Department, School of Pharmacy, Montpellier University, Montpellier, France
- Probabilities and Statistics Department, Institut Montpellierain Alexander Grothendieck (IMAG), Montpellier University, Montpellier, France
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Llovet LP, Gratacós-Ginés J, Ortiz O, Rodriguez-Tajes S, Lens S, Reverter E, Ruiz-Ortiz E, Costa J, Viñas O, Forns X, Parés A, Londoño MC. Higher seroprevalence of hepatitis E virus in autoimmune hepatitis: Role of false-positive antibodies. Liver Int 2020; 40:558-564. [PMID: 31863722 DOI: 10.1111/liv.14332] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 12/01/2019] [Accepted: 12/15/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Recent studies have found an increase in the seroprevalence of hepatitis E virus (HEV) infection in patients with autoimmune hepatitis (AIH). We aimed to assess the prevalence of positive anti-HEV IgM and IgG, and HEV-RNA in a cohort of patients with AIH, to determine the impact of positive HEV serology on patient outcome, and to evaluate the role of hypergammaglobulinemia and positive autoantibodies in the presence of positive anti-HEV serology. METHODS One hundred and five patients tested for HEV infection between 2014 and 2018 were included in the study: 50 with chronic AIH (more than 1 year on treatment), and 55 with an acute hepatitis (30 patients with acute AIH and 25 with non-AIH). RESULTS Seroprevalence of HEV was higher in patients with acute AIH (17% vs 10% in patients with chronic AIH and 8% in patients with non-AIH). Patients with acute AIH and positive anti-HEV IgG were older (58 vs 40; P = .006), had higher IgG levels (27 g/dL vs 13 g/dL; P = .03) and antismooth muscle antibodies (ASMA) titres (1:160 vs 1:80; P = .045), and were more likely to have another autoimmune disease (60% vs 16%; P = .03). At the time of HEV testing, anti-HEV IgG positive patients had significantly higher serum IgG levels (17 g/L vs 11 g/L; P = .009), ANA (1:160 vs 1:60; P = .026) and ASMA titres (1:80 vs 1:40; P = .021). CONCLUSION Seroprevalence of HEV in patients with AIH in Catalonia does not differ from that of the general population. The higher HEV seroprevalence in patients with acute AIH with higher levels of gammaglobulins and high antibody titres suggest the presence of cross-reactivity between HEV and liver antigens.
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Affiliation(s)
| | | | - Oswaldo Ortiz
- Liver Unit, Hospital Clinic Barcelona, CIBERehd, IDIBAPS, Barcelona, Spain
| | | | - Sabela Lens
- Liver Unit, Hospital Clinic Barcelona, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Enric Reverter
- Liver Unit, Hospital Clinic Barcelona, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Estibaliz Ruiz-Ortiz
- Immunology Department, Centre Diagnòstic Biomèdic, Hospital Clínic Barcelona, IDIBAPS, Barcelona, Spain
| | - Josep Costa
- Microbiology Service, Hospital Clinic, University of Barcelona, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Odette Viñas
- Immunology Department, Centre Diagnòstic Biomèdic, Hospital Clínic Barcelona, IDIBAPS, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic Barcelona, CIBERehd, IDIBAPS, Barcelona, Spain
| | - Albert Parés
- Liver Unit, Hospital Clinic Barcelona, CIBERehd, IDIBAPS, Barcelona, Spain
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Rojas M, Restrepo-Jiménez P, Monsalve DM, Pacheco Y, Acosta-Ampudia Y, Ramírez-Santana C, Leung PS, Ansari AA, Gershwin ME, Anaya JM. Molecular mimicry and autoimmunity. J Autoimmun 2018; 95:100-123. [DOI: 10.1016/j.jaut.2018.10.012] [Citation(s) in RCA: 214] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/12/2018] [Accepted: 10/16/2018] [Indexed: 12/15/2022]
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11
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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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12
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Christen U, Hintermann E. Pathogens and autoimmune hepatitis. Clin Exp Immunol 2018; 195:35-51. [PMID: 30113082 DOI: 10.1111/cei.13203] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 07/30/2018] [Accepted: 08/06/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe form of hepatitis resulting in the autoimmune-mediated destruction of the liver parenchyma. Whereas many of the immunopathogenic events have been elucidated and some of the drivers of the disease have been identified, little is known about the aetiology of the disease. There are certain risk factors, such as particular human leucocyte antigen (HLA) haplotypes, that enhance the susceptibility for AIH or influence the severity of the disease. However, as for many other autoimmune diseases, the mere presence of such risk factors does not warrant the occurrence of the disease. Not all individuals carrying risk factors develop AIH, and not all patients with AIH are carriers of high-risk alleles. Thus, additional environmental factors need to be considered as triggers for AIH. Environmental factors include diet, sunlight exposure, stress, medication and hygiene, as well as pathogen infections and vaccinations. This review discusses if pathogens should be considered as triggers for the initiation and/or propagation of AIH.
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Affiliation(s)
- U Christen
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| | - E Hintermann
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
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13
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Christen U. Animal models of autoimmune hepatitis. Biochim Biophys Acta Mol Basis Dis 2018; 1865:970-981. [PMID: 29857050 DOI: 10.1016/j.bbadis.2018.05.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 05/14/2018] [Accepted: 05/22/2018] [Indexed: 02/06/2023]
Abstract
Many animal models for autoimmune hepatitis (AIH) have been described in the past. Most models had to deal with the relative immunosuppressive environment of the liver. Therefore, some models used a combination of several triggering factors often on a susceptible background to generate an aggressive immune response that targets the liver. In addition, in order to be able to track the immune response the models used specific model autoantigens as targets that are either not present or have not been identified as a natural autoantigen in AIH patients. Thereby the feasibility of such models is somewhat questionable. Although many historic approaches included challenges of experimental animals with liver homogenates it was only in the last decade that natural occurring liver autoantigens have been used in animal models. This article reflects on the requirements for breaking liver tolerance and on how an ideal experimental model for AIH would look like. In addition, it discusses historic as well as recent animal models in the context of feasibility of induction, similarity of the clinical outcome to human AIH, and gain of knowledge for possible future therapies.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany.
