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Katsumi Y, Nishimura Y, Goto S, Ozawa S, Nishiura T, Kotera A, Kawahara Y, Higashikawa S, Iwasaki R, Toriiminami Y, Asai N, Fujita N. Case Report: HLA-DRB1 04:01 found in a child with adenovirus type 2 -linked hepatitis. Front Immunol 2025; 16:1544622. [PMID: 40079016 PMCID: PMC11896997 DOI: 10.3389/fimmu.2025.1544622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
Since 2022, cases of hepatitis of unknown origin have been reported in children worldwide. Adeno-associated virus type 2 (AAV2) was identified as a cause, with most affected children having the HLA-DRB1 04:01 genotype. In this study, we hypothesized that HLA-DRB1 04:01 in the host may also be a potential predisposing factor of acute hepatitis caused by other viruses. We report a case that met the definition of severe hepatitis of unknown cause in a child; adenovirus type 2 (AV2) was detected in her specimens. The patient was a 1-year-old girl who visited a doctor because of fever occurring 1-2 days per week, respiratory symptoms, and diarrhea. One month later, the patient was referred to our hospital because of prolonged elevated liver enzyme concentrations. Two weeks after the initial visit, her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations increased to 1558 and 1843 IU/L, respectively. The patient's liver enzyme concentrations decreased markedly with only observation and intravenous hydration during hospitalization within a few days. Thereafter, hepatic enzymes were transiently elevated with each common cold, but all recovered spontaneously. The adenovirus (AV) antibody levels increased substantially 2 weeks after admission. The patient's human leukocyte antigen (HLA) was determined to be of the DRB1 04:01 genotype. The presence of HLA-DRB1 04:01 is consistent with that reported in pediatric patients with AAV2 hepatitis in the United Kingdom, indicating that it may have been involved in the host immune response and acute hepatitis in this child. HLA-DRB1 04:01 may predispose children to acute hepatitis from various viruses, including AV2, AAV2, and possibly respiratory viruses, which requires clinical attention.
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MESH Headings
- Humans
- HLA-DRB1 Chains/genetics
- HLA-DRB1 Chains/immunology
- Female
- Infant
- Adenovirus Infections, Human/immunology
- Adenovirus Infections, Human/diagnosis
- Adenovirus Infections, Human/genetics
- Adenovirus Infections, Human/virology
- Genetic Predisposition to Disease
- Dependovirus
- Hepatitis, Viral, Human/diagnosis
- Hepatitis, Viral, Human/immunology
- Hepatitis, Viral, Human/genetics
- Genotype
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Affiliation(s)
- Yoshiki Katsumi
- Department of Pediatrics, Kyoto Saiseikai Hospital, Kyoto, Japan
| | - Yui Nishimura
- Department of Pediatrics, Kyoto Saiseikai Hospital, Kyoto, Japan
| | - Sachiko Goto
- Department of Pediatrics, Kyoto Saiseikai Hospital, Kyoto, Japan
| | - Seiichiro Ozawa
- Department of Pediatrics, Kyoto Saiseikai Hospital, Kyoto, Japan
| | | | - Akira Kotera
- Kyoto Prefectural Institute of Public Health and Environment, Kyoto, Japan
| | - Yoshiyuki Kawahara
- Kyoto Prefectural Institute of Public Health and Environment, Kyoto, Japan
| | - Shiori Higashikawa
- Kyoto Prefectural Institute of Public Health and Environment, Kyoto, Japan
| | - Rina Iwasaki
- Kyoto Prefectural Institute of Public Health and Environment, Kyoto, Japan
| | - Yutaka Toriiminami
- Kyoto Prefectural Institute of Public Health and Environment, Kyoto, Japan
| | - Norio Asai
- Kyoto Prefectural Institute of Public Health and Environment, Kyoto, Japan
| | - Naohisa Fujita
- Kyoto Prefectural Institute of Public Health and Environment, Kyoto, Japan
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Nakane S, Matsuo H, Nakatsuji Y. Immunological and therapeutic insights in autoimmune autonomic ganglionopathy: What is the position of apheresis in immunotherapy? Transfus Apher Sci 2024; 63:103967. [PMID: 38959810 DOI: 10.1016/j.transci.2024.103967] [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: 07/05/2024]
Abstract
Autoimmune autonomic ganglionopathy (AAG) is characterized by various autonomic and extra-autonomic symptoms and is caused by autoantibodies against nicotinic acetylcholine receptors present in the autonomic ganglia (ganglionic acetylcholine receptor, gAChR), requiring immediate and aggressive intervention to prevent the exacerbation of symptoms. However, there is currently no internationally accepted standard of care for the immunotherapy of AAG, including apheresis. Although the rationale for the use of plasma exchange (PLEX) in AAG is strong, whereby pathogenic gAChR antibodies are removed, its overall impact on patient outcomes is not well-established. Based on previous case reports and small case series studies, we provide a comprehensive overview of the challenges and uncertainties surrounding the use of PLEX for the management of AAG and provide current practice recommendations to guide treatment decisions.
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Affiliation(s)
- Shunya Nakane
- Department of Neurology, Faculty of Medicine, University of Toyama, Toyama, Japan.
| | - Hidenori Matsuo
- Department of Neurology, National Hospital Organization Nagasaki Kawatana Medical Center, Nagasaki, Japan
| | - Yuji Nakatsuji
- Department of Neurology, Faculty of Medicine, University of Toyama, Toyama, Japan
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Li Y, Zhou L, Huang Z, Yang Y, Zhang J, Yang L, Xu Y, Shi J, Tang S, Yuan X, Xu J, Li Y, Han X, Li J, Liu Y, Sun Y, Jin X, Xiao X, Wang B, Lin Q, Zhou Y, Song X, Cui Y, Hu L, Song Y, Bao J, Gong L, Gershwin ME, Zuo X, Yan H, Zou Z, Tang R, Ma X, the Chinese AIH Consortium. Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1. JHEP Rep 2024; 6:100926. [PMID: 38089552 PMCID: PMC10711477 DOI: 10.1016/j.jhepr.2023.100926] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 09/05/2023] [Accepted: 09/20/2023] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND & AIMS Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients. METHODS We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls. RESULTS A total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels. CONCLUSIONS Our study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH. IMPACT AND IMPLICATIONS This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.
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Affiliation(s)
- You Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Yue Yang
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
- Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital and Key Laboratory of Medical Molecular Virology (MOH & MOE), Shanghai Medical College, Fudan University, Shanghai, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Junping Shi
- Department of Infectious disease and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Shanhong Tang
- Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, China
| | - Xiaoling Yuan
- Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Xu
- Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiling Li
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xu Han
- Tianjin Second People’s Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - Jia Li
- Tianjin Second People’s Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - Yanmin Liu
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Ying Sun
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xiaozhi Jin
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Hepatology Institute of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Qiuxiang Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Yang Zhou
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Xuejiao Song
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Yong Cui
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Lilin Hu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhu Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jie Bao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ling Gong
- Department of Infectious disease and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - M. Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Xianbo Zuo
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
- Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China
| | - Huiping Yan
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zhengsheng Zou
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
- Institute of Aging & Tissue Regeneration, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - the Chinese AIH Consortium
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
- Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China
- Department of Infectious Diseases, Huashan Hospital and Key Laboratory of Medical Molecular Virology (MOH & MOE), Shanghai Medical College, Fudan University, Shanghai, China
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Infectious disease and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
- Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, China
- Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
- Tianjin Second People’s Hospital, Tianjin Institute of Hepatology, Tianjin, China
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Hepatology Institute of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou, China
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
- Institute of Aging & Tissue Regeneration, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Zhang Y, Zhang D, Chen L, Zhou J, Ren B, Chen H. The progress of autoimmune hepatitis research and future challenges. Open Med (Wars) 2023; 18:20230823. [PMID: 38025543 PMCID: PMC10655690 DOI: 10.1515/med-2023-0823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/24/2023] [Accepted: 09/28/2023] [Indexed: 12/01/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver inflammatory disease with various immune system manifestations, showing a global trend of increased prevalence. AIH is diagnosed through histological abnormalities, clinical manifestations, and biochemical indicators. The biochemical markers involve interfacial hepatitis, transaminase abnormalities, positive autoantibodies, etc. Although AIH pathogenesis is unclear, gene mutations and immunological factors could be the leading factors. AIH usually presents as a chronic liver disease and sometimes as acute hepatitis, making it challenging to distinguish it from drug-related hepatitis due to similar clinical symptoms. Normalizing transaminases and serum IgG levels is essential in assessing the remission status of AIH treatment. Glucocorticoids and azathioprine are the first-line AIH treatment, with lifelong maintenance therapy in some patients. The quality of life and survival can be improved after appropriate treatment. However, certain limitations jeopardize the quality of treatment, including long treatment cycles, side effects, poor patient compliance, and inability to inhibit liver fibrosis and cirrhosis. Accurate AIH animal models will help us understand the pathophysiology of the disease while providing fresh perspectives for avoiding and treating AIH. This review will help us understand AIH better, from the cellular and molecular causes to the clinical features, and will provide insight into new therapy techniques with fewer side effects.
