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Pérez-Galicia A, Lugo-Caballero C, Martínez-Calvillo S, Ortiz-Navarrete V, Manning-Cela RG. Major Histocompatibility Complex Class I and II Allele Frequencies and Disease Associations in Mexicans: A Systematic Review and Meta-Analysis. Arch Med Res 2025; 56:103201. [PMID: 40199052 DOI: 10.1016/j.arcmed.2025.103201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 12/26/2024] [Accepted: 02/26/2025] [Indexed: 04/10/2025]
Abstract
BACKGROUND The major histocompatibility complex (MHC) plays a crucial role in immune responses and is associated with disease susceptibility. This study systematically reviews MHC class I and class II allele frequencies and their associations with diseases in the Mexican population from 1979 to 2023. METHODS A systematic review following PRISMA guidelines was conducted. Reports were obtained from the Allele Frequency Net Database and PubMed using keywords related to HLA and Mexican populations. A total of 776 reports were screened, and 214 were retained for final analysis. Seventy-six studies comprising allele frequency data from over 20,000 individuals across Mexican states and indigenous communities were analyzed. In addition, over 138 articles were examined to identify alleles associated with various diseases. RESULTS The analysis identified 117 alleles whose frequencies varied regionally within Mexico. While DPA1*01, DPB1*04:01, and DQA1*03 were predominant, DRB1*04, DQB1*03, and DQA1*05 were also prominent but variable. Certain alleles, such as A*02, B*35, C*04, and C*07, were relatively common in the population. Numerous disease correlations were uncovered, such as B*27's strong association with spondyloarthropathies. DRB1*15:01 and DRB1*04 conferred an increase in multiple sclerosis, while DRB1*04 may protect against some skin diseases. CONCLUSION This review improves the understanding of MHC allele frequencies and disease associations in Mexicans, highlighting genetic diversity. The findings lay the groundwork for future research on genetic predispositions and health outcomes, aiding healthcare strategies in this diverse population. Further studies are needed to address data gaps and refine genetic profiles for targeted medical applications.
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Affiliation(s)
- Anahi Pérez-Galicia
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, CDMX, Mexico
| | - Cesar Lugo-Caballero
- Centro Regional de Investigación Dr. Hideyo Noguchi, Universidad Autónoma de Yucatán, Mérida, Yucatán, Mexico
| | - Santiago Martínez-Calvillo
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Edo, de México, Mexico
| | - Vianey Ortiz-Navarrete
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, CDMX, Mexico
| | - Rebeca G Manning-Cela
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, CDMX, Mexico.
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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. 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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Yadav V, Irfan R, Safdar S, Sunkara V, Ekhator C, Pendyala PR, Devi M, Shahzed SMI, Das A, Affaf M, Bellegarde SB, Shrestha R, Naseem MA, Al Khalifa A. Advances in Understanding and Managing Autoimmune Hepatitis: A Narrative Review. Cureus 2023; 15:e43973. [PMID: 37622052 PMCID: PMC10446851 DOI: 10.7759/cureus.43973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2023] [Indexed: 08/26/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease characterized by immune-mediated destruction of hepatocytes, leading to inflammation and fibrosis. In recent years, significant advances have been made in understanding the pathogenesis, epidemiology, diagnosis, and treatment of AIH. This comprehensive narrative review aims to provide an up-to-date overview of these advances. The review begins by outlining the historical background of AIH, dating back to its initial recognition in the 1940s, and highlights the evolution of diagnostic criteria and classification based on autoantibody profiles. The epidemiology of AIH is explored, discussing its varying prevalence across different regions and the role of genetic predisposition, viral infections, and drug exposure as risk factors. Furthermore, the review delves into the pathogenesis of AIH, focusing on the dysregulated immune response, involvement of T cells, and potential contribution of the gut microbiome. Clinical presentation, diagnostic criteria, and liver biopsy as crucial tools for diagnosis are also discussed. Regarding management, the review provides an in-depth analysis of the standard first-line treatments involving glucocorticoids and azathioprine, as well as alternative therapies for non-responsive cases. Additionally, emerging second and third-line treatment options are examined. In conclusion, this narrative review highlights the complexity of AIH and underscores the importance of early diagnosis and individualized treatment approaches to improve patient outcomes. Further research and clinical trials are needed to optimize AIH management and ensure a better long-term prognosis for affected individuals.
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Affiliation(s)
- Vikas Yadav
- Internal Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND
| | | | | | | | - Chukwuyem Ekhator
- Neuro-Oncology, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, USA
| | - Praful R Pendyala
- Neurology, Chalmeda Anand Rao Institute of Medical Sciences, Karimnagar, IND
| | | | | | - Archana Das
- Internal Medicine, North East Medical College and Hospital, Sylhet, BGD
| | - Maryam Affaf
- Medicine, Khyber Medical University, Peshawar, PAK
| | - Sophia B Bellegarde
- Pathology and Laboratory Medicine, American University of Antigua, St. John's, ATG
| | - Riya Shrestha
- Medicine, Nepal Medical College and Teaching Hospital, Kathmandu, NPL
| | | | - Ahmed Al Khalifa
- Medical School, College of Medicine, Sulaiman Alrajhi University, Al Bukayriyah, SAU
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4
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KASL clinical practice guidelines for management of autoimmune hepatitis 2022. Clin Mol Hepatol 2023; 29:542-592. [PMID: 37137334 PMCID: PMC10366804 DOI: 10.3350/cmh.2023.0087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
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Khor SS, Ueno K, Nishida N, Kawashima M, Kawai Y, Aiba Y, Hitomi Y, Nagasaki M, Nakamura M, Tokunaga K. Novel HLA allele associations with susceptibility, staging, symptomatic state, autoimmune hepatitis and hepatocellular carcinoma events for primary biliary cholangitis in the Japanese population. Front Immunol 2023; 14:1151502. [PMID: 37325616 PMCID: PMC10264690 DOI: 10.3389/fimmu.2023.1151502] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 05/18/2023] [Indexed: 06/17/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a rare autoimmune disease with a clear predisposition for human leukocyte antigen (HLA)-DR/DQ-associated loss of immune tolerance for the E2 component of the pyruvate dehydrogenase complex. Three-field-resolution HLA imputation of 1,670 Japanese PBC patients and 2,328 healthy controls was conducted using Japanese population-specific HLA reference panels. Eighteen previously reported Japanese PBC-associated HLA alleles were confirmed and extended to 3-field-resolution, including HLA-DRB1*08:03 to HLA-DRB1*08:03:02, HLA-DQB1*03:01 to HLA-DQB1*03:01:01, HLA-DQB1*04:01 to HLA-DQB1*04:01:01 and HLA-DQB1*06:04 to HLA-DQB1*06:04:01. In addition, additional significant novel HLA alleles were identified, including 3 novel susceptible HLA-DQA1 alleles: HLA-DQA1*03:03:01, HLA-DQA1*04:01:01, HLA-DQA1*01:04:01 and 1 novel protective HLA-DQA1 allele, HLA-DQA1*05:05:01. In addition, PBC patients carrying HLA-DRB1*15:01:01 and HLA-DQA1*03:03:01 would have a higher predisposition toward developing concomitant autoimmune hepatitis (AIH). Further, late-stage and symptomatic PBC shared the same susceptible HLA alleles of HLA-A*26:01:01, HLA-DRB1*09:01:02 and HLA-DQB1*03:03:02. Lastly, HLA-DPB1*05:01:01 was identified as a potential risk HLA allele for development of hepatocellular carcinoma (HCC) in PBC patients. In conclusion, we have extended the current knowledge of HLA allele associations to 3-field resolution and identified novel HLA allele associations with predisposition risk, staging, symptomatic state, and AIH and HCC events for Japanese PBC patients.