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14
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Christen U, Hintermann E. Autoantibodies in Autoimmune Hepatitis: Can Epitopes Tell Us about the Etiology of the Disease? Front Immunol 2018; 9:163. [PMID: 29503645 PMCID: PMC5820307 DOI: 10.3389/fimmu.2018.00163] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/18/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are serious autoimmune liver diseases that are characterized by a progressive destruction of the liver parenchyma and/or the hepatic bile ducts and the development of chronic fibrosis. Left untreated autoimmune liver diseases are often life-threatening, and patients require a liver transplantation to survive. Thus, an early and reliable diagnosis is paramount for the initiation of a proper therapy with immunosuppressive and/or anticholelithic drugs. Besides the analysis of liver biopsies and serum markers indicating liver damage, the screening for specific autoantibodies is an indispensable tool for the diagnosis of autoimmune liver diseases. Such liver autoantigen-specific antibodies might be involved in the disease pathogenesis, and their epitope specificity may give some insight into the etiology of the disease. Here, we will mainly focus on the generation and specificity of autoantibodies in AIH patients. In addition, we will review data from animal models that aim toward a better understanding of the origins and pathogenicity of such autoantibodies.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
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15
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Christen U, Hintermann E. Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models? Int J Mol Sci 2016; 17:ijms17122007. [PMID: 27916939 PMCID: PMC5187807 DOI: 10.3390/ijms17122007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/22/2016] [Accepted: 11/23/2016] [Indexed: 12/14/2022] Open
Abstract
Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel therapeutic strategies has been hampered by a lack of understanding the basic immunopathogenic mechanisms of AIH and the absence of valid animal models. However, in the past decade, knowledge from clinical observations in AIH patients and the development of innovative animal models have led to a situation where critical factors driving the disease have been identified and alternative treatments are being evaluated. Here we will review the insight on the immunopathogenesis of AIH as gained from clinical observation and from animal models.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
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Murira A, Lapierre P, Lamarre A. Evolution of the Humoral Response during HCV Infection: Theories on the Origin of Broadly Neutralizing Antibodies and Implications for Vaccine Design. Adv Immunol 2015; 129:55-107. [PMID: 26791858 DOI: 10.1016/bs.ai.2015.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Similar to human immunodeficiency virus (HIV)-1, vaccine-induced elicitation of broadly neutralizing (bNt) antibodies (Abs) is gaining traction as a key goal toward the eradication of the hepatitis C virus (HCV) pandemic. Previously, the significance of the Ab response against HCV was underappreciated given the prevailing evidence advancing the role of the cellular immune response in clearance and overall control of the infection. However, recent findings have driven growing interest in the humoral arm of the immune response and in particular the role of bNt responses due to their ability to confer protective immunity upon passive transfer in animal models. Nevertheless, the origin and development of bNt Abs is poorly understood and their occurrence is rare as well as delayed with emergence only observed in the chronic phase of infection. In this review, we characterize the interplay between the host immune response and HCV as it progresses from the acute to chronic phase of infection. In addition, we place these events in the context of current hypotheses on the origin of bNt Abs against the HIV-1, whose humoral immune response is better characterized. Based on the increasing significance of the humoral immune response against HCV, characterization of these events may be critical in understanding the development of the bNt responses and, thus, provide strategies toward effective vaccine design.
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Affiliation(s)
- Armstrong Murira
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
| | - Pascal Lapierre
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, Quebec, Canada
| | - Alain Lamarre
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
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17
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Escape of pathogens from the host immune response by mutations and mimicry. Possible means to improve vaccine performance. Med Hypotheses 2015; 85:664-9. [PMID: 26341417 DOI: 10.1016/j.mehy.2015.08.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 08/13/2015] [Indexed: 11/21/2022]
Abstract
The ability of certain pathogens, such as human immunodeficiency, hepatitis C, herpes simplex, influenza viruses, Plasmodium falciparum, etc., to escape from host immune response is generally ascribed to high mutation rate of their genome. We challenge this assumption and propose that molecular mimicry of host antigens by these pathogens could also participate to this resistance. Several studies show that there is no correlation between the mutation rate value of a pathogen and the possibility to develop an effective vaccine. On the other hand, pathogens which do not respond to vaccine are usually reported to display host protein mimicry. We propose to suppress in the thymus the epitopes of the self which are in common with the pathogen. This could be achieved by intrathymic injection of antibodies against this microorganism. These antibodies would be obtained by vaccination of a foreign animal species. It is expected that the negative selection of the CD4(+) and CD8(+) T lymphocytes specific for these epitopes would be prevented, that the number of epitopes recognized as foreign to the host would be increased and that the immune response diversity would be enhanced.
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Ohira H, Abe K, Takahashi A, Watanabe H. Autoimmune hepatitis: recent advances in the pathogenesis and new diagnostic guidelines in Japan. Intern Med 2015; 54:1323-8. [PMID: 26027981 DOI: 10.2169/internalmedicine.54.4125] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Autoimmune hepatitis (AIH) is thought to be associated with various genetic and immunological abnormalities. Concerning the pathogenesis of AIH, increasing attention has been paid to genome-wide association studies, toll-like receptors and Treg/Th17 balance. For Japanese patients with AIH, novel diagnostic guidelines have been proposed in view of the differential clinical features between Japanese and Caucasian patients. However, the diagnosis of some patients in acute hepatitis phase is not easy. Histologically, centrilobular necrosis without portal inflammation is particularly characteristic in the acute hepatitis phase. Some patients become resistant to steroid therapy and have a very poor prognosis once they progress to acute hepatic failure. Therefore, additional revision of the current diagnostic criteria, including severity grading, will be needed in the future.