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Affiliation(s)
- Yang Zhang
- Graduate Department of Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Dehe Zhang
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Ling Chen
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jing Zhou
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Binbin Ren
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Haijun Chen
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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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: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [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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Yuksel M, Nazmi F, Wardat D, Akgül S, Polat E, Akyildiz M, Arikan Ç. Standard immunosuppressive treatment reduces regulatory B cells in children with autoimmune liver disease. Front Immunol 2023; 13:1053216. [PMID: 36685568 PMCID: PMC9849683 DOI: 10.3389/fimmu.2022.1053216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 12/06/2022] [Indexed: 01/06/2023] Open
Abstract
Introduction Autoimmune hepatitis (AIH) is a chronic liver disease caused by a perturbed immune system. The scarcity of short- and long-term immune monitoring of AIH hampered us to comprehend the interaction between immunosuppressive medication and immune homeostasis. Methods and patients We recruited children with AIH at the time of diagnosis and at the 1st, 3rd, 6th, 12th, 18th, and 24th months of immunosuppression (IS). We also enrolled children with AIH being on IS for >2 years. Children with drug-induced liver injury (DILI), and those receiving tacrolimus after liver transplantation (LT), were enrolled as disease/IS control subjects. Healthy children (HC) were also recruited. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Healthy liver tissue from adult donors and from livers without inflammation were obtained from children with hepatoblastoma. By using flow cytometry, we performed multi-parametric immune profiling of PBMCs and intrahepatic lymphocytes. Additionally, after IS with prednisolone, tacrolimus, rapamycin, or 6-mercaptopurine, we carried out an in vitro cytokine stimulation assay. Finally, a Lifecodes SSO typing kit was used to type HLA-DRB1 and Luminex was used to analyze the results. Results Untreated AIH patients had lower total CD8 T-cell frequencies than HC, but these cells were more naïve. While the percentage of naïve regulatory T cells (Tregs) (CD4+FOXP3lowCD45RA+) and regulatory B cells (Bregs, CD20+CD24+CD38+) was similar, AIH patients had fewer activated Tregs (CD4+FOXP3highCD45RA - ) compared to HC. Mucosal-associated-invariant-T-cells (MAIT) were also lower in these patients. Following the initiation of IS, the immune profiles demonstrated fluctuations. Bregs frequency decreased substantially at 1 month and did not recover anymore. Additionally, the frequency of intrahepatic Bregs in treated AIH patients was lower, compared to control livers, DILI, and LT patients. Following in vitro IS drugs incubation, only the frequency of IL-10-producing total B-cells increased with tacrolimus and 6MP. Lastly, 70% of AIH patients possessed HLA-DR11, whereas HLA-DR03/DR07/DR13 was present in only some patients. Conclusion HLA-DR11 was prominent in our AIH cohort. Activated Tregs and MAIT cell frequencies were lower before IS. Importantly, we discovered a previously unrecognized and long-lasting Bregs scarcity in AIH patients after IS. Tacrolimus and 6MP increased IL-10+ B-cells in vitro.
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Affiliation(s)
- Muhammed Yuksel
- Paediatric Gastroenterology-Hepatology, Koç University Hospital, Istanbul, Türkiye,Liver Immunology Lab, Koç University Research Centre for Translational Medicine (KUTTAM), Istanbul, Türkiye
| | - Farinaz Nazmi
- Paediatric Gastroenterology-Hepatology, Koç University Hospital, Istanbul, Türkiye,Liver Immunology Lab, Koç University Research Centre for Translational Medicine (KUTTAM), Istanbul, Türkiye
| | - Dima Wardat
- Liver Immunology Lab, Koç University Research Centre for Translational Medicine (KUTTAM), Istanbul, Türkiye
| | - Sebahat Akgül
- Transplant Immunology Research Centre of Excellence (TIREX) Tissue Typing Lab, Koç University Hospital, Istanbul, Türkiye
| | - Esra Polat
- Paediatric Gastroenterology and Hepatology, Sancaktepe Education and Research Hospital, Istanbul, Türkiye
| | - Murat Akyildiz
- Adult Gastroenterology-Hepatology, Koç University Hospital, Istanbul, Türkiye
| | - Çigdem Arikan
- Paediatric Gastroenterology-Hepatology, Koç University Hospital, Istanbul, Türkiye,Liver Immunology Lab, Koç University Research Centre for Translational Medicine (KUTTAM), Istanbul, Türkiye,*Correspondence: Çigdem Arikan,
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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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Li Y, Sun Y, Liu Y, Wang B, Li J, Wang H, Zhang H, Wang X, Han X, Lin Q, Zhou Y, Hu L, Song Y, Bao J, Gong L, Sun M, Yuan X, Zhang X, Lian M, Xiao X, Miao Q, Wang Q, Li KK, Du S, Ma A, Li Y, Xu J, Tang S, Shi J, Xu Y, Yang L, Zhang J, Huang Z, Zhou L, Cui Y, Seldin MF, Gershwin ME, Yan H, Zou Z, Zuo X, Tang R, Ma X. Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1. Hepatology 2022; 76:564-575. [PMID: 35184318 DOI: 10.1002/hep.32417] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease. APPROACH AND RESULTS We conducted a case-control association study of 1,622 Chinese patients with AIH type 1 and 10,466 population controls from two independent cohorts. A meta-analysis was performed to ascertain variants associated with AIH type 1. A single-nucleotide polymorphism within the human leukocyte antigen (HLA) region showed the strongest association with AIH (rs6932730: OR = 2.32; p = 9.21 × 10-73 ). The meta-analysis also identified two non-HLA loci significantly associated with AIH: CD28/CTLA4/ICOS on 2q33.3 (rs72929257: OR = 1.31; p = 2.92 × 10-9 ) and SYNPR on 3p14.2 (rs6809477: OR = 1.25; p = 5.48 × 10-9 ). In silico annotation, reporter gene assays, and CRISPR activation experiments identified a distal enhancer at 2q33.3 that regulated expression of CTLA4. In addition, variants near STAT1/STAT4 (rs11889341: OR = 1.24; p = 1.34 × 10-7 ), LINC00392 (rs9564997: OR = 0.81; p = 2.53 × 10-7 ), IRF8 (rs11117432: OR = 0.72; p = 6.10 × 10-6 ), and LILRA4/LILRA5 (rs11084330: OR = 0.65; p = 5.19 × 10-6 ) had suggestive association signals with AIH. CONCLUSIONS Our study identifies two novel loci (CD28/CTLA4/ICOS and SYNPR) exceeding genome-wide significance and suggests four loci as potential risk factors. These findings highlight the importance of costimulatory signaling and neuro-immune interaction in the pathogenesis of AIH.