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Affiliation(s)
- Seik-Soon Khor
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kazuko Ueno
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Nao Nishida
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
- The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Minae Kawashima
- Database Center for Life Science (DBCLS), Research Organization of Information and Systems, Chiba, Japan
| | - Yosuke Kawai
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yoshihiro Aiba
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
| | - Yuki Hitomi
- Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masao Nagasaki
- Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
- Headquarters of Primary Biliary Cholangitis (PBC) Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
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Cancado ELR, Goldbaum-Crescente J, Terrabuio DRB. HLA-related genetic susceptibility in autoimmune hepatitis according to autoantibody profile. Front Immunol 2022; 13:1032591. [PMID: 36311739 PMCID: PMC9606223 DOI: 10.3389/fimmu.2022.1032591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
Although the prevalence of autoimmune hepatitis in first-degree relatives is small, the relationship between genetic markers, especially human leucocyte antigens (HLA), and susceptibility to this disease, has been studied for over three decades. The genetic susceptibility to AIH is believed to be different in the two subtypes of the disease, AIH type 1 and AIH type 2. Type 1 AIH has anti-smooth muscle and anti-nuclear antibodies as its main markers, while those of type 2 AIH are the anti-liver/kidney microsome type 1 and anti-liver cytosol type 1 antibodies. The anti-soluble liver antigen/liver-pancreas antibodies, which, in addition to being present in both subtypes, mark an important number of patients without serological markers. Therefore, a third type of disease is questionable. The vast majority of immunogenetic studies compare the differences between the two main types and make no difference between which antibodies are present to define the subtype. This review seeks to analyze what was most important published in the AIH in this context, trying to relate the HLA alleles according to the AIH marker autoantibodies.
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Affiliation(s)
- Eduardo Luiz Rachid Cancado
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Instituto de Medicina Tropical da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- *Correspondence: Eduardo Luiz Rachid Cancado,
| | - Juliana Goldbaum-Crescente
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Instituto de Medicina Tropical da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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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: 10] [Impact Index Per Article: 3.3] [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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8
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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] [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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Choi KD, Oh EH, Kim HS, Kim HS, Park JY, Choi SY, Choi JH. Transcriptional Down-Regulation of Major Histocompatibility Complex as a Possible Pathogenesis for Meniere's Disease. Front Neurol 2022; 13:938740. [PMID: 35923832 PMCID: PMC9339969 DOI: 10.3389/fneur.2022.938740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 06/20/2022] [Indexed: 12/13/2022] Open
Abstract
Objectives This study aimed to determine the underlying pathogenesis of Meniere's disease (MD) using transcriptome analysis. Methods Total RNA was extracted from the peripheral blood mononuclear cells of 39 patients with MD and 39 controls. Through microarray analysis for nine patients and controls, the differentially expressed genes (DEGs) of those two groups were screened based on cut-off criteria (|fold changes| > 2.0 and adjusted p-value < 0.05). The functional enrichment analysis of DEGs was performed using Gene Ontology (GO). Results There were 996 DEGs identified in the MD group: 415 were upregulated and 581 were downregulated. A functional enrichment analysis indicated that the downregulated DEGs were significantly enriched in terms related to immune system processes. Among them, 17 genes were enriched in terms for the major histocompatibility complex (MHC) protein complex, and the relative messenger RNA (mRNA) levels of three markedly downregulated DEGs [fold changes < −5: human leukocyte antigen (HLA)-DMA, HLA-DRB1, and HLA-DPB1] were significantly decreased in another 30 patients with MD compared with normal controls by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). However, there were no correlations between the expression levels of these three genes and clinical data, such as age, onset age, time course, or hearing threshold. Conclusions Our transcriptome analysis showed that the downregulated DEGs in MD were mainly associated with the immune system pathways including the MHC protein complex in MD. Remarkably, a breakdown in immunological tolerance mediated by MHC class II may contribute to the MD development, which has implications for targeted treatment.
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Affiliation(s)
- Kwang-Dong Choi
- Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea
| | - Eun Hye Oh
- Department of Neurology, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea
| | - Hyun Sung Kim
- Department of Neurology, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea
| | - Hyang-Sook Kim
- Department of Neurology, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea
| | - Ji-Yun Park
- Department of Neurology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea
| | - Seo Young Choi
- Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea
| | - Jae-Hwan Choi
- Department of Neurology, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea
- *Correspondence: Jae-Hwan Choi
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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: 78] [Impact Index Per Article: 26.0] [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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Sirbe C, Simu G, Szabo I, Grama A, Pop TL. Pathogenesis of Autoimmune Hepatitis-Cellular and Molecular Mechanisms. Int J Mol Sci 2021; 22:13578. [PMID: 34948375 PMCID: PMC8703580 DOI: 10.3390/ijms222413578] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/09/2021] [Accepted: 12/14/2021] [Indexed: 02/05/2023] Open
Abstract
Pediatric autoimmune liver disorders include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is an idiopathic disease characterized by immune-mediated hepatocyte injury associated with the destruction of liver cells, causing inflammation, liver failure, and fibrosis, typically associated with autoantibodies. The etiology of AIH is not entirely unraveled, but evidence supports an intricate interaction among genetic variants, environmental factors, and epigenetic modifications. The pathogenesis of AIH comprises the interaction between specific genetic traits and molecular mimicry for disease development, impaired immunoregulatory mechanisms, including CD4+ T cell population and Treg cells, alongside other contributory roles played by CD8+ cytotoxicity and autoantibody production by B cells. These findings delineate an intricate pathway that includes gene to gene and gene to environment interactions with various drugs, viral infections, and the complex microbiome. Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. The current first-line therapy comprises prednisolone plus azathioprine to induce clinical and biochemical remission. Further understanding of the cellular and molecular mechanisms encountered in AIH may depict their impact on clinical aspects, detect biomarkers, and guide toward novel, effective, and better-targeted therapies with fewer side effects.
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Affiliation(s)
- Claudia Sirbe
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Gelu Simu
- Cardiology Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania
| | - Iulia Szabo
- Department of Rheumatology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Alina Grama
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Tudor Lucian Pop
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
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12
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Lee BT, Tana MM, Kahn JA, Dara L. We Are Not Immune: Racial and Ethnic Disparities in Autoimmune Liver Diseases. Hepatology 2021; 74:2876-2887. [PMID: 34056734 DOI: 10.1002/hep.31985] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 04/29/2021] [Accepted: 05/25/2021] [Indexed: 12/11/2022]
Abstract
Autoimmune liver diseases are attributed to a complex interplay of biologic, acquired, and environmental factors. Increased prevalence, later stage at presentation, worse response to standard therapy, and transplant-related disparities have all been reported in racial and ethnic minorities such as Black and Latinx patients with autoimmune liver diseases. While biology and inherited genetic predispositions may partly explain these disparities, definitive and universal genetic variations underlying these differences in outcomes have not been defined. Nonetheless, socioeconomic status, access to health care, environmental and societal factors, and implicit provider bias can all contribute to poor patient outcomes. There remains an unmet need to understand and mitigate the factors contributing to health inequity in autoimmune liver diseases. In this review, we summarize the data on racial and ethnic disparities in presentation, treatment response, and outcomes pertaining to autoimmune liver diseases in minority populations, on the premise that understanding disparities is the first step toward reaching health equity.