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Affiliation(s)
- Hiromasa Ohira
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Japan
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Sutti S, Rigamonti C, Vidali M, Albano E. CYP2E1 autoantibodies in liver diseases. Redox Biol 2014; 3:72-78. [PMID: 25462068 PMCID: PMC4297929 DOI: 10.1016/j.redox.2014.11.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 11/10/2014] [Accepted: 11/11/2014] [Indexed: 12/11/2022] Open
Abstract
Autoimmune reactions involving cytochrome P4502E1 (CYP2E1) are a feature of idiosyncratic liver injury induced by halogenated hydrocarbons and isoniazid, but are also detectable in about one third of the patients with advanced alcoholic liver disease (ALD) and chronic hepatitis C (CHC). In these latter the presence of anti-CYP2E1 auto-antibodies is an independent predictor of extensive necro-inflammation and fibrosis and worsens the recurrence of hepatitis following liver transplantation, indicating that CYP2E1-directed autoimmunity can contribute to hepatic injury. The molecular characterization of the antigens recognized by anti-CYP2E1 auto-antibodies in ALD and CHC has shown that the targeted conformational epitopes are located in close proximity on the molecular surface. Furthermore, these epitopes can be recognized on CYP2E1 expressed on hepatocyte plasma membranes where they can trigger antibody-mediated cytotoxicity. This does not exclude that T cell-mediated responses against CYP2E1 might also be involved in causing hepatocyte damage. CYP2E1 structural modifications by reactive metabolites and molecular mimicry represent important factors in the breaking of self-tolerance against CYP2E1 in, respectively, ALD and CHC. However, genetic or acquired interferences with the mechanisms controlling the homeostasis of the immune system are also likely to contribute. More studies are needed to better characterize the impact of anti-CYP2E1 autoimmunity in liver diseases particularly in relation to the fact that common metabolic alterations such as obesity and diabetes stimulates hepatic CYP2E1 expression.
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Affiliation(s)
- Salvatore Sutti
- Department of Health Sciences, University "Amedeo Avogadro" of East Piedmont and Interdepartmental Research Centre for Autoimmune Diseases (IRCAD), Novara, Italy
| | | | - Matteo Vidali
- Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy
| | - Emanuele Albano
- Department of Health Sciences, University "Amedeo Avogadro" of East Piedmont and Interdepartmental Research Centre for Autoimmune Diseases (IRCAD), Novara, Italy.
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Abstract
Autoimmune disorders afflicting the liver comprise the bona fide autoimmune diseases, primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis as well as drug-induced autoimmune-like diseases, such as halothane hepatitis. Whereas drug-induced forms of acute or chronic hepatitis often have a clear triggering factor, the etiology of classical autoimmune liver diseases is only poorly understood. Besides a genetic component present in disease susceptible individuals, environmental triggering factors are likely to play a role in the initiation and/or propagation of the disease. In this article, we will review on current evidence obtained from epidemiological associations, case studies, and findings in animal models for pathogens, to be involved in the etiology of autoimmune liver disease with a special focus on autoimmune hepatitis.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital , Frankfurt am Main , Germany
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21
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Abstract
Antibodies play an important role in autoimmune liver diseases, such as autoimmune hepatitis (AIH). On the one hand, they are essential diagnostic markers to identify not only the presentation of AIH, but also the AIH subtype characterized by the presence of particular antibodies to target autoantigens in the liver. On the other hand, such autoantibodies might be directly involved in the etiology and/or pathogenesis of AIH. This review will reflect on the evidence of how specific autoantibodies influence AIH and will further provide insight into the necessities for generating therapeutic antibodies to treat AIH in the future.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital Frankfurt, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany
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Uzicanin S, Hu YW, Alsousi H, Pelchat M, Rocheleau L, Nair RC, Brown EG. Hepatitis C virus: the role of molecular mimicry in response to interferon treatment. J Med Virol 2013; 84:1571-85. [PMID: 22930505 DOI: 10.1002/jmv.23361] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease worldwide. In order for HCV to persist, the virus must escape immune recognition or inhibit the host immune response. The NS5A protein contains the interferon sensitivity-determining region (ISDR) and is able to repress dsRNA-dependent protein kinase (PKR) thus influencing the response to interferon (IFN) therapy. Patients who respond to IFN therapy have stronger antibody reactivity against the NS5A compared to IFN non-responders. Therefore, given the possible role for the ISDR in IFN resistance and differential antibody reactivity, it is possible that variation in ISDR may be involved in viral immune escape and development of persistent HCV infection employing aspects of host mimicry. In this study, pre-treatment samples obtained from HCV infected patients were used to investigate the effect of different NS5A ISDR variants on the IFN antiviral response and their involvement in immune evasion. The NS5A was identified as a homologue of the variable region of immunoglobulins (Ig). The IFN resistant genotypes had higher levels of similarity to Ig compared to IFN sensitive genotypes. Expression of NS5A-6003 (HCV genotype 1b) and NS5A-6074 (HCV genotype 2a) was able to rescue vesicular stomatitis virus (VSV) from IFN inhibition and restore luciferase activity. A correlation between Ig-like NS5A structure and also antibody response with the outcome of IFN treatment was observed.
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Affiliation(s)
- Samra Uzicanin
- Department of Epidemiology and Surveillance, Canadian Blood Services, Ottawa, Ontario, Canada.
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23
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Ehser J, Holdener M, Christen S, Bayer M, Pfeilschifter JM, Hintermann E, Bogdanos D, Christen U. Molecular mimicry rather than identity breaks T-cell tolerance in the CYP2D6 mouse model for human autoimmune hepatitis. J Autoimmun 2012. [PMID: 23200317 DOI: 10.1016/j.jaut.2012.11.001] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
In our novel mouse model for autoimmune hepatitis (AIH), wildtype FVB mice infected with an Adenovirus (Ad) expressing the major AIH autoantigen human cytochrome P450 2D6 (hCYP2D6) show persistent histological and immunological features associated with AIH, including the generation of anti-hCYP2D6 antibodies with an epitope specificity identical to LKM-1 autoantibodies in AIH-patients. Since FVB mice do not express hCYP2D6, the immune response was directed against mouse CYP (mCYP) homologues. Additional expression of hCYP2D6 in transgenic mice resulted in amelioration of the liver disease. In the present study we used the CYP2D6 model to assess why tolerance breakdown and induction of autoimmune liver disease is more efficient if the triggering antigen is similar but not identical to the target autoantigen. We found that in contrast to the specificity and magnitude of anti-hCYP2D6 antibody responses, T-cell responses differ profoundly between wildtype and transgenic mice. Detailed T-cell epitope mapping studies show a robust, antigen-specific T-cell reactivity in FVB mice largely directed against one CD4 and three CD8 epitopes, activating a total of approximately 1% CD4 and 10% CD8 T-cells, respectively, while infected hCYP2D6 mice generated almost no hCYP2D6-specific T-cells. The frequency of hCYP2D6-specific T-cells was approximately 3-fold higher in the liver compared with the spleen. Amino acid sequence comparison revealed that the immunodominant epitopes were located in hCYP2D6-segments of intermediate homology between hCYP2D6 and its mCYP homologues. Our data indicate that self/non-self molecular mimicry, rather than molecular identity, is a prerequisite for breaking T-cell tolerance in the liver.