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Affiliation(s)
- You Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ying Sun
- Department of Liver Disease, Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yanmin Liu
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Jia Li
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - Hanxiao Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Haiping Zhang
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyi Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Xu Han
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - Qiuxiang Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Yang Zhou
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Lilin Hu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhu Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jie Bao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ling Gong
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Mengying Sun
- Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, China
| | - Xiaoling Yuan
- Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinhe Zhang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, ShenYang, China
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ke-Ke Li
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Shiyu Du
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Anlin Ma
- Department of infection disease, China-Japan Friendship Hospital, Beijing, China
| | - Yiling Li
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, ShenYang, China
| | - Jie Xu
- Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shanhong Tang
- Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, China
| | - Junping Shi
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Yun Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital and Key Laboratory of Medical Molecular Virology (MOH & MOE), Shanghai Medical College, Fudan University, Shanghai, China
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Yong Cui
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Michael F Seldin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA
- Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, California, USA
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA
| | - Huiping Yan
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zhengsheng Zou
- Department of Liver Disease, Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xianbo Zuo
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
- Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China
- Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
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9
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. HLA, gut microbiome and hepatic autoimmunity. Front Immunol 2022; 13:980768. [PMID: 36059527 PMCID: PMC9433828 DOI: 10.3389/fimmu.2022.980768] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022] Open
Abstract
Genetic susceptibility to autoimmune liver diseases is conferred mainly by polymorphisms of genes encoding for the human leukocyte antigens (HLA). The strongest predisposition to autoimmune hepatitis type 1 (AIH-1) is linked to the allele DRB1*03:01, possession of which is associated with earlier disease onset and more severe course. In populations where this allele is very rare, such as in Asia, and in DRB1*03-negative patients, risk of AIH-1 is conferred by DRB1*04, which is associated with later disease onset and milder phenotype. AIH type 2 (AIH-2) is associated with DRB1*07. The pediatric condition referred to as autoimmune sclerosing cholangitis (ASC), is associated with the DRB1*13 in populations of Northern European ancestry. DRB1*1501 is protective from AIH-1, AIH-2 and ASC in Northern European populations. Possession of the DRB1*08 allele is associated with an increased risk of primary biliary cholangitis (PBC) across different populations. DRB1*03:01 and B*08:01 confer susceptibility to primary sclerosing cholangitis (PSC), as well as DRB1*13 and DRB1*15 in Europe. The hepatic blood supply is largely derived from the splanchnic circulation, suggesting a pathophysiological role of the gut microbiome. AIH appears to be associated with dysbiosis, increased gut permeability, and translocation of intestinal microbial products into the circulation; molecular mimicry between microbial and host antigens may trigger an autoaggressive response in genetically-predisposed individuals. In PBC an altered enteric microbiome may affect intestinal motility, immunological function and bile secretion. Patients with PSC have a gut microbial profile different from health as well as from patients with inflammatory bowel disease without PSC.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Faculty of Biomedical Sciences, Epatocentro Ticino and Università della Svizzera Italiana, Lugano, Switzerland
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
- *Correspondence: Benedetta Terziroli Beretta-Piccoli,
| | - Giorgina Mieli-Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
| | - Diego Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
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10
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmmune hepatitis. Cell Mol Immunol 2022; 19:158-176. [PMID: 34580437 PMCID: PMC8475398 DOI: 10.1038/s41423-021-00768-8] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/29/2021] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a T-cell mediated, inflammatory liver disease affecting all ages and characterized by female preponderance, elevated serum transaminase and immunoglobulin G levels, positive circulating autoantibodies, and presence of interface hepatitis at liver histology. AIH type 1, affecting both adults and children, is defined by positive anti-nuclear and/or anti-smooth muscle antibodies, while type 2 AIH, affecting mostly children, is defined by positive anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibody. While the autoantigens of type 2 AIH are well defined, being the cytochrome P4502D6 (CYP2D6) and the formiminotransferase cyclodeaminase (FTCD), in type 1 AIH they remain to be identified. AIH-1 predisposition is conferred by possession of the MHC class II HLA DRB1*03 at all ages, while DRB1*04 predisposes to late onset disease; AIH-2 is associated with possession of DRB1*07 and DRB1*03. The majority of patients responds well to standard immunosuppressive treatment, based on steroid and azathioprine; second- and third-line drugs should be considered in case of intolerance or insufficient response. This review offers a comprehensive overview of pathophysiological and clinical aspects of AIH.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino & Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Lugano, Switzerland.
- Institute for Research in Biomedicine, Bellinzona, Switzerland.
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK.
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK
| | - Diego Vergani
- King's College London Faculty of Life Sciences & Medicine at King's College Hospital, London, UK
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK
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11
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Ma Y, Su H, Yuksel M, Longhi MS, McPhail M, Wang P, Bansal S, Wong GW, Graham J, Yang L, Thompson R, Doherty DG, Hadzic N, Zen Y, Quaglia A, Henghan M, Samyn M, Vergani D, Mieli-Vergani G. Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry. Hepatology 2021; 74:2032-2046. [PMID: 33971035 PMCID: PMC8463472 DOI: 10.1002/hep.31893] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 04/03/2021] [Accepted: 04/28/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Genetic predisposition to autoimmune hepatitis (AIH) in adults is associated with possession of human leukocyte antigen (HLA) class I (A*01, B*08) and class II (DRB1*03, -04, -07, or -13) alleles, depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH-1, AIH-2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD. APPROACH AND RESULTS We studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8-17), including 100 with AIH-1, 59 with AIH-2, and 77 with ASC. The follow-up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence-specific primers. HLA B*08, -DRB1*03, and the A1-B8-DR3 haplotype impart predisposition to all three forms of AILD. Homozygosity for DRB1*03 represented the strongest risk factor (8.8). HLA DRB1*04, which independently confers susceptibility to AIH in adults, was infrequent in AIH-1 and ASC, suggesting protection; and DRB1*15 (DR15) was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD: DRB1*03 to AIH-1, DRB1*13 to ASC, and DRB1*07 to AIH-2. Possession of homozygous DRB1*03 or of DRB1*13 is associated with fibrosis at disease onset, and possession of these two genes in addition to DRB1*07 is associated with a more severe disease in all three subgroups. CONCLUSIONS Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predicting responsiveness to immunosuppressive treatment and course.
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Affiliation(s)
- Yun Ma
- 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, UK
| | - Habin Su
- 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, UK,Department of Liver Disease of Chinese PLA General Hospital, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Muhammed Yuksel
- 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, UK,Koc University Research Centre for Translational Medicine (KUTTAM), Istanbul, Turkey
| | - Maria Serena Longhi
- 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, UK,Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Mark McPhail
- 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, UK
| | - Pengyun Wang
- 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, UK
| | - Sanjay Bansal
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Guan-Wee Wong
- 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, UK,Department of Medicine, Ng Teng Fong General Hospital, 1 Jurong East Street, Singapore 609606
| | - Jonathon Graham
- 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, UK
| | - Li Yang
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Richard Thompson
- 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, UK,Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Derek G. Doherty
- Division of Immunology, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Nedim Hadzic
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - Yoh Zen
- 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, UK
| | - Alberto Quaglia
- 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, UK,Department of Cellular Pathology, Royal Free London NHS Foundation Trust, UCL Cancer Institute, Research Department of Pathology, London, UK
| | - Michael Henghan
- 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, UK
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
| | - 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, UK
| | - 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, UK,Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK
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12
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Zachou K, Arvaniti P, Lyberopoulou A, Dalekos GN. Impact of genetic and environmental factors on autoimmune hepatitis. J Transl Autoimmun 2021; 4:100125. [PMID: 34622188 PMCID: PMC8479787 DOI: 10.1016/j.jtauto.2021.100125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic non-resolving liver disease characterized by diffuse hypergammaglobulinemia, the presence of autoantibodies and characteristic histological findings. The disease can have catastrophic outcome with the development of end-stage liver disease if misdiagnosed/undiagnosed and left untreated. AIH pathogenesis remains obscure and the main hypothesis supports its development in genetically predisposed individuals after being exposed to certain environmental triggers. Genetic predisposition is linked to the presence of certain HLA alleles, mainly HLA-DR3 and HLA-DR4. However, a wide number of non-HLA epitopes have also been associated with the disease although data vary significantly among different ethnic groups. Therefore, it is likely that epigenetic alterations may also play a crucial role in disease's pathogenesis, although not yet extensively studied. The aim of this review was to summarize the genetic and environmental factors that have been associated with AIH, but also to open new insights towards the role of epigenetic modifications in the etiology of the disease.