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Affiliation(s)
- Brian T Lee
- Division of Gastroenterology and Transplant Institute, Loma Linda University Health, Loma Linda, CA
| | - Michele M Tana
- UCSF Liver Center, University of California, San Francisco, CA
- Division of Gastroenterology, Zuckerberg San Francisco General Hospital and Trauma Center, University of California, San Francisco, CA
| | - Jeffrey A Kahn
- USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Lily Dara
- USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA
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13
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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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14
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Wang G, Tanaka A, Zhao H, Jia J, Ma X, Harada K, Wang FS, Wei L, Wang Q, Sun Y, Hong Y, Rao H, Efe C, Lau G, Payawal D, Gani R, Lindor K, Jafri W, Omata M, Sarin SK. The Asian Pacific Association for the Study of the Liver clinical practice guidance: the diagnosis and management of patients with autoimmune hepatitis. Hepatol Int 2021; 15:223-257. [PMID: 33942203 PMCID: PMC8144150 DOI: 10.1007/s12072-021-10170-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/27/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Guiqiang Wang
- Peking University First Hospital, Beijing, China. .,Peking University International Hospital, Beijing, China.
| | | | - Hong Zhao
- Peking University First Hospital, Beijing, China.,Peking University International Hospital, Beijing, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine Kanazawa, Kanazawa, Japan
| | - Fu-Sheng Wang
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Beijing, China
| | - Qixia Wang
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Sun
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuan Hong
- Peking University First Hospital, Beijing, China
| | - Huiying Rao
- Peking University People's Hospital, Beijing, China
| | - Cumali Efe
- Department of Gastroenterology, Harran University, Şanlıurfa, Turkey
| | - George Lau
- Humanity and Health Medical Group, Hong Kong Special Administrative Region, China
| | - Diana Payawal
- Department of Hepatology, Cardinal Santos Medical Center, Manila, Philippines
| | - Rino Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Keith Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | | | - Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu-City, Yamanashi, Japan.,The University of Tokyo, Tokyo, Japan
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15
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Engel B, Laschtowitz A, Janik MK, Junge N, Baumann U, Milkiewicz P, Taubert R, Sebode M. Genetic aspects of adult and pediatric autoimmune hepatitis: A concise review. Eur J Med Genet 2021; 64:104214. [PMID: 33812046 DOI: 10.1016/j.ejmg.2021.104214] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/25/2021] [Accepted: 03/28/2021] [Indexed: 02/06/2023]
Abstract
Autoimmune Hepatitis (AIH) is a heterogenous, mostly chronic liver disease that affects people of all age groups, women more often than men. The aim of therapy is to prevent cirrhosis, as it mainly accounts for liver-related mortality in patients with AIH. Rates of remission are high in patients with AIH, but life-long immunosuppressive therapy is required. AIH is hypothesized to originate from immunologic reactivity targeted against mostly unknown self-antigens, potentially triggered by viral infections among other factors. While AIH does not follow a Mendelian inheritance pattern, part of the risk of developing AIH or worse disease course, is attributed to specific genetic risk factors. Major associations for the risk of development of AIH were found for HLA-DRB1*03:01 and HLA-DRB1*04:01 in adult AIH in the only genome-wide association study on AIH. However, other potential risk loci in SH2B3, CARD10 and KIR genes were described. This review covers the current knowledge on genetic risk factors in adult and pediatric AIH.
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Affiliation(s)
- Bastian Engel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany.
| | - Alena Laschtowitz
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Maciej K Janik
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Norman Junge
- Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Ulrich Baumann
- Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland; Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Marcial Sebode
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
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16
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Fedrizzi RS, Coral GP, Mattos AAD, Mattos ÂZD, Tovo CV. EVALUATION OF PATIENTS WITH AUTOIMMUNE HEPATITIS IN A SPECIALIZED OUTPATIENT CLINIC IN SOUTHERN BRAZIL. ARQUIVOS DE GASTROENTEROLOGIA 2021; 57:361-365. [PMID: 33237214 DOI: 10.1590/s0004-2803.202000000-69] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a chronic liver disease, characterized by necroinflammation and autoimmune etiology. Studies evaluating the characteristics of patients with AIH are scarce in Brazil. OBJECTIVE Our objective was to evaluate the profile of patients with AIH in a specialized center in Southern Brazil and to verify factors related to treatment response. METHODS this was a retrospective cohort study, which analyzed demographic, epidemiological, clinical, laboratory, and histologic data. Patients with AIH diagnosed according to the criteria of the International Autoimmune Hepatitis Group (IAIHG) were included. In liver biopsies, the degree of fibrosis, histological activity, presence of hepatocyte rosettes, plasma cell infiltrates, and confluent necrosis were evaluated. In the statistical analysis, the significance level was 5%. RESULTS Forty adults patients diagnosed with AIH were included. The evaluated population predominantly consisted of women (75.0%) and the average age at diagnosis was 44.2 years. The association with extrahepatic autoimmune diseases occurred in 20.0% of cases. Clinically, 35.0% of patients presented with acute onset hepatitis, 37.5% with cirrhosis, and 27.5% with other forms of presentation. The most common clinical manifestation was jaundice (47.5%). Thirty-five patients were treated, and of these, 97.1% used prednisone combined with azathioprine. The average treatment time was 2.7 years. Response to treatment was complete or partial in 30 (85.7%) and absent in 5 (14.3%) patients. There was no statistically significant difference when evaluating response to treatment in relation to forms of presentation, histological findings, and the presence of autoantibodies. Regarding fibrosis, regression was observed in 18.75% of the cases. CONCLUSION Most patients with AIH were young at presentation and of female sex. The association with extrahepatic autoimmune diseases and cirrhosis at presentation was seen in a considerable proportion of patients. Treatment was effective, but there were no clinical, histological or serological parameters capable of predicting treatment response.
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Affiliation(s)
- Renata S Fedrizzi
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brasil
| | - Gabriela P Coral
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brasil
| | - Angelo A de Mattos
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brasil
| | - Ângelo Z de Mattos
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brasil
| | - Cristiane V Tovo
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brasil
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17
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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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18
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Czaja AJ. Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions. World J Gastroenterol 2019; 25:6579-6606. [PMID: 31832000 PMCID: PMC6906207 DOI: 10.3748/wjg.v25.i45.6579] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/25/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple pathogenic mechanisms have been implicated in autoimmune hepatitis, but they have not fully explained susceptibility, triggering events, and maintenance or escalation of the disease. Furthermore, they have not identified a critical defect that can be targeted. The goals of this review are to examine the diverse pathogenic mechanisms that have been considered in autoimmune hepatitis, indicate investigational opportunities to validate their contribution, and suggest interventions that might evolve to modify their impact. English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Genetic and epigenetic factors can affect susceptibility by influencing the expression of immune regulatory genes. Thymic dysfunction, possibly related to deficient production of programmed cell death protein-1, can allow autoreactive T cells to escape deletion, and alterations in the intestinal microbiome may help overcome immune tolerance and affect gender bias. Environmental factors may trigger the disease or induce epigenetic changes in gene function. Molecular mimicry, epitope spread, bystander activation, neo-antigen production, lymphocytic polyspecificity, and disturbances in immune inhibitory mechanisms may maintain or escalate the disease. Interventions that modify epigenetic effects on gene expression, alter intestinal dysbiosis, eliminate deleterious environmental factors, and target critical pathogenic mechanisms are therapeutic possibilities that might reduce risk, individualize management, and improve outcome. In conclusion, diverse pathogenic mechanisms have been implicated in autoimmune hepatitis, and they may identify a critical factor or sequence that can be validated and used to direct future management and preventive strategies.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States
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19
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Mendoza-Carrera F, Gastélum-Meza MÁ, Ramírez-García J, Dávalos-Cobián C, Castro-Martínez XH, Arellano-Olivera MIC, Hernández-Ramos LE, Leal-Cortés C. No association of HLA–DRB1 and TNF alleles in Mexican patients with autoimmune hepatitis. Genes Immun 2019; 20:678-683. [DOI: 10.1038/s41435-019-0086-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 09/04/2019] [Accepted: 09/18/2019] [Indexed: 01/20/2023]
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20
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Chen RL, Wang QX, Ma X. Precision medicine for autoimmune hepatitis. J Dig Dis 2019; 20:331-337. [PMID: 31099976 DOI: 10.1111/1751-2980.12786] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 05/07/2019] [Indexed: 01/10/2023]
Abstract
Autoimmune hepatitis (AIH) is an autoimmune liver disease induced by environmental factors in genetically susceptible individuals. AIH is characterized by hypergammaglobulinemia, elevation of serum autoantibodies and transaminases, and interface hepatitis. Personalized therapy is necessary in AIH because of its heterogeneity in clinical manifestations. Precision medicine is a recent and novel therapeutic pattern which ultimately aims to achieve personalized therapy. In this review we summarize the research progress of precision medicine to treat AIH by an exploration of the susceptible genes, precision diagnosis and prognosis of AIH, pharmacogenomics and precision medication, and the precision treatment for special types of AIH.