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Affiliation(s)
- Janine Ehser
- Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe Universität, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany
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24
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Human poly- and cross-reactive anti-viral antibodies and their impact on protection and pathology. Immunol Res 2012; 53:148-61. [DOI: 10.1007/s12026-012-8268-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Lapierre P, Troesch M, Alvarez F, Soudeyns H. Structural basis for broad neutralization of hepatitis C virus quasispecies. PLoS One 2011; 6:e26981. [PMID: 22046426 PMCID: PMC3202596 DOI: 10.1371/journal.pone.0026981] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Accepted: 10/07/2011] [Indexed: 12/14/2022] Open
Abstract
Monoclonal antibodies directed against hepatitis C virus (HCV) E2 protein can neutralize cell-cultured HCV and pseudoparticles expressing envelopes derived from multiple HCV subtypes. For example, based on antibody blocking experiments and alanine scanning mutagenesis, it was proposed that the AR3B monoclonal antibody recognized a discontinuous conformational epitope comprised of amino acid residues 396-424, 436-447, and 523-540 of HCV E2 envelope protein. Intriguingly, one of these segments (436-447) overlapped with hypervariable region 3 (HVR3), a domain that exhibited significant intrahost and interhost genetic diversity. To reconcile these observations, amino-acid sequence variability was examined and homology-based structural modelling of E2 based on tick-borne encephalitis virus (TBEV) E protein was performed based on 413 HCV sequences derived from 18 subjects with chronic hepatitis C. Here we report that despite a high degree of amino-acid sequence variability, the three-dimensional structure of E2 is remarkably conserved, suggesting broad recognition of structural determinants rather than specific residues. Regions 396-424 and 523-540 were largely exposed and in close spatial proximity at the surface of E2. In contrast, region 436-447, which overlaps with HVR3, was >35 Å away, and estimates of buried surface were inconsistent with HVR3 being part of the AR3B binding interface. High-throughput structural analysis of HCV quasispecies could facilitate the development of novel vaccines that target conserved structural features of HCV envelope and elicit neutralizing antibody responses that are less vulnerable to viral escape.
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Affiliation(s)
- Pascal Lapierre
- Service de Gastroentérologie, Hépatologie et Nutrition, Centre de Recherche du Centre Hospitalier Universitaire, Sainte-Justine, Montreal, Quebec, Canada
| | - Myriam Troesch
- Unité d'Iimmunopathologie Virale, Centre de Recherche du Centre Hospitalier Universitaire, Sainte-Justine, Montreal, Quebec, Canada
- Department of Microbiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Fernando Alvarez
- Service de Gastroentérologie, Hépatologie et Nutrition, Centre de Recherche du Centre Hospitalier Universitaire, Sainte-Justine, Montreal, Quebec, Canada
- Department of Microbiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
- Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Hugo Soudeyns
- Unité d'Iimmunopathologie Virale, Centre de Recherche du Centre Hospitalier Universitaire, Sainte-Justine, Montreal, Quebec, Canada
- Department of Microbiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
- Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
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26
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Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model. J Autoimmun 2011; 37:242-53. [PMID: 21795021 DOI: 10.1016/j.jaut.2011.06.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Revised: 06/17/2011] [Accepted: 06/24/2011] [Indexed: 12/13/2022]
Abstract
Autoimmune hepatitis (AIH) is a serious chronic inflammatory disease of the liver with yet unknown etiology and largely uncertain immunopathology. The hallmark of type 2 AIH is the generation of liver kidney microsomal-1 (LKM-1) autoantibodies, which predominantly react to cytochrome P450 2D6 (CYP2D6). The identification of disease initiating factors has been hampered in the past, since antibody epitope mapping was mostly performed using serum samples collected late during disease resulting in the identification of immunodominant epitopes not necessarily representing those involved in disease initiation. In order to identify possible environmental triggers for AIH, we analyzed for the first time the spreading of the anti-CYP2D6 antibody response over a prolonged period of time in AIH patients and in the CYP2D6 mouse model, in which mice infected with Adenovirus-human CYP2D6 (Ad-h2D6) develop antibodies with a similar specificity than AIH patients. Epitope spreading was analyzed in six AIH-2-patients and in the CYP2D6 mouse model using SPOTs membranes containing peptides covering the entire CYP2D6 protein. Despite of a considerable variation, both mice and AIH patients largely focus their humoral immune response on an immunodominant epitope early after infection (mice) or diagnosis (patients). The CYP2D6 mouse model revealed that epitope spreading is initiated at the immunodominant epitope and later expands to neighboring and remote regions. Sequence homologies to human pathogens have been detected for all identified epitopes. Our study demonstrates that epitope spreading does indeed occur during the pathogenesis of AIH and supports the concept of molecular mimicry as a possible initiating mechanism for AIH.
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27
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Sutti S, Vidali M, Mombello C, Sartori M, Ingelman-Sundberg M, Albano E. Breaking self-tolerance toward cytochrome P4502E1 (CYP2E1) in chronic hepatitis C: possible role for molecular mimicry. J Hepatol 2010; 53:431-438. [PMID: 20576306 DOI: 10.1016/j.jhep.2010.03.030] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2010] [Revised: 03/09/2010] [Accepted: 03/22/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Circulating auto-antibodies targeting conformational antigens on cytochrome P4502E1 (CYP2E1) are detectable in patients with chronic hepatitis C (CHC) and are associated with more severe necro-inflammation. This study investigated the antigen specificity and the possible origin of these auto-antibodies. METHODS CYP2E1 site-directed mutagenesis and molecular simulation were used to characterize the epitope specificity of CHC-associated anti-CYP2E1 auto-antibodies. RESULTS Immunoprecipitation experiments using differently mutated human CYP2E1s revealed that conformational anti-CYP2E1 antibodies targeted two epitopes located on the molecule surface in an area between Lys(324)-Glu(346) at J-K'' helices overlapping. Such epitopes were not recognized by the sera targeting linear CYP2E1 antigens. The CYP2E1(324-346) peptide showed good homology with two sequences (NS5b(438-449) and NS5b(456-465)) within the NS5b protein of hepatitis C virus (HCV). Consistently, conformational anti-CYP2E1 IgG bind to GST-conjugated NS5b(438-449) and NS5b(456-465) more efficiently than those recognizing CYP2E1 linear antigens. Competition experiments confirmed the cross-reactivity of conformational anti-CYP2E1 IgG with both NS5b(438-449) and NS5b(456-465). Moreover, mice immunized with GST-conjugated NS5b(438-449) or NS5b(456-465) peptides developed antibodies recognizing human CYP2E1. CONCLUSIONS In CHC patients cross-reactivity between CYP2E1 and specific sequences in HCV-NS5b protein can promote the development of auto-antibodies targeting conformational epitopes on the CYP2E1 surface that might contribute to hepatic injury.