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Affiliation(s)
- Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center in Autoimmune Liver Diseases, University Hospital of Larissa, Larissa, Greece
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13
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Muscate F, Woestemeier A, Gagliani N. Functional heterogeneity of CD4 + T cells in liver inflammation. Semin Immunopathol 2021; 43:549-561. [PMID: 34463867 PMCID: PMC8443520 DOI: 10.1007/s00281-021-00881-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/14/2021] [Indexed: 12/24/2022]
Abstract
CD4+ T cells play an essential role in orchestrating adequate immunity, but their overactivity has been associated with the development of immune-mediated inflammatory diseases, including liver inflammatory diseases. These cells can be subclassified according to their maturation stage, cytokine profile, and pro or anti-inflammatory functions, i.e., functional heterogeneity. In this review, we summarize what has been discovered so far regarding the role of the different CD4+ T cell polarization states in the progression of two prominent and still different liver inflammatory diseases: non-alcoholic steatohepatitis (NASH) and autoimmune hepatitis (AIH). Finally, the potential of CD4+ T cells as a therapeutic target in both NASH and AIH is discussed.
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Affiliation(s)
- Franziska Muscate
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Woestemeier
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Gagliani
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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14
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Liberal R, de Boer YS, Heneghan MA. Established and novel therapeutic options for autoimmune hepatitis. Lancet Gastroenterol Hepatol 2021; 6:315-326. [DOI: 10.1016/s2468-1253(20)30328-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 08/14/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023]
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15
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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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16
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HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization. Sci Rep 2021; 11:2599. [PMID: 33510427 PMCID: PMC7844024 DOI: 10.1038/s41598-021-82195-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 01/18/2021] [Indexed: 01/30/2023] Open
Abstract
Associations between particular human leukocyte antigen (HLA) alleles and susceptibility to-or protection from-autoimmune diseases have been long observed. Allele-specific antigen presentation (AP) has been widely proposed as a culprit, but it is unclear whether HLA molecules might also have non-AP, disease-modulating effects. Here we demonstrate differential macrophage activation by HLA-DRB1 alleles known to associate with autoimmune disease risk or protection with resultant polarization of pro-inflammatory ("M1") versus anti-inflammatory ("M2") macrophages, respectively. RNA-sequencing analyses of in vitro-polarized macrophages in the presence of AP-incompetent short synthetic peptides corresponding to the third allelic hypervariable regions coded by those two HLA-DRB1 alleles showed reciprocal activation of pro- versus anti-inflammatory transcriptomes, with implication of corresponding gene ontologies and upstream regulators. These results identify a previously unrecognized mechanism of differential immune modulation by short HLA-DRB1-coded allelic epitopes independent of AP, and could shed new light on the mechanistic basis of HLA-disease association.
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17
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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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18
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Halliday N, Dyson JK, Thorburn D, Lohse AW, Heneghan MA. Review article: experimental therapies in autoimmune hepatitis. Aliment Pharmacol Ther 2020; 52:1134-1149. [PMID: 32794592 DOI: 10.1111/apt.16035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 03/02/2020] [Accepted: 07/22/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Current therapeutic options for autoimmune hepatitis (AIH) are limited by adverse events associated with corticosteroids and thiopurines and the limited evidence base for second- and third-line treatment options. Furthermore, current treatment approaches require long-term exposure of patients to pharmacological agents. There have been significant advances in the understanding of the mechanisms underpinning autoimmunity and an expansion in the available therapeutic agents for suppressing autoimmune responses or potentially restoring self-tolerance. AIM To review the mechanisms and evidence for experimental therapies that are being actively explored in the management of AIH. METHODS We have reviewed the literature relating to a range of novel therapeutic immunomodulatory treatment strategies and drugs. RESULTS Drugs which block B cell-activating factor of the tumour necrosis factor family (BAFF) and tumour necrosis factor α are currently in clinical trials for the treatment of AIH. Experimental therapies and technologies to increase immune tolerance, such as pre-implantation factor and regulatory T cell therapies, are undergoing development for application in autoimmune disorders. There is also evidence for targeting inflammatory pathways to control other autoimmune conditions, such as blockade of IL1 and IL6 and Janus-associated kinase (JAK) inhibitors. CONCLUSIONS With the range of tools available to clinicians and patients increasing, it is likely that the therapeutic landscape of AIH will change over the coming years and treatment approaches offering lower corticosteroid use and aiming to restore immune self-tolerance should be sought.
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Affiliation(s)
- Neil Halliday
- Institute of Liver and Digestive Health, University College London, London, UK.,The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
| | - Jessica Katharine Dyson
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK.,Hepatology Department, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Douglas Thorburn
- Institute of Liver and Digestive Health, University College London, London, UK.,The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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19
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Novel HLA Class I Alleles Outside the Extended DR3 Haplotype Are Protective against Autoimmune Hepatitis. Clin Transl Gastroenterol 2020; 10:e00032. [PMID: 31211758 PMCID: PMC6613860 DOI: 10.14309/ctg.0000000000000032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
HLA class II allele, DRB1*03:01, is the most common genetic risk factor for autoimmune hepatitis (AIH), but other unrecognized HLA related risks exist.
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20
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Stuart L, Lambourne B, Turner P, Jones DEJ, Plummer R, Cresti N, Dyson JK. Pembrolizumab as a Cause of Cholangiopathy in a Patient With Metastatic Melanoma. Hepatology 2020; 71:2164-2166. [PMID: 31872447 DOI: 10.1002/hep.31089] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 12/19/2019] [Indexed: 12/07/2022]
Affiliation(s)
- Laura Stuart
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Beth Lambourne
- Oncology Department, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Paul Turner
- Radiology Department, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - David E J Jones
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Ruth Plummer
- Oncology Department, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Nicola Cresti
- Oncology Department, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Jessica K Dyson
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.,NIHR Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
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21
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Lucchino B, Spinelli FR, Iannuccelli C, Guzzo MP, Conti F, Di Franco M. Mucosa-Environment Interactions in the Pathogenesis of Rheumatoid Arthritis. Cells 2019; 8:E700. [PMID: 31295951 PMCID: PMC6678242 DOI: 10.3390/cells8070700] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/04/2019] [Accepted: 07/05/2019] [Indexed: 12/15/2022] Open
Abstract
Mucosal surfaces play a central role in the pathogenesis of rheumatoid arthritis (RA). Several risk factors, such as cigarette smoking, environmental pollution, and periodontitis interact with the host at the mucosal level, triggering immune system activation. Moreover, the alteration of microbiota homeostasis is gaining increased attention for its involvement in the disease pathogenesis, modulating the immune cell response at a local and subsequently at a systemic level. Currently, the onset of the clinical manifest arthritis is thought to be the last step of a series of pathogenic events lasting years. The positivity for anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), in absence of symptoms, characterizes a preclinical phase of RA-namely systemic autoimmune phase- which is at high risk for disease progression. Several immune abnormalities, such as local ACPA production, increased T cell polarization towards a pro-inflammatory phenotype, and innate immune cell activation can be documented in at-risk subjects. Many of these abnormalities are direct consequences of the interaction between the environment and the host, which takes place at the mucosal level. The purpose of this review is to describe the humoral and cellular immune abnormalities detected in subjects at risk of RA, highlighting their origin from the mucosa-environment interaction.
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Affiliation(s)
- Bruno Lucchino
- Rheumatology Unit, Department of Internal Medicine and Medical Specialities, Sapienza University of Rome, 00161 Rome, Italy.