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Affiliation(s)
- Rui Ling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Xia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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21
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Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME. Cellular and Molecular Mechanisms of Autoimmune Hepatitis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:247-292. [PMID: 29140756 DOI: 10.1146/annurev-pathol-020117-043534] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.
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Affiliation(s)
- G J Webb
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - G M Hirschfield
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - E L Krawitt
- Department of Medicine, University of Vermont, Burlington, Vermont 05405, USA; .,Department of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA
| | - M E Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, California 95817, USA;
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22
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Floreani A, Restrepo-Jiménez P, Secchi MF, De Martin S, Leung PS, Krawitt E, Bowlus CL, Gershwin ME, Anaya JM. Etiopathogenesis of autoimmune hepatitis. J Autoimmun 2018; 95:133-143. [DOI: 10.1016/j.jaut.2018.10.020] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/18/2018] [Accepted: 10/22/2018] [Indexed: 12/13/2022]
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23
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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: 7] [Impact Index Per Article: 1.0] [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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24
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Gambino CM, Aiello A, Accardi G, Caruso C, Candore G. Autoimmune diseases and 8.1 ancestral haplotype: An update. HLA 2018; 92:137-143. [PMID: 29877054 DOI: 10.1111/tan.13305] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 05/08/2018] [Accepted: 06/01/2018] [Indexed: 12/11/2022]
Abstract
The aim of the present review is to provide an update of the current research into the pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype. This is a common Caucasoid haplotype carried by most people who type for HLA-B8, DR3. Numerous genetic studies reported that individuals with certain HLA alleles have a higher risk of specific autoimmune disorders than those without these alleles. However, much remains to be learned about the heritability of autoimmune conditions. Recently, progress and advances in the field of genome-wide-association studies have revolutionized the capacity to perform large, economically feasible, and statistically robust analyses of HLA within 8.1 ancestral haplotype, and understand its contribute to autoimmune events. In this paper, the characteristic features of this haplotype that might give rise to diverse autoimmune phenotypes are reviewed, focusing on the contribution of the HLA-DRB1 gene, the most polymorphic sequence within the HLA II region.
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Affiliation(s)
- C M Gambino
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| | - A Aiello
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| | - G Accardi
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| | - C Caruso
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
| | - G Candore
- Department of Pathobiology and Medical Biotechnologies (Di.Bi.Med.), University of Palermo, Palermo, Italy
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25
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Chaouali M, Azaiez MB, Tezeghdenti A, Lagha A, Yacoubi-Oueslati B, Ghazouani E, Abdallah HB, Kochkar R. Association of TNF-α-308 Polymorphism with Susceptibility to Autoimmune Hepatitis in Tunisians. Biochem Genet 2018; 56:650-662. [PMID: 29845365 DOI: 10.1007/s10528-018-9867-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 05/23/2018] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology and several proinflammatory cytokines are implicated in its pathogenesis. The association of TNF-α gene polymorphism with AIH onset is not fully elucidated especially in the Tunisian population. The aim of this study was to determine the association of TNF-α (-308 G > A) polymorphism with AIH susceptibility and with TNF-α expression or clinical manifestations of AIH. A total of 50 AIH patients and 150 controls were included. Evaluation of TNF-α polymorphism was performed by ARMS PCR method. A significantly higher frequence of the AA genotype was found in AIH patients compared to controls (34 vs. 8%, p = 0.00002, OR 5.88). The frequency of the A-allele was significantly higher in patients with AIH compared to controls (55 vs. 37.3%, p = 0.002, OR 2.05). The G-allele was significantly more frequent in healthy controls compared to AIH patients [43 vs. 61.3%, p = 0.001, OR 0.47 (0.3-0.75)]. There was a positive correlation between the A/A genotype and a higher serum expression of TNF-α. The TNF*A allele confer susceptibility to AIH in the Tunisian patients and is associated with increased production of TNF-α. Anti-TNF antibodies could be an alternative to the use of corticotherapy and may avoid the exacerbated immune response in AIH.
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Affiliation(s)
- Marwa Chaouali
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia.
- Laboratory of Mycology, Pathologies and Biomarkers, El Manar University, 1092, Tunis, Tunisia.
| | - Mouna Ben Azaiez
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
| | - Aymen Tezeghdenti
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
| | - Awatef Lagha
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
| | - Basma Yacoubi-Oueslati
- Laboratory of Mycology, Pathologies and Biomarkers, El Manar University, 1092, Tunis, Tunisia
| | - Ezzeddine Ghazouani
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
| | - Hatem Ben Abdallah
- Department of Gastroenterology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
| | - Radhia Kochkar
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
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26
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Czaja AJ. Epigenetic changes and their implications in autoimmune hepatitis. Eur J Clin Invest 2018; 48. [PMID: 29383703 DOI: 10.1111/eci.12899] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 01/25/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND The genetic risk of autoimmune hepatitis is insufficient to explain the observed risk, and epigenetic changes may explain disparities in disease occurrence in different populations within and between countries. The goal of this review was to examine how epigenetic changes induced by the environment or inherited as a phenotypic trait may affect autoimmune hepatitis and be amenable to therapeutic intervention. MATERIALS AND METHODS Pertinent abstracts were identified in PubMed by multiple search terms. The number of abstracts reviewed was 1689, and the number of full-length articles reviewed exceeded 150. RESULTS Activation of pro-inflammatory genes in autoimmune disease is associated with hypomethylation of deoxyribonucleic acid and modification of histones within chromatin. Organ-specific microribonucleic acids can silence genes by marking messenger ribonucleic acids for degradation, and they can promote inflammatory activity or immunosuppression. High circulating levels of the microribonucleic acids 21 and 122 have been demonstrated in autoimmune hepatitis, and they may increase production of pro-inflammatory cytokines. Microribonucleic acids are also essential for maintaining regulatory T cells. Drugs, pollutants, infections, diet and ageing can induce inheritable epigenetic changes favouring autoimmunity. Reversal is feasible by manipulating enzymes, transcription factors, gene-silencing molecules and toxic exposures or by administering methyl donors and correcting vitamin D deficiency. Gene targets, site specificity, efficacy and consequences are uncertain. CONCLUSIONS Potentially reversible epigenetic changes may affect the occurrence and outcome of autoimmune hepatitis, and investigations are warranted to determine the nature of these changes, key genomic targets, and feasible interventions and their consequences.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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27