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Affiliation(s)
- Salvatore Sutti
- Department of Medical Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University Amedeo Avogadro of East Piedmont Novara, Italy
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28
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Czaja AJ. The role of autoantibodies as diagnostic markers of autoimmune hepatitis. Expert Rev Clin Immunol 2010; 2:33-48. [PMID: 20477086 DOI: 10.1586/1744666x.2.1.33] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autoantibody testing is the first step towards the diagnosis of autoimmune hepatitis, and it is essential in the evaluation of acute and chronic hepatitis of undetermined cause and allograft dysfunction following liver transplantation. A standard diagnostic repertoire has been promulgated, and other autoantibodies are emerging that may have prognostic value. Supplemental autoantibodies may prove useful in assessing patients who lack the standard markers or who are distinctive among those with conventional markers. Serologic testing will improve as assays are standardized by serum exchange workshops, core diagnostic batteries are codified and promulgated, and markers emerge that are tightly associated with pathogenic mechanisms, and closely reflect disease activity and outcome.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA.
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29
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Ferri S, Muratori L, Quarneti C, Muratori P, Menichella R, Pappas G, Granito A, Ballardini G, Bianchi FB, Lenzi M. Clinical features and effect of antiviral therapy on anti-liver/kidney microsomal antibody type 1 positive chronic hepatitis C. J Hepatol 2009; 50:1093-1101. [PMID: 19398235 DOI: 10.1016/j.jhep.2009.02.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2008] [Revised: 01/31/2009] [Accepted: 02/03/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Anti-liver/kidney microsomal antibody type 1 (anti-LKM1), a serological marker of type 2 autoimmune hepatitis, is also detected in a small proportion of patients with hepatitis C. This study aimed to evaluate clinical features and effect of antiviral therapy in patients with hepatitis C who are anti-LKM1 positive. METHODS Sixty consecutive anti-LKM1 positive and 120 age and sex-matched anti-LKM1 negative chronic hepatitis C patients were assessed at diagnosis and during follow-up. Of these, 26 anti-LKM1 positive and 72 anti-LKM1 negative received antiviral therapy. Anti-LKM1 was detected by indirect immunofluorescence and immunoblot. Number of HCV-infected hepatocytes and intrahepatic CD8+ lymphocytes was determined by immunohistochemistry. RESULTS At diagnosis anti-LKM1 positive patients had higher IgG levels and more intrahepatic CD8+ lymphocytes (p 0.022 and 0.046, respectively). Viral genotypes distribution and response to therapy were identical. Hepatic flares during antiviral treatment only occurred in a minority of patients in concomitance with anti-LKM1 positivity. CONCLUSIONS Immune system activation is more pronounced in anti-LKM1 positive patients with hepatitis C, possibly representing the expression of autoimmune mechanisms of liver damage. Antiviral treatment is as beneficial in these patients as in anti-LKM1 negative patients, and the rare necroinflammatory flares are effectively controlled by corticosteroids, allowing subsequent resumption of antiviral therapy.
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Affiliation(s)
- Silvia Ferri
- Department of Clinical Medicine, University of Bologna, S. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy.
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Thyroid disorders and occurrence of nonorgan-specific autoantibodies (NOSA) in patients with chronic hepatitis C before and during antiviral induction therapy with consensus interferon (interferon alfacon-1). J Clin Gastroenterol 2009; 43:470-6. [PMID: 19247202 DOI: 10.1097/mcg.0b013e318184a470] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Thyroid disorders represent a common side effect of antiviral therapy in patients with chronic hepatitis C (CHC). However, there is strong evidence for a higher prevalence of thyroidal antibodies (TA) and nonorgan-specific autoantibodies (NOSA) even before interferon (IFN) administration. Here, we report for the first time on the distribution and occurrence of TA and NOSA before, during, and after treatment with daily highdosed IFN alfacon-1 [consensus IFN (CIFN)]. METHODS Thyrotropin (TSH) levels and antibodies to different autoantigens were analyzed in 217 patients with CHC (29.8% females) who were treated with CIFN induction therapy (27 or 18 mg q.d.). RESULTS Pretreatment abnormal TSH levels (TSH>3.0 mU/L or <0.4 mU/L) were detected in 15.6% and occurred significantly more often in females (24.6%; P=0.018). TA could be detected only in 2.6%, NOSA in up to 29.9% (47.4% females vs. 24.2% males). During CIFN induction therapy, low TSH levels were detected in 14.1% whereas elevated TSH levels occurred later (week 48) in up to 15.5%, again preferentially in females (42%, P=0.005). In 1.4% of all patients, treatment had to be discontinued because of symptomatic hyperthyroidism. TAs were detected in 10.5% (30.5% females) and NOSA up to 58% during CIFN treatment. CONCLUSIONS During CIFN induction therapy, alterations in TSH levels and an increased prevalence of TA and NOSA are quite common, especially in females. Clinically relevant symptoms occur, however, only in a small number (1.4%). Thus, treatment with daily and high-dose CIFN does not appear to increase the incidence of (severe) thyroidal or other autoimmune disorders compared with standard IFN in patients with CHC.