| | - Francesca Romani Spinelli
- Rheumatology Unit, Department of Internal Medicine and Medical Specialities, Sapienza University of Rome, 00161 Rome, Italy
| | - Cristina Iannuccelli
- Rheumatology Unit, Department of Internal Medicine and Medical Specialities, Sapienza University of Rome, 00161 Rome, Italy
| | - Maria Paola Guzzo
- Rheumatology Unit, Department of Internal Medicine and Medical Specialities, Sapienza University of Rome, 00161 Rome, Italy
| | - Fabrizio Conti
- Rheumatology Unit, Department of Internal Medicine and Medical Specialities, Sapienza University of Rome, 00161 Rome, Italy
| | - Manuela Di Franco
- Rheumatology Unit, Department of Internal Medicine and Medical Specialities, Sapienza University of Rome, 00161 Rome, Italy
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22
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de Boer YS, Gerussi A, van den Brand FF, Wong GW, Halliday N, Liberal R, Drenth JPH, Thorburn D, Bouma G, Heneghan MA. Association Between Black Race and Presentation and Liver-Related Outcomes of Patients With Autoimmune Hepatitis. Clin Gastroenterol Hepatol 2019; 17:1616-1624.e2. [PMID: 30471454 DOI: 10.1016/j.cgh.2018.11.028] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 11/01/2018] [Accepted: 11/06/2018] [Indexed: 02/06/2023]
Abstract
INTRODUCTION & AIMS Small studies have found that black patients with autoimmune hepatitis (AIH) present with more aggressive disease. We aimed to characterize the presentation and outcome in black and white patients with AIH. METHODS We performed a retrospective study, collecting information from databases of patients with AIH attending the Institute of Liver studies at King's College Hospital, London (1971-October 2015, the Royal Free Hospital, London (1982 through December 2016) and the multicenter Dutch Autoimmune Hepatitis Study Group cohort (2006-August 2016). We identified 88 black patients with AIH and we compared their clinical characteristics and outcomes to 897 white patients with AIH. RESULTS Black patients presented at a younger age (median 38 years vs 45 years) (P = .007), had higher IgG levels (mean 31.0 mg/dL vs 27.5 mg/dL) (P = .04), but there were no significant differences between groups in auto-antibody profiles, International AIH Group scores, or sex distribution of disease. A higher proportion of black patients had systemic lupus erythematosus (10%) than white patients (2%) (P ≤ .001). There was no significant difference in proportions of patients with a response to standard therapy (86% for black patients vs 91% for white patients; P = .20) or in rate of relapse (57% vs 50%; P = .3). Despite this, black patients had an increased risk of liver transplantation and liver-related death (hazard ratio 2.4, 95% confidence interval, 1.4-4.0; P < .001). Overall mortality was similar between the two groups. CONCLUSION In a comparison of black and white patients with AIH in Europe, we found that black patients present at a younger age, have higher levels of IgG levels, and a greater proportion have SLE. We also found black patients to have a greater risk of liver transplantation and liver-related mortality, indicating more aggressive disease.
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Affiliation(s)
- Ynto S de Boer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers - VU University Medical Center, Amsterdam, the Netherlands; Institute of Liver Studies, King's College Hospital, Denmark Hill, London, London, United Kingdom
| | - Alessio Gerussi
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom; Department of Medicine, University of Udine, Udine, Italy
| | - Floris F van den Brand
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers - VU University Medical Center, Amsterdam, the Netherlands
| | - Guan-Wee Wong
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, London, United Kingdom
| | - Neil Halliday
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom; Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, Royal Free Hospital, London, United Kingdom
| | - Rodrigo Liberal
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, London, United Kingdom
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers - VU University Medical Center, Amsterdam, the Netherlands
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, London, United Kingdom.
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23
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NUNES MEG, ROSA DV, FAGUNDES EDT, FERREIRA AR, MIRANDA DMD, FERRI LIU PM. HLA-DRB1 GENE POLYMORPHISMS IN PEDIATRIC PATIENTS WITH TYPE 1 AUTOIMMUNE HEPATITIS AND TYPE 1 AUTOIMMUNE HEPATITIS OVERLAP SYNDROME WITH AUTOIMMUNE CHOLANGITIS. ARQUIVOS DE GASTROENTEROLOGIA 2019; 56:146-150. [DOI: 10.1590/s0004-2803.201900000-29] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 03/19/2019] [Indexed: 12/25/2022]
Abstract
ABSTRACT BACKGROUND: Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease associated with a loss of immunological tolerance to self-antigens. Susceptibility to AIH is partially determined by the presence of genes related to human leukocyte antigen (HLA), mainly allelic variants of DRB1. OBJECTIVE: The purpose of this study was to investigate the frequencies of the polymorphisms in HLA-DRB1 gene in children and adolescents with type 1 AIH and type 1 AIH overlap syndrome with autoimmune cholangitis (overlap syndrome, OS) in comparison to healthy sex and age-matched individuals (control group). METHODS: This is a cross-sectional study of 25 pediatric patients diagnosed with type 1 AIH and 18 with OS. Fifty-seven healthy individuals were included as controls. The polymorphisms of the HLA-DRB1 gene were evaluated by PCR and included HLA-DRB1*03, HLA-DRB1*04, HLA-DRB1*07, and HLA-DRB1*13. RESULTS: Our results showed that the presence of the allele HLA-DRB1*13 increased the chance of autoimmune cholangitis (OR=3.96, CI 1.07 to 14.61, P=0.04). The HLA-DRB1*04 and HLA- DRB1*07 have no association with the AIH and autoimmune cholangitis in a young sample. CONCLUSION: This work demonstrates an association of the main polymorphisms in the HLA-DRB1 gene to AIH with or without cholangitis in a Brazilian sample.
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24
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Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME. Cellular and Molecular Mechanisms of Autoimmune Hepatitis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:247-292. [PMID: 29140756 DOI: 10.1146/annurev-pathol-020117-043534] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.
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Affiliation(s)
- G J Webb
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - G M Hirschfield
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - E L Krawitt
- Department of Medicine, University of Vermont, Burlington, Vermont 05405, USA; .,Department of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA
| | - M E Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, California 95817, USA;
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25
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Fogel R, Comerford M, Chilukuri P, Orman E, Chalasani N, Lammert C. Extrahepatic Autoimmune Diseases are Prevalent in Autoimmune Hepatitis Patients and Their First-Degree Relatives: Survey Study. Interact J Med Res 2018; 7:e18. [PMID: 30567687 PMCID: PMC6315230 DOI: 10.2196/ijmr.9625] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 07/11/2018] [Accepted: 07/17/2018] [Indexed: 12/11/2022] Open
Abstract
Background Concurrent autoimmune illnesses contribute to increased medical burden and reduced quality of life in patients with autoimmune hepatitis (AIH). The frequency of coexisting autoimmune conditions among North American patients with AIH and their families remains incomplete. Challenges associated with disease capture in the electronic medical record, high study costs, and geographic spread of patients are formidable barriers to understanding the extent of concurrent autoimmune conditions in these groups. Objective This objective of this study was to examine the frequency of extrahepatic autoimmune diseases (EHAD) among AIH cases and healthy controls as well as their first-degree relatives using social networking sites (SNS). Methods We developed a 53-question survey detailing the history of autoimmune diseases. A survey link was posted at routine intervals within specific Web-based cohorts on SNS. Healthy controls, without self-reported autoimmune liver disease, were recruited from Amazon’s Mechanical Turk. Continuous variables were summarized using medians and P values obtained with the Wilcoxon rank-sum test. Categorical variables were compared using the chi-square test. Results Compared with controls (n=1162), cases (n=306) were more likely to be older (median age: 49 vs 33 years), female (284/306, 92.81% vs 955/1162, 82.18%), and have an EHAD (128/306, 41.83% vs 218/1162, 18.76%; P=.001). The most frequent EHADs among cases were thyroid disease (49/306, 16.01% ), Sjögren syndrome (27/306, 8.82%), Raynaud phenomenon (23/306, 7.52%), and psoriasis (22/306, 7.19%). Overall, 55.88% (171/306) of cases and 35.71% (1601/4484) of controls reported at least 1 first-degree relative (FDR) with a history of EHAD (P=.001). Cases had a significantly higher risk of EHAD than controls after the adjustment for age, sex, race, and body mass index: odds ratio 2.46 (95% CI 1.8-3.3); P=.001. Conclusions Patients with AIH report higher prevalence of coexistent EHAD than healthy controls, and their FDRs are also more likely to have autoimmune disorders.