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Oka S, Furukawa H, Yasunami M, Kawasaki A, Nakamura H, Nakamura M, Komori A, Abiru S, Nagaoka S, Hashimoto S, Naganuma A, Naeshiro N, Yoshizawa K, Yamashita H, Ario K, Ohta H, Sakai H, Yabuuchi I, Takahashi A, Abe K, Yatsuhashi H, Tohma S, Ohira H, Tsuchiya N, Migita K. HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype. PLoS One 2017; 12:e0187325. [PMID: 29088299 PMCID: PMC5663488 DOI: 10.1371/journal.pone.0187325] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 10/17/2017] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE Autoimmune hepatitis (AIH) is a chronic progressive liver disease. AIH is composed predominantly of type 1 in Japanese populations. The genetic and environmental factors are associated with the pathogenesis of AIH. HLA-DRB1*03:01 and *04:01 are associated with type 1 AIH in European and *04:05 in Japanese populations. Here, we conducted an HLA association study in order to find HLA alleles or haplotypes predisposing or protective for Japanese AIH. METHODS HLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed. RESULTS The predisposing association of DRB1*04:01 (P = 0.0006, corrected P [Pc] = 0.0193, odds ratio [OR] 2.97, 95% confidence interval [CI] 1.62-5.43), DRB1*04:05 (P = 1.89×10-21, Pc = 5.86×10-20, OR 3.41, 95% CI 2.65-4.38), and DQB1*04:01 (P = 4.66×10-18, Pc = 6.99×10-17, OR 3.89, 95% CI 2.84-5.33) and the protective association of DRB1*13:02 (P = 0.0003, Pc = 0.0080, OR 0.48, 95% CI 0.32-0.72) with Japanese type 1 AIH were observed. An association of the DR4/DR8 heterozygous genotype with Japanese AIH was identified for the first time (P = 3.12×10-9, OR 3.52, 95% CI 2.34-5.29). Susceptible diplotypes were DRB1*04:05-DQB1*04:01/DRB1*08:02-DQB1*03:02 (P = 0.0004, OR 24.77, 95% CI 1.45-424.31) and DRB1*04:05-DQB1*04:01/DRB1*08:03-DQB1*06:01 (P = 1.18×10-6, OR 10.64, 95% CI 3.19-35.46). Serum levels of Immunoglobulin G and Immunoglobulin M, International Autoimmune Hepatitis Group score, positive rate of anti-smooth muscle antibodies, and the rate of definite AIH were higher in AIH patients with DRB1*04:05 than without. CONCLUSIONS The important roles of specific combinations of DRB1 and DQB1 alleles or haplotypes in the pathogenesis of type 1 AIH were suggested. The association of DR4/DR8 heterozygous genotype suggested the pathologic importance of trans-complementing DQα-β heterodimer molecules encoded by DQA1 allele of one haplotype and the DQB1 allele of the other haplotype, as it was proposed in the HLA association studies of Type 1 diabetes.
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Affiliation(s)
- Shomi Oka
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan
- Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18–1 Sakuradai, Minami-ku, Sagamihara, Japan
| | - Hiroshi Furukawa
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan
- Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18–1 Sakuradai, Minami-ku, Sagamihara, Japan
- * E-mail:
| | - Michio Yasunami
- Department of Medical Genomics, Life Science Institute, Saga-ken Medical Centre Koseikan, 400 Kasemachi-Nakabaru, Saga, Japan
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, Japan
| | - Aya Kawasaki
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan
| | - Hitomi Nakamura
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, Japan
| | - Minoru Nakamura
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, Japan
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Seigo Abiru
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Shinya Nagaoka
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Satoru Hashimoto
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Atsushi Naganuma
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Noriaki Naeshiro
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Kaname Yoshizawa
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Haruhiro Yamashita
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Keisuke Ario
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Hajime Ohta
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Hironori Sakai
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Iwao Yabuuchi
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan
| | - Kazumichi Abe
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Shigeto Tohma
- Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18–1 Sakuradai, Minami-ku, Sagamihara, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan
| | - Naoyuki Tsuchiya
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan
| | - Kiyoshi Migita
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan
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Chaouali M, Kochkar R, Messadi A, Tezeghdenti A, Azaiez MB, Abdallah HB, Yacoubi-Oueslati B, Ghazouani E. Distribution of HLA-DRB1/DQB1 alleles and DRB1-DQB1 haplotypes among Tunisian patients with autoimmune hepatitis. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2017. [DOI: 10.1016/j.ejmhg.2017.02.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Chaouali M, Kochkar R, Tezeghdenti A, Messadi A, ben Azaiez M, lagha A, ghazouani E, ben Abdallah H, yacoubi-Oueslati B, Nabil Abdelli M. Hépatite auto-immune chronique de l’adulte : étude clinique de 30 patients tunisiens. ACTA ACUST UNITED AC 2017. [DOI: 10.1016/s1773-035x(17)30121-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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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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31
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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: 32] [Impact Index Per Article: 3.6] [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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Baharlou R, Faghihi-Kashani A, Faraji F, Najafi-Samei M, Setareh M, Zamani F, Tajik N. HLA-DRB1 alleles of susceptibility and protection in Iranians with autoimmune hepatitis. Hum Immunol 2016; 77:330-5. [PMID: 26780502 DOI: 10.1016/j.humimm.2016.01.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 11/03/2015] [Accepted: 01/07/2016] [Indexed: 01/20/2023]
Abstract
Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. The aim of this study was to determine the frequency of HLA-DRB1 alleles in Iranian patients with AIH and investigate the association between HLA alleles and the different types of the disease. Fifty-four AIH patients and 100 age- and sex-matched healthy controls were subjected to low resolution HLA-DRB typing performed by polymerase chain reaction-sequence-specific primers (PCR-SSP) technique. The results revealed higher frequencies of HLA-DRB1(∗)03, and DRB1(∗)13 alleles in patients with AIH compared to controls. However, DRB1(∗)11 was less frequent in AIH patients. In type I AIH patients HLA-DRB1(∗)03, HLA-DRB1(∗)04, HLA-DRB1(∗)08, and HLA-DRB1(∗)13 were the most frequent alleles. While in type II, the most frequent alleles were HLA-DRB1(∗)07 and HLA-DRB1(∗)13. The seronegative patients showed more frequency of HLA-DRB1(∗)03 and HLA-DRB3. In contrary, the frequency of HLA-DRB1(∗)11, HLA-DRB1(∗)15 and HLA-DRB5 in type 1 was less than healthy individuals. These findings indicate the role of HLA-DRB haplotypes in AIH susceptibility and protection, in the Iranian population.
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Affiliation(s)
- Rasoul Baharlou
- Gastrointestinal and Liver Diseases Research Center (GILDRC), Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center (IRC), Iran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Faghihi-Kashani
- Gastrointestinal and Liver Diseases Research Center (GILDRC), Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Faraji
- Immunology Research Center (IRC), Iran University of Medical Sciences, Tehran, Iran
| | | | - Masoumeh Setareh
- Gastrointestinal and Liver Diseases Research Center (GILDRC), Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Diseases Research Center (GILDRC), Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Nader Tajik
- Immunology Research Center (IRC), Iran University of Medical Sciences, Tehran, Iran.