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31
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Chrétien P, Chousterman M, Alsamad IA, Ozenne V, Rosa I, Barrault C, Lons T, Hagège H. Non-organ-specific autoantibodies in chronic hepatitis C patients: Association with histological activity and fibrosis. J Autoimmun 2009; 32:201-5. [DOI: 10.1016/j.jaut.2009.02.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2009] [Accepted: 02/11/2009] [Indexed: 12/15/2022]
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32
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Béland K, Lapierre P, Alvarez F. Influence of genes, sex, age and environment on the onset of autoimmune hepatitis. World J Gastroenterol 2009; 15:1025-34. [PMID: 19266593 PMCID: PMC2655185 DOI: 10.3748/wjg.15.1025] [Citation(s) in RCA: 36] [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] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of autoimmune hepatitis (AIH) is complex. However, it is believed that a susceptible individual, owing to his genetic background, sex and age, can develop the disease following exposure to an environmental trigger. Autoimmune hepatitis does not follow a Mendelian pattern of inheritance; hence no single causative genetic locus has been identified. However, several genes, inside and outside the HLA locus, have been linked to an increased susceptibility to AIH. Epidemiological evidence also suggests that the sex and age of the patient plays a role in AIH pathogenesis as the disease onset occurs mainly in the two first decades of life and a higher disease incidence is observed in females. No environmental trigger has been identified, but several have been proposed, mainly viruses and xenobiotics. This article aims at reviewing the current knowledge on susceptibility factors leading to AIH and putative triggers, emphasizing fundamental mechanisms responsible for the break of liver immunological tolerance.
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Rigamonti C, Vidali M, Donato MF, Sutti S, Occhino G, Ivaldi A, Arosio E, Agnelli F, Rossi G, Colombo M, Albano E. Serum autoantibodies against cytochrome P450 2E1 (CYP2E1) predict severity of necroinflammation of recurrent hepatitis C. Am J Transplant 2009; 9:601-609. [PMID: 19191768 DOI: 10.1111/j.1600-6143.2008.02520.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We previously reported that autoantibodies against cytochrome P4502E1 (CYP2E1) are frequent in patients with chronic hepatitis C. As autoimmune reactions are increasingly detected after orthotopic liver transplantation (OLT), this study investigates prevalence and significance of anti-CYP2E1 autoantibodies in 46 patients with post-OLT recurrent hepatitis C. IgG against recombinant human CYP2E1 above the control threshold was detected in 19 out 46 (41%) sera collected immediately before OLT and in 15 out 46 (33%) sera collected at the time of the 12 months follow-up liver biopsy. Although anti-CYP2E1 reactivity was not modified by OLT, the patients with persistently elevated anti-CYP2E1 IgG (n = 12; 26%) showed significantly higher prevalence of recurrent hepatitis with severe necroinflammation and fibrosis than those persistently negative or positive only either before or after OLT. Moreover, the probability of developing severe necroinflammation was significantly higher in persistently anti-CYP2E1-positive subjects. Multivariate regression and Cox analysis confirmed that the persistence of anti-CYP2E1 IgG, together with a history of acute cellular rejection and donor age >50 years, was an independent risk factor for developing recurrent hepatitis C with severe necroinflammation. We propose that autoimmune reactions involving CYP2E1 might contribute to hepatic damage in a subgroup of transplanted patients with recurrent hepatitis C.
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Affiliation(s)
- C Rigamonti
- First Division of Gastroenterology, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena and University of Milan, Italy.
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34
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Abstract
Autoinflammatory liver disease represents an important aspect of global hepatological practice. The three principal disease divisions recognized are autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis. Largely, but not exclusively, these diseases are considered to be autoimmune in origin. Increased recognition of outlier and overlap syndromes, changes in presentation and natural history, as well as the increased awareness of IgG4-associated sclerosing cholangitis, all highlight the limitations of the classic terminology. New insights continue to improve the care given to patients, and have arisen from carefully conducted clinical studies, therapeutic trials, as well as genetic and laboratory investigations. The challenges remain to treat patients before liver injury becomes permanent and to prevent the development of organ failure.
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Affiliation(s)
- Teru Kumagi
- Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Holdener M, Hintermann E, Bayer M, Rhode A, Rodrigo E, Hintereder G, Johnson EF, Gonzalez FJ, Pfeilschifter J, Manns MP, Herrath MVG, Christen U. Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection. ACTA ACUST UNITED AC 2008; 205:1409-22. [PMID: 18474629 PMCID: PMC2413037 DOI: 10.1084/jem.20071859] [Citation(s) in RCA: 146] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Autoimmune liver diseases, such as autoimmune hepatitis (AIH) and primary biliary cirrhosis, often have severe consequences for the patient. Because of a lack of appropriate animal models, not much is known about their potential viral etiology. Infection by liver-tropic viruses is one possibility for the breakdown of self-tolerance. Therefore, we infected mice with adenovirus Ad5 expressing human cytochrome P450 2D6 (Ad-2D6). Ad-2D6–infected mice developed persistent autoimmune liver disease, apparent by cellular infiltration, hepatic fibrosis, “fused” liver lobules, and necrosis. Similar to type 2 AIH patients, Ad-2D6–infected mice generated type 1 liver kidney microsomal–like antibodies recognizing the immunodominant epitope WDPAQPPRD of cytochrome P450 2D6 (CYP2D6). Interestingly, Ad-2D6–infected wild-type FVB/N mice displayed exacerbated liver damage when compared with transgenic mice expressing the identical human CYP2D6 protein in the liver, indicating the presence of a stronger immunological tolerance in CYP2D6 mice. We demonstrate for the first time that infection with a virus expressing a natural human autoantigen breaks tolerance, resulting in a chronic form of severe, autoimmune liver damage. Our novel model system should be instrumental for studying mechanisms involved in the initiation, propagation, and precipitation of virus-induced autoimmune liver diseases.
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Affiliation(s)
- Martin Holdener
- Pharmazentrum Frankfurt/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany
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36
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Tarantino G, Gagliardi G, Conca P. Do thyroid abnormalities detected in patients treated for HCV-related chronic hepatitis persist? Int J Immunopathol Pharmacol 2008; 21:467-469. [PMID: 18547494 DOI: 10.1177/039463200802100228] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
One hundred and twenty-one patients with HCV-related chronic hepatitis and normal baseline thyroid function were studied. Forty-six patients received IFN alpha-2b, while 75 patients had Peg-IFN alpha-2b with ribavirin more recently. Thirty patients (ten belonging to the standard IFN group) were re-treated. The pre-treatment prevalence of thyroid antibodies was 3.3%. At the end of the first antiviral treatment, the prevalence of laboratory alterations (presence of antibodies and abnormal hormonal levels) of thyroid was assessed to be 20.7% (25 patients), being quite similar for standard-interferon- and pegylated-interferon-treated patients (P = 0.63). TSH level alteration was seen in eleven patients (9.1% of the overall population and 44% of the antibodies positive patients), of whom ten were females. The anti-microsomal, anti-thyroperoxidase and anti-thyroglobulin antibodies, in combined or isolated presence, were detected in all 25 patients. During the re-treatment we noticed worsening only of previous thyroid abnormalities. No patient changed the antiviral schedule after the emerging of thyroid alterations. All eleven patients remained thyroid dysfunctional at the end of the follow-up (ten with Hashimoto's thyroiditis and one with Graves disease), meanwhile the near totality of patients with presence of antibodies remained positive. Interestingly, eight out the 14 patients who showed mood disorders after antiviral therapy, belonged to the aforementioned cohort.