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Affiliation(s)
- Rachel Fogel
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, United States
| | - Megan Comerford
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, United States
| | - Prianka Chilukuri
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, United States
| | - Eric Orman
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, United States
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, United States
| | - Craig Lammert
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, IN, United States
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26
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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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27
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Yamazaki T, Umemura T, Joshita S, Yoshizawa K, Tanaka E, Ota M. A cis-eQTL of HLA-DPB1 Affects Susceptibility to Type 1 Autoimmune Hepatitis. Sci Rep 2018; 8:11924. [PMID: 30093645 PMCID: PMC6085285 DOI: 10.1038/s41598-018-30406-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 07/30/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. A single nucleotide polymorphism in the 3′ untranslated region of HLA-DPB1, rs9277534, is associated with HLA-DPB1 expression. rs9277534 has been linked to hepatitis B virus recovery/persistence and the risk of graft-versus-host disease with HLA-DPB1 mismatching transplantation of hematopoietic cells, but its role along with that of HLA-DP expression in AIH have not been fully clarified. We genotyped rs9277534 in 146 Japanese patients with AIH and 326 healthy subjects. HLA-DPB1 expression was determined by quantitative PCR. HLA-DPB1 expression was significantly higher for rs9277534G than for rs9277534A (P < 0.05). rs9277534 genotype was in strong linkage disequilibrium with the HLA-DPB1 allele (pairwise D′ = 0.82–1.00). Although HLA-DP alleles were not significantly associated with AIH, the frequency of the rs9277534G allele was significantly higher in AIH patients compared with healthy subjects (P = 0.002, odds ratio [OR] = 1.56). Logistic regression analysis revealed that the HLA-DRB1*04:05 allele (P < 0.001, OR = 4.61) and rs9277534 (P = 0.004, OR = 1.67) were independently associated with AIH susceptibility. rs9277534G in the HLA-DP gene is an eQTL that affects gene expression and may contribute to AIH susceptibility.
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Affiliation(s)
- Tomoo Yamazaki
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan. .,Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan.
| | - Satoru Joshita
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.,Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan
| | - Kaname Yoshizawa
- Department of Gastroenterology, NHO Ueda Medical Center, Ueda, Japan
| | - Eiji Tanaka
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masao Ota
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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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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29
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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: 27] [Impact Index Per Article: 3.9] [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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Impact of Antibodies That React With Liver Tissue and Donor-Specific Anti-HLA Antibodies in Pediatric Idiopathic Posttransplantation Hepatitis. Transplantation 2017; 101:1074-1083. [PMID: 28118175 PMCID: PMC5642348 DOI: 10.1097/tp.0000000000001653] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background The cause of late graft dysfunction has not been elucidated. Although an antibody-mediated reaction is suspected as a potential mechanism, the target antigens have not been clarified. Methods To clarify the etiology of idiopathic posttransplantation hepatitis (IPTH), we simultaneously examined the presence of antibodies that react with liver tissue (ARLT) by means of indirect immunofluorescence staining, as well as the presence of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA). A subanalysis of the IPTH group was also performed. Within the IPTH group, the correlation between ARLT titer and clinical data were analyzed. Results In the sera of patients with IPTH (30 patients), ARLT were found at a significantly higher frequency than in patients without IPTH (42 patients; P < 0.001). Moreover, the ARLT titer appeared to be correlated with the severity of hepatitis or hepatic injury. In contrast, the frequency of HLA-DSA was significantly lower in patients with IPTH than in patients without IPTH (P = 0.001). Conclusion Our findings indicate that ARLT, and not HLA-DSA, profoundly influence the etiology of IPTH. The authors show that antibodies that react with liver tissue and not donor-specific anti-human leukocyte antigen antibodies, profoundly influence the etiology of idiopathic posttransplantation hepatitis in children providing a rationale for therapy.
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Enomoto H, Nishiguchi S. Similarities and Differences in Autoimmune Hepatitis Epidemiology between East and West: Autoimmune Hepatitis in East Asia, Southeast Asia, and South Asia. Inflamm Intest Dis 2017; 1:150-158. [PMID: 29922671 PMCID: PMC5988198 DOI: 10.1159/000454879] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a relatively rare disease that can develop regardless of age or ethnicity. However, its clinical features differ between eastern and western populations due to several heterogeneous genetic and environmental factors. We herein report the clinical characteristics of AIH patients in East Asia, Southeast Asia, and South Asia. SUMMARY AND KEY MESSAGES The prevalence of AIH in eastern countries is considered to be lower than in western countries. Although a few young patients with type 2 AIH have been observed in South Asia, most patients in Asia are middle-aged women with type 1 AIH who respond well to steroid-based immunosuppressive therapy. Human leukocyte antigen DR4 is suggested to be an influential factor in the genetic background of AIH patients in Asia, particularly in East Asia. Notably, AIH may be induced by some societal- or culture-associated medicines, including herbal medicines. The IAIHG (International Autoimmune Hepatitis Group) scoring systems are generally accepted as the standard diagnostic methods for AIH in Asian countries. The results of repeated nationwide surveys in Japan suggest that the clinical features of AIH patients in East Asia are changing, with IgG levels and rates of anti-nuclear antibody positivity decreasing.
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Affiliation(s)
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
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32
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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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33
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Yousefi A, Mahmoudi E, Zare Bidoki A, Najmi Varzaneh F, Baradaran Noveiry B, Sadr M, Motamed F, Najafi M, Farahmand F, Rezaei N. IL4 gene polymorphisms in Iranian patients with autoimmune hepatitis. Expert Rev Gastroenterol Hepatol 2017; 10:659-63. [PMID: 26735262 DOI: 10.1586/17474124.2016.1139449] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a chronic long-lasting hepatocellular inflammation associated with circulating auto antibodies. In addition to the genetic component, several cytokines have been implicated to be involved in AIH. This study was performed to investigate potential associations of AIH with IL4 gene variants. METHOD The studied alleles and genotypes included: IL4G/T allele polymorphisms at position -1098 and C/T allele polymorphisms at two positions (-33 and -590) on the IL4 gene, in addition to the A/G allele polymorphisms at position +1902 on the IL4RA gene. RESULT The IL4 C allele and CC genotype at position -590 and TT genotype at position -33 had a significantly higher frequency in AIH patients. CONCLUSION This study identified the IL4 C allele and CC genotype susceptibility gene in AIH, which will provide better insights into the mechanisms of AIH and potential therapeutic interventions.
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Affiliation(s)
- Azizollah Yousefi
- a Department of Gastroenterology, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Elham Mahmoudi
- b Molecular Immunology Research Center; Department of Immunology, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Alireza Zare Bidoki
- c Thrombosis Hemostasis Research Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Farnaz Najmi Varzaneh
- b Molecular Immunology Research Center; Department of Immunology, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran.,d Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Behnoud Baradaran Noveiry
- b Molecular Immunology Research Center; Department of Immunology, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran.,d Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Maryam Sadr
- b Molecular Immunology Research Center; Department of Immunology, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Farzaneh Motamed
- a Department of Gastroenterology, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Mehri Najafi
- a Department of Gastroenterology, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Fatemeh Farahmand
- a Department of Gastroenterology, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Nima Rezaei
- b Molecular Immunology Research Center; Department of Immunology, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran.,d Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA) , Universal Scientific Education and Research Network (USERN) , Tehran , Iran.,e Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran
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34
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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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35
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Yuksel M, Xiao X, Tai N, Vijay M, Gülden E, Beland K, Lapierre P, Alvarez F, Hu Z, Colle I, Ma Y, Wen L. The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model. Clin Exp Immunol 2016; 186:164-176. [PMID: 27414259 DOI: 10.1111/cei.12843] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2016] [Indexed: 12/17/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti-smooth muscle actin and/or anti-nuclear, anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)-DR3, -DR7 and -DR13. HLA-DR4 has the second strongest association with adult AIH, after HLA-DR3. We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti-LKM1/anti-LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (Tregs ), which had decreased programmed death (PD)-1 expression. Splenic Tregs from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8+ T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild-type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of Tregs and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8+ T effectors, facilitating the induction of AIH and persistent liver damage.
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Affiliation(s)
- M Yuksel
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.,Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium.,Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK
| | - X Xiao
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.,Department of Nephrology, Qilu Hospital, Shandong University, China
| | - N Tai
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
| | - Manakkat Vijay
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.,Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK
| | - E Gülden
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA
| | - K Beland
- Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada
| | - P Lapierre
- Immunovirology Laboratory, Institut National De La Recherche Scientifique, INRS-Institut Armand-Frappier, Laval, Québec, Canada
| | - F Alvarez
- Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Canada
| | - Z Hu
- Department of Nephrology, Qilu Hospital, Shandong University, China
| | - I Colle
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium
| | - Y Ma
- Institute of Liver Studies and Transplantation, King's College London Faculty of Life Sciences and Medicine, King's College Hospital, London, UK
| | - L Wen
- Section of Endocrinology, Yale University School of Medicine, New Haven, USA.