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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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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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Yang F, Wang Q, Bian Z, Ren LL, Jia J, Ma X. Autoimmune hepatitis: East meets west. J Gastroenterol Hepatol 2015; 30:1230-6. [PMID: 25765710 DOI: 10.1111/jgh.12952] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [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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Nares-Cisneros J, Jaramillo-Rodríguez Y. Hepatitis autoinmune en niños: evolución de 20 casos del norte de México. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2014; 79:238-43. [DOI: 10.1016/j.rgmx.2014.08.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 08/10/2014] [Accepted: 08/13/2014] [Indexed: 12/11/2022]
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Nares-Cisneros J, Jaramillo-Rodríguez Y. Autoimmune hepatitis in children: Progression of 20 cases in northern Mexico. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2014. [DOI: 10.1016/j.rgmxen.2014.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Totè E, Lamperti M, Bondani M, Salerno D, Cassina V, Nardo L. Full genotyping of a highly polymorphic human gene trait by time-resolved fluorescence resonance energy transfer. PLoS One 2014; 9:e107310. [PMID: 25215592 PMCID: PMC4162610 DOI: 10.1371/journal.pone.0107310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 08/10/2014] [Indexed: 11/19/2022] Open
Abstract
The ability of detecting the subtle variations occurring, among different individuals, within specific DNA sequences encompassed in highly polymorphic genes discloses new applications in genomics and diagnostics. DQB1 is a gene of the HLA-II DQ locus of the Human Leukocyte Antigens (HLA) system. The polymorphisms of the trait of the DQB1 gene including codons 52-57 modulate the susceptibility to a number of severe pathologies. Moreover, the donor-receiver tissue compatibility in bone marrow transplantations is routinely assessed through crossed genotyping of DQB and DQA. For the above reasons, the development of rapid, reliable and cost-effective typing technologies of DQB1 in general, and more specifically of the codons 52-57, is a relevant although challenging task. Quantitative assessment of the fluorescence resonance energy transfer (FRET) efficiency between chromophores labelling the opposite ends of gene-specific oligonucleotide probes has proven to be a powerful tool to type DNA polymorphisms with single-nucleotide resolution. The FRET efficiency can be most conveniently quantified by applying a time-resolved fluorescence analysis methodology, i.e. time-correlated single-photon counting, which allows working on very diluted template specimens and in the presence of fluorescent contaminants. Here we present a full in-vitro characterization of the fluorescence responses of two probes when hybridized to oligonucleotide mixtures mimicking all the possible genotypes of the codons 52-57 trait of DQB1 (8 homozygous and 28 heterozygous). We show that each genotype can be effectively tagged by the combination of the fluorescence decay constants extrapolated from the data obtained with such probes.
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Affiliation(s)
- Edoardo Totè
- Department of Science and High Technology, University of Insubria, Como, Italy
| | - Marco Lamperti
- Department of Science and High Technology, University of Insubria, Como, Italy
| | - Maria Bondani
- C. N. R. (Consiglio Nazionale delle Ricerche), Institute for Photonics and Nanotechnology, Como, Italy
| | - Domenico Salerno
- Department of Health Sciences, University of Milan Bicocca, Monza, Italy
| | - Valeria Cassina
- Department of Health Sciences, University of Milan Bicocca, Monza, Italy
| | - Luca Nardo
- Department of Health Sciences, University of Milan Bicocca, Monza, Italy
- * E-mail:
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Maggiore G, Nastasio S, Sciveres M. Juvenile autoimmune hepatitis: Spectrum of the disease. World J Hepatol 2014; 6:464-476. [PMID: 25067998 PMCID: PMC4110538 DOI: 10.4254/wjh.v6.i7.464] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 03/19/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Juvenile autoimmune hepatitis (JAIH) is a progressive inflammatory liver disease, affecting mainly young girls, from infancy to late adolescence, characterized by active liver damage, as shown by high serum activity of aminotransferases, by elevated immunoglobulin G levels, high titers of serum non organ-specific and organ-specific autoantibodies, and by interface hepatitis on liver biopsy. It is a multifactorial disease of unknown etiology in which environmental factors act as a trigger in genetically predisposed individuals. Two types of JAIH are identified according to the autoantibody panel detected at diagnosis: AIH-1, characterized by the presence of anti-smooth muscle antibody and/or antinuclear antibody and AIH-2, by anti-liver-kidney microsomal antibody type 1 and/or by the presence of anti-liver cytosol type 1 antibody. Epidemiological distribution, genetic markers, clinical presentation and pattern of serum cytokines differentiate the two types of AIH suggesting possible pathogenetic mechanisms. The most effective therapy for AIH is pharmacological suppression of the immune response. Treatment should be started as soon as the diagnosis is made to avoid severe liver damage and progression of fibrosis. The aim of this review is to outline the most significant and peculiar features of JAIH, based largely on our own personal database and on a review of current literature.
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Hassan N, Siddiqui AR, Abbas Z, Hassan SM, Soomro GB, Mubarak M, Anis S, Muzaffar R, Zafar MN. Clinical Profile and HLA Typing of Autoimmune Hepatitis From Pakistan. HEPATITIS MONTHLY 2013; 13:e13598. [PMID: 24358040 PMCID: PMC3867004 DOI: 10.5812/hepatmon.13598] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 10/22/2013] [Accepted: 11/16/2013] [Indexed: 01/10/2023]
Abstract
BACKGROUND Human leukocyte antigen (HLA) typing in autoimmune hepatitis (AIH) has been investigated in different populations and ethnic groups, but no such data is available from Pakistan. OBJECTIVES The aim of this study was to evaluate the clinical profile of autoimmune hepatitis (AIH), and determine the associated antigens and alleles by performing HLA typing. PATIENTS AND METHODS A total of 58 patients, diagnosed and treated as AIH in the last 10 years were reviewed. Diagnosis was based on International AIH Group criteria. Forty one patients underwent liver biopsy. HLA typing was performed in 44 patients and 912 controls by serological method for HLA A and B, and by PCR technique using sequence specific primers for DR alleles. RESULTS Of 58 cases, 35 were females (60.3%). The median age was 14.5 (range 4-70 years), and AIH score was 14 (10-22). Thirty-six (62.0%) patients had type 1 AIH, 10 (17.2%) type 2, and the remaining 12 were seronegative with biopsy proven AIH. Forty-nine patients (84.4%) had cirrhosis. Twenty-four (41.4%) patients had ascites at the time of presentation. Among 41 patients who underwent liver biopsy, thirty-two had advance stages III and IV disease, and twenty had severe grade of inflammation. Fifteen patients had other associated autoimmune diseases and one developed hepatocellular carcinoma. HLA A2 (P = 0.036), HLA A9 (23) (P = 0.018), HLA A10 (25) (P = 0.000), HLA A19 (33) (P = 0.000), HLA B15 (63) (P = 0.007), HLA B40 (61) ( P = 0.002), HLA DR6 (P = 0.001) with its subtypes HLA-DRB1*13 (P = 0.032) and HLA-DRB1*14 (p = 0.017) were more prevalent in AIH with statistical significance than controls. CONCLUSIONS AIH in our region presents with advanced disease affecting predominantly children and adolescents. There is a genetic association of HLA DR6 along with other alleles and antigens in our patients with AIH.