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37
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Genter MB, Yost GS, Rettie AE. Localization of CYP4B1 in the rat nasal cavity and analysis of CYPs as secreted proteins. J Biochem Mol Toxicol 2007; 20:139-41. [PMID: 16788951 DOI: 10.1002/jbt.20123] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
CYP4B1 is highly expressed in rat nasal respiratory mucosa, and to a lesser extent in olfactory mucosa. Examination of high-power photomicrographs suggests that CYP4B1 may be a secreted protein, based on the fact that immunoreactivity appears to be present in the lumens of ducts of Bowman's glands (rather than intracellular localization, as we observed with an antibody recognizing CYP2F4) and in secretory granules in respiratory mucosa. Furthermore, anti-CYP4B1 immunoreactivity is present on the surface of both respiratory and olfactory mucosa. We used SignalP 3.0 analysis to ascertain the likelihood that rat CYP4B1 is a secreted protein. While this analysis does not suggest that rat CYP4B1 is a secreted protein, several other cytochrome P450 enzymes were predicted to be secreted proteins. The observation that multiple human cytochrome P450s appear to be secreted proteins helps to explain the appearance of anti-cytochrome P450 antigens in cases of human autoimmune liver diseases.
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Affiliation(s)
- Mary Beth Genter
- Department of Environmental Health, University of Cincinnati, ML 670056, Cincinnati, OH 45267-0056, USA.
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Abstract
To describe a case of probable relapsing autoimmune hepatitis associated with vaccination against hepatitis A virus (HAV). A case report and review of literature were written concerning autoimmune hepatitis in association with hepatitis A and other hepatotropic viruses. Soon after the administration of formalin-inactivated hepatitis A vaccine, a man who had recently recovered from an uncharacterized but self-limiting hepatitic illness, experienced a severe deterioration (AST 1687 U/L, INR 1.4). Anti-nuclear antibodies were detectable, and liver biopsy was compatible with autoimmune hepatitis. The observation supports the role of HAV as a trigger of autoimmune hepatitis. Studies in helper T-cell activity and antibody expression against hepatic proteins in the context of hepatitis A infection are summarized, and the concept of molecular mimicry with regard to other forms of viral hepatitis and autoimmunity is briefly explored.
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Affiliation(s)
- P-A Berry
- Medway Maritime Hospital, 31 Pentlow Street, Putney, London, SW15 1LX, United Kingdom.
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Vidali M, Occhino G, Ivaldi A, Serino R, Moia S, Alchera E, Carini R, Rigamonti C, Sartori M, Albano E. Detection of auto-antibodies against cytochrome P4502E1 (CYP2E1) in chronic hepatitis C. J Hepatol 2007; 46:605-12. [PMID: 17196701 DOI: 10.1016/j.jhep.2006.11.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2006] [Revised: 11/13/2006] [Accepted: 11/21/2006] [Indexed: 12/23/2022]
Abstract
BACKGROUND/AIMS Chronic hepatitis C (CHC) is often associated with auto-immune reactions. In the light of the role of alcohol in promoting CHC progression, we have investigated the possible presence of auto-reactivity against the ethanol-inducible cytochrome P4502E1 (CYP2E1) in CHC patients with and without alcohol consumption. METHODS The IgG reactivity against recombinant human CYP2E1 was evaluated by solid-phase immunoassays in 102 CHC patients with different alcohol consumption and 59 HCV-free controls. RESULTS Auto-antibodies against CYP2E1 were significantly (p<0.0001) increased in CHC patients as compared to controls. Anti-CYP2E1 IgG above the 97th percentile in the controls were evident in 41 (40%) CHC patients. Competition experiments revealed that CYP2E1 recognition was not due to the cross-reactivity with CYP2D6. The detection of anti-CYP2E1 IgG was unrelated to alcohol consumption and no difference in gender, age, aminotransferase levels and virus genotype was evident among the patients with or without anti-CYP2E1 auto-antibodies. However, anti-CYP2E1 auto-reactivity was significantly (p=0.025) associated with the severity of periportal/periseptal interface hepatitis. Moreover, confocal microscopy demonstrated that anti-CYP2E1 IgG associated with CHC recognized CYP2E1 exposed on the outer side of hepatocyte plasma membranes. CONCLUSIONS HCV infection favours the breaking of self-tolerance against CYP2E1 that might contribute to hepatocyte injury.
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Affiliation(s)
- Matteo Vidali
- Department of Medical Sciences, University Amedeo Avogadro of East Piedmont and Interdepartmental Research Centre for Autoimmune Diseases (IRCAD), Novara, Italy
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40
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Lapierre P, Béland K, Alvarez F. Pathogenesis of autoimmune hepatitis: from break of tolerance to immune-mediated hepatocyte apoptosis. Transl Res 2007; 149:107-13. [PMID: 17320796 DOI: 10.1016/j.trsl.2006.11.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2006] [Revised: 11/25/2006] [Accepted: 11/28/2006] [Indexed: 01/06/2023]
Abstract
Understanding the pathogenesis and progression of autoimmune hepatitis (AIH) at the molecular level could prove essential in developing new preventive and therapeutic strategies. Recently developed murine models have enabled the identification of various mechanisms involved in the development and perpetuation of this autoimmune disorder. Studies on these models have shown that a peripheral break of tolerance against liver-expressed antigens is sufficient to induce an autoimmune liver disease, which can occur without prior liver damage. Recent data have also shown that the liver selectively recruits and induces the apoptosis of activated CD8+ T cells after an immune response. This process of T-cell trapping involves the expression of specific chemokines and adhesion molecules, and these molecules are believed to play an important role in the initiation and perpetuation of autoimmune hepatitis. Hepatocyte apoptosis, induced by autoreactive T cells, follows specific pathways that could be targeted by new therapeutic agents. Basic research on the break of immune tolerance against liver antigens would be beneficial for patients with autoimmune hepatitis, as well as those suffering from other chronic inflammatory liver diseases, such as primary biliary cirrhosis and graft-versus-host diseases.