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36
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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: 36] [Impact Index Per Article: 4.0] [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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37
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Kerkar N, Yanni G. ‘De novo’ and ‘recurrent’ autoimmune hepatitis after liver transplantation: A comprehensive review. J Autoimmun 2016; 66:17-24. [DOI: 10.1016/j.jaut.2015.08.017] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 08/23/2015] [Indexed: 02/08/2023]
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38
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Autoimmune Hepatitis: Progress from Global Immunosuppression to Personalised Regulatory T Cell Therapy. Can J Gastroenterol Hepatol 2016; 2016:7181685. [PMID: 27446862 PMCID: PMC4904688 DOI: 10.1155/2016/7181685] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 11/20/2015] [Indexed: 12/23/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an immune mediated liver injury. The precise aetiology of AIH is still unknown but current evidence suggests both genetic and environmental factors are involved. Breakdown in peripheral self-tolerance, and impaired functions of FOXP3(+) regulatory T cell along with effector cell resistance to suppression at the tissue level seem to play an important role in AIH immunopathogenesis. AIH is predominantly a T lymphocytes driven disease but B lymphocytes are also involved in the immunopathology. Innate immune cells are crucial in the initial onset of disease and their response is followed by adaptive T (Th1, Th17, and cytotoxic T cells) and B cell responses evidenced by liver histology and peripheral blood serology. Standard treatment regimens involving steroid and immunosuppressive medications lead to global immune suppression requiring life-long therapy with many side effects. Biologic therapies have been attempted but duration of remission is short-lived. Future direction of diagnosis and treatment for AIH should be guided by "omics" and the immunology profile of the individual patient and clinicians should aim to deliver personalised medicine for their patients. Cell therapy such as infusion of autologous, antigen-specific, and liver-homing regulatory T cells to restore hepatic immune tolerance may soon be a potential future treatment for AIH patients.
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39
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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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40
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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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41
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Doherty DG. Immunity, tolerance and autoimmunity in the liver: A comprehensive review. J Autoimmun 2015; 66:60-75. [PMID: 26358406 DOI: 10.1016/j.jaut.2015.08.020] [Citation(s) in RCA: 224] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 08/26/2015] [Indexed: 12/14/2022]
Abstract
The hepatic immune system is constantly exposed to a massive load of harmless dietary and commensal antigens, to which it must remain tolerant. Immune tolerance in the liver is mediated by a number of specialized antigen-presenting cells, including dendritic cells, Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells. These cells are capable of presenting antigens to T cells leading to T cell apoptosis, anergy, or differentiation into regulatory T cells. However, the hepatic immune system must also be able to respond to pathogens and tumours and therefore must be equipped with mechanisms to override immune tolerance. The liver is a site of accumulation of a number of innate lymphocyte populations, including natural killer cells, CD56(+) T cells, natural killer T cells, γδ T cells, and mucosal-associated invariant T cells. Innate lymphocytes recognize conserved metabolites derived from microorganisms and host cells and respond by killing target cells or promoting the differentiation and/or activation of other cells of the immune system. Innate lymphocytes can promote the maturation of antigen-presenting cells from their precursors and thereby contribute to the generation of immunogenic T cell responses. These cells may be responsible for overriding hepatic immune tolerance to autoantigens, resulting in the induction and maintenance of autoreactive T cells that mediate liver injury causing autoimmune liver disease. Some innate lymphocyte populations can also directly mediate liver injury by killing hepatocytes or bile duct cells in murine models of hepatitis, whilst other populations may protect against liver disease. It is likely that innate lymphocyte populations can promote or protect against autoimmune liver disease in humans and that these cells can be targeted therapeutically. Here I review the cellular mechanisms by which hepatic antigen-presenting cells and innate lymphocytes control the balance between immunity, tolerance and autoimmunity in the liver.
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Affiliation(s)
- Derek G Doherty
- Division of Immunology, School of Medicine, Trinity College Dublin, Ireland.
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42
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Yang F, Wang Q, Bian Z, Ren LL, Jia J, Ma X. Autoimmune hepatitis: East meets west. J Gastroenterol Hepatol 2015; 30:1230-1236. [PMID: 25765710 DOI: 10.1111/jgh.12952] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/28/2015] [Indexed: 01/10/2023]
Abstract
Autoimmune hepatitis (AIH) is an inflammatory liver disease with diverse clinical spectrum, which predominantly affects females. This review provides detailed comparisons of epidemiology, genetic predispositions, clinical features, risk factors of hepatocellular carcinoma, and mortality in AIH patients between eastern and western countries. AIH prevalence and incidence are lower in Asia-Pacific area than in Europe and America. European and American patients seem to have more severe disease, characterized with human leukocyte antigen-DR3 haplotype, younger age, more AIH-induced "cirrhosis" at diagnosis, higher elevated serum immunoglobulin G levels, and positive rate of antisoluble liver antigen/liver pancreatitis. The overall AIH diagnostic accuracy of revised original criteria and simplified scoring system are similar in European/American populations and Asian. Cirrhosis at presentation and non-response to immunosuppressive therapy within 1 year are the most important predictors for poor prognosis of AIH patients.
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Affiliation(s)
- Fan Yang
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qixia Wang
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhaolian Bian
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Lin-Lin Ren
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jidong Jia
- Liver Research Center & Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiong Ma
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
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HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes Immun 2015; 16:247-52. [PMID: 25611558 DOI: 10.1038/gene.2014.82] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 12/16/2014] [Accepted: 12/16/2014] [Indexed: 12/20/2022]
Abstract
The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.
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de Boer YS, van Gerven NMF, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, Beuers U, van Buuren HR, Drenth JPH, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MMJ, Vrolijk JM, Kraal G, Mulder CJJ, van Nieuwkerk CMJ, Fischer J, Berg T, Stickel F, Sarrazin C, Schramm C, Lohse AW, Weiler-Normann C, Lerch MM, Nauck M, Völzke H, Homuth G, Bloemena E, Verspaget HW, Kumar V, Zhernakova A, Wijmenga C, Franke L, Bouma G. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology 2014; 147:443-52.e5. [PMID: 24768677 DOI: 10.1053/j.gastro.2014.04.022] [Citation(s) in RCA: 223] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 03/17/2014] [Accepted: 04/09/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. METHODS We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. RESULTS We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. CONCLUSIONS In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.
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Affiliation(s)
- Ynto S de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Nicole M F van Gerven
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Antonie Zwiers
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands; Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Bart J Verwer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Karel J van Erpecum
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Henk R van Buuren
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Jannie W den Ouden
- Department of Gastroenterology and Hepatology, Haga Hospital, The Hague, The Netherlands
| | - Robert C Verdonk
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands; Department of Gastroenterology and Hepatology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands
| | - Ger H Koek
- Department of Gastroenterology and Hepatology, University Medical Center Maastricht, Maastricht, The Netherlands
| | - Johannes T Brouwer
- Department of Gastroenterology and Hepatology, Reinier de Graaf Hospital, Delft, The Netherlands
| | - Maureen M J Guichelaar
- Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Jan M Vrolijk
- Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands
| | - Georg Kraal
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Chris J J Mulder
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Carin M J van Nieuwkerk
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Janett Fischer
- Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Thomas Berg
- Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Felix Stickel
- Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | | | - Christoph Schramm
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Markus M Lerch
- Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Matthias Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
| | - Elisabeth Bloemena
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Hein W Verspaget
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Vinod Kumar
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Alexandra Zhernakova
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Cisca Wijmenga
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Lude Franke
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands; Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
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Umemura T, Katsuyama Y, Yoshizawa K, Kimura T, Joshita S, Komatsu M, Matsumoto A, Tanaka E, Ota M. Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan. PLoS One 2014; 9:e100565. [PMID: 24956105 PMCID: PMC4067340 DOI: 10.1371/journal.pone.0100565] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 05/25/2014] [Indexed: 12/31/2022] Open
Abstract
Although we earlier demonstrated that the human leukocyte antigen (HLA) DRB1*04:05 allele was associated with susceptibility to autoimmune hepatitis (AIH) in Japan, the precise relationship of HLA haplotype and the role of amino acid alignment with disease susceptibility and progression has not been fully clarified. We reinvestigated HLA class I A, B, and C and HLA class II DRB1, DQB1, and DPB1 alleles and haplotypes in a larger new cohort of 156 Japanese patients with type 1 AIH and compared them with the published data of 210 healthy subjects. The DRB1*04:05-DQB1*04:01 haplotype was significantly associated with AIH susceptibility (30% vs. 11%, P = 1.2×10−10; odds ratio [OR] = 3.51) and correlated with elevated serum IgG (3042 vs. 2606 mg/dL, P = 0.041) and anti-smooth muscle antigen positivity (77% vs. 34%, P = 0.000006). No associations with HLA-DPB1 alleles were found. The HLA A*24:02 and C*01:02 alleles were associated with disease susceptibility (corrected P = 0.0053 and 0.036, respectively), but this likely constituents of a long ranged haplotype including DRB1*04:05-DQB1*04:01 haplotype. Conversely, the DRB1*15:01-DQB1*06:02 haplotype was associated with protection from both disease onset (5% vs. 13%, P = 0.00057; OR = 0.38) and the development of hepatocellular carcinoma (25% vs. 5%, P = 0.017; OR = 6.81). The frequency of the DRB1*08:03-DQB1*06:01 haplotype was significantly higher in patients who developed hepatic failure (22% vs. 6%, P = 0.034; OR = 4.38). In conclusion, this study established the role of HLA haplotypes in determining AIH susceptibility and progression in the Japanese population. Additional sequencing of the entire HLA region is required to more precisely identify the genetic components of AIH.