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Affiliation(s)
- Nasir Hassan
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Adeelur Rehman Siddiqui
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Zaigham Abbas
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
- Corresponding Author: Zaigham Abbas, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, 74200, Karachi, Pakistan. Tel: +92-2199215718; Fax: +92-2199215469, E-mail:
| | - Syed Mujahid Hassan
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ghous Bux Soomro
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Muhammed Mubarak
- Department of Pathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Sabiha Anis
- Molecular Diagnostics and Immunology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Rana Muzaffar
- Molecular Diagnostics and Immunology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Mirza Naqi Zafar
- Department of Pathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
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Ngu JH, Wallace MC, Merriman TR, Gearry RB, Stedman CA, Roberts RL. Association of the HLA locus and TNF with type I autoimmune hepatitis susceptibility in New Zealand Caucasians. SPRINGERPLUS 2013; 2:355. [PMID: 23961418 PMCID: PMC3733077 DOI: 10.1186/2193-1801-2-355] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 07/29/2013] [Indexed: 02/06/2023]
Abstract
Purpose The precise etiology of autoimmune hepatitis (AIH) remains unknown, although a number of genetic loci have been implicated in the susceptibility of type 1 AIH. The purpose of this study was to test for association of these loci with type 1 AIH in New Zealand Caucasians. Methods 77 AIH patients and 485 healthy controls were genotyped for the SNPs rs2187668 (HLA-DRB*03:01), rs660895 (HLA-DRB*04:01), rs3749971 (HLA-A1-B8-DR3), rs231775 (CLTLA4), rs1800629 (TNF), and rs1800682 (FAS) using predesigned TaqMan SNP genotyping assays. Chi square analysis was used to test for association of allele and genotype with overall AIH, and with severe fibrosis and ALT levels at 6 months. Results Significant risk of AIH was conferred by the minor alleles of rs2187668 (OR = 2.45, 95% CI 1.65-3.61, p < 0.0001), rs3749971 (OR = 1.89, 95% CI 1.21-2.94, p = 0.004) and rs1800629 (OR = 2.06, 95% CI 1.41-3.01, p = 0.0001). Multivariate analysis showed that rs2187668 was independently associated with type 1 AIH susceptibility (OR = 2.40, 95% CI 1.46-3.93, p = 0.001). The C allele of FAS SNP rs1800682 was associated with increased risk of severe fibrosis at diagnosis (OR = 2.03, 95% CI 1.05-3.93, p = 0.035) and with incomplete normalization of ALT levels at 6 months post-diagnosis (OR = 3.94, 95% CI 1.62-9.54, p = 0.0015). Conclusions This is the first population-based study to investigate genetic risk loci for type 1 AIH in New Zealand Caucasians. We report significant independent association of HLA-DRB1*03:01 with overall susceptibility to type 1 AIH, as well as FAS with a more aggressive disease phenotype.
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Affiliation(s)
- Jing H Ngu
- Department of Medicine, University of Otago, PO Box 434, Christchurch, 8140 New Zealand ; Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
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Ferri Liu PM, de Miranda DM, Fagundes EDT, Ferreira AR, Simões e Silva AC. Autoimmune hepatitis in childhood: The role of genetic and immune factors. World J Gastroenterol 2013; 19:4455-4463. [PMID: 23901220 PMCID: PMC3725369 DOI: 10.3748/wjg.v19.i28.4455] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 06/10/2013] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a rare chronic inflammatory disease of the liver, which affects a group of patients who lost their immunological tolerance to antigens of the liver. It is clinically characterized by hypergammaglobulinemia, elevated liver enzymes, presence of autoantibodies and histological changes. Although being rare in children, it represents a serious cause of chronic hepatic disease that can lead to cirrhosis and hepatic failure. Clinical findings, exclusion of more common liver disorders and the detection of antibodies antinuclear antibodies, smooth muscle antibodies and anti-LKM1 are usually enough for diagnosis on clinical practice. The pathogenic mechanisms that lead to AIH remain obscure, but some research findings suggest the participation of immunologic and genetic factors. It is not yet knew the triggering factor or factors that stimulate inflammatory response. Several mechanisms proposed partially explain the immunologic findings of AIH. The knowledge of immune factors evolved might result in better markers of prognosis and response to treatment. In this review, we aim to evaluate the findings of research about genetic and immune markers and their perspectives of application in clinical practice especially in pediatric population.
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Czaja AJ. Autoimmune hepatitis in diverse ethnic populations and geographical regions. Expert Rev Gastroenterol Hepatol 2013; 7:365-85. [PMID: 23639095 DOI: 10.1586/egh.13.21] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis has diverse clinical phenotypes and outcomes in ethnic groups within a country and between countries, and these differences may reflect genetic predispositions, indigenous etiological agents, pharmacogenomic mechanisms and socioeconomic reasons. In the USA, African-American patients have cirrhosis more commonly, treatment failure more frequently and higher mortality than white American patients. Survival is poorest in Asian-American patients. Autoimmune hepatitis in other countries is frequently associated with genetic predispositions that may favor susceptibility to indigenous etiological agents. Cholestatic features influence treatment response; acute-on-chronic liver disease increases mortality and socioeconomic and cultural factors affect prognosis. Ethnic-based deviations from classical phenotypes and the frequency of late-stage disease can complicate the diagnosis and management of autoimmune hepatitis in non-white populations.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Czaja AJ. Diagnosis, pathogenesis, and treatment of autoimmune hepatitis after liver transplantation. Dig Dis Sci 2012; 57:2248-66. [PMID: 22562533 DOI: 10.1007/s10620-012-2179-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 04/12/2012] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis can recur or appear de novo after liver transplantation, and it can result in hepatic fibrosis, graft loss, and re-transplantation. The goals of this review are to describe the prevalence, manifestations, putative pathogenic mechanisms, outcomes, and management of these occurrences. Autoimmune hepatitis recurs in 8-12 % of transplanted patients at 1 year and 36-68 % at 5 years. Recurrence may be asymptomatic and detected only by surveillance liver test abnormalities or protocol liver tissue examination. Autoantibodies that characterized the original disease, hypergammaglobulinemia, increased serum immunoglobulin G level, and histological findings of interface hepatitis, lymphoplasmacytic infiltration, perivenular hepatocyte necrosis, pseudo-rosetting, and acidophil bodies typify recurrence. Premature corticosteroid withdrawal and pre-transplant severity of the original disease are possible risk factors. De novo autoimmune hepatitis occurs in 1-7 % of patients 0.1-9 years after transplantation, especially in children. The appearance of autoantibodies may herald its emergence, and antibodies to glutathione-S-transferase T1 have been predictive of the disease. Recurrent disease may reflect recruitment of residual memory T lymphocytes and host-specific genetic predispositions, whereas de novo disease may reflect an allo-antigenic immune response and molecular mimicries that override self-tolerance. Treatment should be appropriate for autoimmune hepatitis and not based on anti-rejection drugs. Corticosteroid therapy alone or combined with azathioprine is the essential treatment. The substitution of mycophenolate mofetil for azathioprine and switch of the calcineurin inhibitor or its replacement with rapamycin have also been used for refractory disease. Re-transplantation has been necessary in 8-23 %.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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Abstract
GOALS To evaluate race/ethnicity-specific variations in autoimmune hepatitis (AIH) with a focus on Asians and Hispanics, the fastest growing populations in the United States. BACKGROUND AIH is a chronic inflammatory disease in which race/ethnicity-specific variations in clinical epidemiology have been reported. However, earlier studies were small or did not include a comprehensive analysis of Asians and Hispanics, the 2 fastest growing population cohorts in the United States. STUDY A retrospective study analyzing patient data from 1999 to 2010 in a large tertiary-care community hospital to assess AIH epidemiology among a racially diverse population. RESULTS One hundred eighty-three patients with AIH were included in the study with 81 patients having "definite" AIH by International Autoimmune Hepatitis Group criteria and 63 were diagnosed with overlap syndromes. Women and whites were the largest cohorts. The average age of diagnosis was similar among all groups. Biopsy-confirmed cirrhosis was present in 34% of AIH patients with Hispanics demonstrating the highest prevalence of cirrhosis (55%). When compared with whites, Asians had higher international normalized ratio (INR) (1.4 U vs. 1.1 U, P<0.01), and Hispanics had lower serum albumin (3.3 g/dL vs. 3.7 g/dL, P<0.001) and platelets (123.8 thousand/mcL vs. 187.5 thousand/mcL, P<0.001) and higher international normalized ratio (1.5 U vs. 1.1 U, P=0.05). Kaplan-Meier survival analysis demonstrated a trend toward worse outcomes among Asians. CONCLUSIONS Among AIH patients, Hispanics had the highest prevalence of cirrhosis, and Asians had poorer survival outcomes. Race/ethnicity-specific disparities in AIH epidemiology may reflect underlying genetic differences, contributing to variations in disease severity, response to therapy, and overall mortality.