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Affiliation(s)
- Pascal Lapierre
- Service de gastroentérologie, hépatologie et nutrition, Hôpital Sainte-Justine, Montréal, Québec, Canada
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41
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Abstract
The three main categories of autoimmune liver disease are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC); all are well-defined entities with diagnosis based upon a constellation of clinical, serologic, and liver pathology findings. Although these diseases are considered autoimmune in nature, the etiology and possible environmental triggers of each remain obscure. The characteristic morphologic patterns of injury are a chronic hepatitis pattern of injury with prominent plasma cells in AIH, destruction of small intrahepatic bile ducts and canals of Hering in PBC, and periductal fibrosis and inflammation involving larger bile ducts with variable small duct damage in PSC. Serological findings include the presence of antimitochondrial antibodies in PBC, antinuclear, anti-smooth muscle, and anti-LKM antibodies in AIH, and pANCA in PSC. Although most cases of autoimmune liver disease fit readily into one of these three categories, overlap syndromes (primarily of AIH with PBC or PSC) may comprise up to 10% of cases, and variant syndromes such as antimitochondrial antibody-negative PBC also occur. Sequential syndromes with transition from one form of autoimmune liver disease to another are rare.
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Affiliation(s)
- Mary K Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
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Sène D, Saadoun D, Limal N, Piette JC, Cacoub P. [Update in Hepatitis C virus associated extrahepatic manifestations]. Rev Med Interne 2006; 28:388-93. [PMID: 17137683 DOI: 10.1016/j.revmed.2006.10.321] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2006] [Revised: 10/09/2006] [Accepted: 10/18/2006] [Indexed: 01/12/2023]
Abstract
INTRODUCTION Since the discovery of the hepatitis C virus, many manifestations, so called extra-hepatic manifestations (EHM), are largely reported with more or less relationship proofs. ACTUALITIES AND MAIN POINTS This article proposes a review of the main extra-hepatic manifestations associated with the Hepatis C Virus infection and which remain a topical subject, more than fifteen years after the discovery of this virus. Mixed cryoglobulin and its vasculitic manifestations are still one of the more frequent Hepatis C Virus associated-extra-hepatic manifestations. Its management may be critically changed due to the increasing use of anti-CD20 therapy. Among other HCV-EHM, the following extra-hepatic manifestations are still of interest: the chronic fatigue syndrome, the sicca syndrome, the non-insulin-dependent diabetes mellitus, malignant B cell proliferations, mainly the Hepatis C Virus-related splenic lymphoma with villous lymphocytes and the production of auto-antibodies. PERSPECTIVES AND PROJECTS The mechanisms underlying these HCV-associated EHM are ill-elucidated and still remain of great interest as proved by current studies. The use of anti-CD20 antibodies in the treatment of cryoglobulinemic vasculitis is also under investigation.
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Affiliation(s)
- D Sène
- Service de Médecine Interne, Hôpital de la Pitié-Salpêtrière, 91, boulevard de l'Hôpital, 75651 Paris cedex 13, France
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43
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Muratori P, Sutherland SE, Muratori L, Granito A, Guidi M, Pappas G, Lenzi M, Bianchi FB, Pandey JP. Immunoglobulin GM and KM allotypes and prevalence of anti-LKM1 autoantibodies in patients with hepatitis C virus infection. J Virol 2006; 80:5097-5099. [PMID: 16641304 PMCID: PMC1472085 DOI: 10.1128/jvi.80.10.5097-5099.2006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2006] [Accepted: 02/28/2006] [Indexed: 12/30/2022] Open
Abstract
GM and KM allotypes-genetic markers of immunoglobulin (Ig) gamma and kappa chains, respectively-are associated with humoral immunity to several infection- and autoimmunity-related epitopes. We hypothesized that GM and KM allotypes contribute to the generation of autoantibodies to liver/kidney microsomal antigen 1 (LKM1) in hepatitis C virus (HCV)-infected persons. To test this hypothesis, we characterized 129 persons with persistent HCV infection for several GM and KM markers and for anti-LKM1 antibodies. The heterozygous GM 1,3,17 23 5,13,21 phenotype was significantly associated with the prevalence of anti-LKM1 antibodies (odds ratio, 5.13; P=0.002), suggesting its involvement in this autoimmune phenomenon in HCV infection.
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Affiliation(s)
- Paolo Muratori
- Department of Internal Medicine, Alma Mater Stadiorum-University of Bologna, Italy
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44
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Abstract
In 1950, Waldenström was the first to describe a chronic form of hepatitis in young women. Subsequently, the disease was found to be associated with other autoimmune syndromes and was later termed "lupoid hepatitis" because of the presence of antinuclear antibodies. In 1965, it became designated by Mackay et al. as "autoimmune hepatitis" at an international meeting, at which the general concept of autoimmunity was endorsed by the scientific community. In the early 1960s and 1970s, the value of immunosuppressive therapy with glucocorticoids and/or azathioprine was well documented in several studies. The original association of autoimmune hepatitis (AIH) and HLA alleles, which has remarkably stood the test of time, was published in 1972. In the 1970s and 1980s, several autoantibodies were identified in patients with autoimmune hepatitis directed against proteins of the endoplasmatic reticulum expressed in liver and kidney and against soluble liver antigens. Subsequently, the molecular targets of these antibodies were identified and more precisely characterized. In the last two decades many additional pieces of the AIH puzzle have been collected leading to the identification of additional antibodies and genes associated with AIH and to the emergence of new therapeutic agents. Meanwhile, the immunoserological and genetic heterogeneity of AIH is well established and it has become obvious that clinical manifestations, disease behavior, and treatment outcome may vary by racial groups, geographical regions and genetic predisposition. Currently, the International Autoimmune hepatitis group is endorsing multi-center collaborative studies to more precisely define the features at disease presentation and to define prognostic indices and appropriate treatment algorithms. Given the importance of serological testing, the IAHG is also working on guidelines and procedures for more reliable and standardized testing of autoantibodies.
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Affiliation(s)
- Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.
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