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Affiliation(s)
- Takeji Umemura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | | | - Kaname Yoshizawa
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan; Department of Gastroenterology, NHO Ueda Medical Center, Ueda, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Michiharu Komatsu
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masao Ota
- Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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Yamagiwa S, Kamimura H, Takamura M, Genda T, Ichida T, Nomoto M, Aoyagi Y. Presence of antibodies against self human leukocyte antigen class II molecules in autoimmune hepatitis. Int J Med Sci 2014; 11:850-856. [PMID: 25013363 PMCID: PMC4081305 DOI: 10.7150/ijms.8633] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 05/15/2014] [Indexed: 12/16/2022] Open
Abstract
Autoimmune hepatitis (AIH) can arise de novo after liver transplantation (LT) for non-autoimmune liver diseases. Considering the identical features of de novo AIH after LT and classical AIH, as well as the importance of anti-human leukocyte antigen (HLA) antibodies in graft rejection, we investigated the presence of circulating anti-HLA class II antibodies in the sera of 35 patients with AIH, 30 patients with primary biliary cirrhosis (PBC), and 30 healthy donors using fluorescent dye-impregnated beads bound to HLA molecules. We then investigated the allele specificity of the antibodies and identified the HLA alleles in each patient using DNA-based HLA typing. We also examined HLA class II expression in liver samples using immunohistochemistry. Anti-HLA class II antibodies were detected significantly more frequently in the patients with AIH (88.1%) than in the patients with PBC (33.3%) or in the healthy donors (13.3%) (both P <0.01). We confirmed that the anti-HLA class II antibodies in the AIH patients showed specificity for several HLA class II alleles, including self HLA class II alleles. Moreover, positive reactivity with anti-self HLA class II antibodies was associated with higher serum transaminase levels. In conclusion, we demonstrated, for the first time, that antibodies against self HLA class II alleles were detectable in patients with AIH. Our results suggest that an antibody-mediated immune response against HLA class II molecules on hepatocytes may be involved in the pathogenesis or acceleration of liver injury in AIH.
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Affiliation(s)
- Satoshi Yamagiwa
- 1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
| | - Hiroteru Kamimura
- 1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
| | - Masaaki Takamura
- 1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
| | - Takuya Genda
- 2. Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni 410-2295, Japan
| | - Takafumi Ichida
- 2. Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni 410-2295, Japan
| | - Minoru Nomoto
- 1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
| | - Yutaka Aoyagi
- 1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
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Czaja AJ. Review article: permanent drug withdrawal is desirable and achievable for autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39:1043-58. [PMID: 24628539 DOI: 10.1111/apt.12701] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 02/09/2014] [Accepted: 02/23/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autoimmune hepatitis can be rendered treatment-free, but the difficulty, frequency and risks associated with the pursuit of this outcome are unclear. AIM To describe the frequency that autoimmune hepatitis can be rendered treatment-free, identify the features that characterise these patients, examine the pathogenic pathways that may sustain or terminate the disease and indicate management protocols that can obtain this result. METHODS Studies cited in Pub Med from 1972-2014 for autoimmune hepatitis, treatment, relapse, remission and outcome were selected. RESULTS The frequency of a treatment-free state varies from 19% to 40% in patients observed for ≥3 years after drug withdrawal. Complete laboratory resolution and reversion to normal liver tissue prior to drug withdrawal favours this response. The development of cirrhosis during therapy may increase treatment-dependence. Persistent liver damage and the generation of neo-antigens during the apoptosis of hepatocytes may perpetuate the disease. Genetic and age-related effects on the vigour of the immune response may also contribute. Reversion to normal liver tissue is achieved in only 22% of patients during conventional corticosteroid therapy, and the emerging pharmacological and biological interventions may improve this frequency. A management strategy designed to achieve a treatment-free state accommodates all candidates for this outcome, and it can be modified to a long-term maintenance strategy as warranted by the clinical response. CONCLUSIONS Permanent drug withdrawal is a treatment outcome that is desirable and achievable in patients with autoimmune hepatitis. Normalisation of liver tests and liver tissue during treatment enhances this occurrence.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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48
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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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Assis DN, Leng L, Du X, Zhang CK, Grieb G, Merk M, Garcia AB, McCrann C, Chapiro J, Meinhardt A, Mizue Y, Nikolic-Paterson DJ, Bernhagen J, Kaplan MM, Zhao H, Boyer JL, Bucala R. The role of macrophage migration inhibitory factor in autoimmune liver disease. Hepatology 2014; 59:580-91. [PMID: 23913513 PMCID: PMC3877200 DOI: 10.1002/hep.26664] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 07/28/2013] [Indexed: 01/24/2023]
Abstract
UNLABELLED The role of the cytokine, macrophage migration inhibitory factor (MIF), and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Two MIF promoter polymorphisms, a functional -794 CATT5-8 microsatellite repeat (rs5844572) and a -173 G/C single-nucleotide polymorphism (rs755622), were analyzed in DNA samples from over 500 patients with AIH, PBC, and controls. We found a higher frequency of the proinflammatory and high-expression -794 CATT7 allele in AIH, compared to PBC, whereas lower frequency was found in PBC, compared to both AIH and healthy controls. MIF and soluble MIF receptor (CD74) were measured by enzyme-linked immunosorbent assay in 165 serum samples of AIH, PBC, and controls. Circulating serum and hepatic MIF expression was elevated in patients with AIH and PBC versus healthy controls. We also identified a truncated circulating form of the MIF receptor, CD74, that is released from hepatic stellate cells and that binds MIF, neutralizing its signal transduction activity. Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls. CONCLUSIONS These data suggest a distinct genetic and immunopathogenic basis for AIH and PBC at the MIF locus. Circulating MIF and MIF receptor profiles distinguish PBC from the more inflammatory phenotype of AIH and may play a role in pathogenesis and as biomarkers of these diseases.
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Affiliation(s)
- David N. Assis
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Lin Leng
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Xin Du
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Clarence K. Zhang
- Department of Biostatistics, Yale School of Public Health, 60 College Street, New Haven, CT 06520, USA
| | - Gerrit Grieb
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA,Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany,Department of Plastic Surgery, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany
| | - Melanie Merk
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Alvaro Baeza Garcia
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Catherine McCrann
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Julius Chapiro
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA,Department of Anatomy and Cell Biology, Justus-Liebig-University, 35385 Giessen, Germany
| | - Andreas Meinhardt
- Department of Anatomy and Cell Biology, Justus-Liebig-University, 35385 Giessen, Germany
| | - Yuka Mizue
- Sapporo Immuno Diagnostic Laboratory, Sapporo, Japan
| | - David J. Nikolic-Paterson
- Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, 3168, Australia
| | - Jürgen Bernhagen
- Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany
| | - Marshall M. Kaplan
- Division of Gastroenterology, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA
| | - Hongyu Zhao
- Department of Biostatistics, Yale School of Public Health, 60 College Street, New Haven, CT 06520, USA
| | - James L. Boyer
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
| | - Richard Bucala
- Department of Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA
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50
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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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