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Muñoz-Espinosa L, Alarcon G, Mercado-Moreira A, Cordero P, Caballero E, Avalos V, Villarreal G, Senties K, Puente D, Soto J, Esqueda B, Campos G, Martínez M, Jaquez J, Ramirez A, Reyes I, Kershenobich D, Montano-Loza AJ. Performance of the international classifications criteria for autoimmune hepatitis diagnosis in Mexican patients. Autoimmunity 2011; 44:543-8. [PMID: 21875376 DOI: 10.3109/08916934.2011.592884] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The revised score of the International Autoimmune Hepatitis Group (R-IAIHG) and the simplified criteria (SC) are used for diagnosis of autoimmune hepatitis (AIH). Our aim is to evaluate the performance of these classifications to differentiate AIH from other autoimmune liver diseases. The frequency of diagnosis of definite AIH was similar both by the R-IAIHG and the SC systems (41% versus 40%), whereas diagnosis of probable AIH was made more commonly by the R-IAIHG than the SC (59% versus 29%), and 23 patients that have been graded as definite (n = 7) or probable (n = 16) AIH by the R-IAIHG had non-diagnostic scores by the SC system. The scoring systems rendered concordant diagnosis of definite (n = 15) and probable (n = 13) AIH in 28/73 patients (38%). Discordant diagnoses of AIH were rendered in 45/73 patients (62%). The R-IAIHG exhibited a sensitivity of 95%, specificity of 90%, and positive predictive value (PPV) and negative predictive value (NPV) of 93% for both. On the other hand, the SC had a lower sensitivity (65%) but a higher specificity (100%), PPV of 100%, and NPV of 68%. In conclusion, both international scoring systems diagnosed the same number of cases as definite AIH. The R-IAIHG showed a higher sensitivity in diagnosing AIH, whereas the SC showed a higher specificity. SC are easier to apply at the bedside and exclude more patients that could have a different etiology.
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Affiliation(s)
- Linda Muñoz-Espinosa
- Liver Unit, "Dr. Jose E. Gonzalez" University Hospital, UANL, Monterrey, Nuevo Leon, Mexico.
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Autoimmune hepatitis: a review of current diagnosis and treatment. HEPATITIS RESEARCH AND TREATMENT 2011; 2011:390916. [PMID: 21760995 PMCID: PMC3132488 DOI: 10.1155/2011/390916] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2010] [Revised: 02/15/2011] [Accepted: 03/03/2011] [Indexed: 12/20/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory disorder characterized by periportal inflammation, elevated immunoglobulins, autoantibodies, and a dramatic response to immunosuppression. An environmental agent is hypothesized to trigger an immune-mediated attack directed against liver antigens in genetically predisposed individuals. A plethora of clinical presentations can be seen ranging from chronic indolent disease to fulminant hepatic failure, and diagnosis requires exclusion of other causes of liver disease. Corticosteroid therapy must be instituted early and modified in an individualized fashion. Treatment decisions are often complicated by the diverse clinical manifestations, uncertainty about natural history, evolving ideas about treatment end points, and a multitude of alternative immunosuppressive agents. Achieving normal liver tests and tissue is the ideal treatment end point, but needs to be weighed against the risk of side effects. Decompensated patients may benefit from early liver transplantation. Long-term prognosis is excellent with early and aggressive initiation of therapy. Our paper discusses AIH, giving a detailed overview of its clinical presentation, risk factors, immunopathogenesis, up-to-date diagnostic criteria, current updates in therapy with a brief discussion of AIH in pregnancy, and long-term implications for cirrhosis and hepatocellular carcinoma in AIH patients.
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Genetic background of autoimmune hepatitis in Japan. J Gastroenterol 2011; 46 Suppl 1:42-7. [PMID: 20957499 DOI: 10.1007/s00535-010-0333-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2010] [Accepted: 09/15/2010] [Indexed: 02/04/2023]
Abstract
Autoimmune hepatitis (AIH) is an organ-specific autoimmune disease characterized by chronic inflammation of the liver. Several studies from ethnically different countries have clarified that the genetic predisposition to type 1 AIH is linked mainly to human leukocyte antigen (HLA)-class II genes. Recently, molecular analysis using polymerase chain reaction (PCR)-based DNA typing has revealed that susceptibility to type 1 AIH is primarily associated with the HLA class II DRB1 locus, which encodes a polymorphic β chain of the HLA-DR antigen. However, additional susceptibility genes (either HLA or non-HLA) and/or environmental factors may also contribute to the development of type 1 AIH; in Japanese type 1 AIH patients, although the most influential gene in disease susceptibility is HLA-DRB1*04:05, several other genes have been identified as being involved in AIH pathogenesis or resistance and are the currently the focus of single nucleotide polymorphism analysis.
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Abstract
Animal models of autoimmune hepatitis have been important in defining pathogenic mechanisms, and they promise to aid in the evaluation of new molecular and cellular treatments. They have evolved from models based on crude liver homogenates that produced a transient hepatitis to models that express antibodies to human antigens, manifest liver-infiltrating T cells, persist for at least 3 months and develop fibrosis. Animal models allow the study of autoimmune hepatitis from its inception, and they can detail the progression of pathological events. Key imbalances in counter-regulatory mechanisms can be isolated and manipulated. Models can be humanized by the insertion of human genetic promoters and the expression of human antigens. Genetic engineering and preconditioning have been milestones in the evolution of animal models. Vaccination or infection of murine models with viral vectors carrying human antigens are the most recent developments. Animal models promise to extend the knowledge of etiological agents and improve treatment algorithms.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
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Czaja AJ, Manns MP. Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis. Gastroenterology 2010; 139:58-72.e4. [PMID: 20451521 DOI: 10.1053/j.gastro.2010.04.053] [Citation(s) in RCA: 189] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2010] [Revised: 04/27/2010] [Accepted: 04/30/2010] [Indexed: 12/13/2022]
Abstract
Autoimmune hepatitis (AIH) is characterized by chronic inflammation of the liver, interface hepatitis (based on histologic examination), hypergammaglobulinemia, and production of autoantibodies. Many clinical and basic science studies have provided important insights into the pathogenesis and treatment of AIH. Transgenic mice that express human antigens and develop autoantibodies, liver-infiltrating CD4(+) T cells, liver inflammation, and fibrosis have been developed as models of AIH. AIH has been associated with autoantibodies against members of the cytochrome P450 superfamily of enzymes, transfer RNA selenocysteine synthase, formiminotransferase cyclodeaminase, and the uridine diphosphate glucuronosyltransferases, whereas alleles such as DRB1*0301 and DRB1*0401 are genetic risk factors in white North American and northern European populations. Deficiencies in the number and function of CD4(+)CD25(+) (regulatory) T cells disrupt immune homeostasis and might be corrected as a therapeutic strategy. Treatment can be improved by continuing corticosteroid therapy until normal liver test results and normal liver tissue are within normal limits, instituting ancillary therapies to prevent drug-related side effects, identifying problematic patients early, and providing long-term maintenance therapy after patients experience a first relapse. Calcineurin inhibitors and mycophenolate mofetil are potential salvage therapies, and reagents such as recombinant interleukin-10, abatacept, and CD3-specific antibodies are feasible as therapeutics. Liver transplantation is an effective salvage therapy, even in the elderly, and AIH must be considered in all patients with graft dysfunction after liver transplantation. Identification of the key defects in immune homeostasis and antigen targets will direct new therapies.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
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