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Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
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MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
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Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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Bauer A, Habior A. Antibodies directed against bacterial antigens in sera of Polish patients with primary biliary cholangitis. Front Cell Infect Microbiol 2025; 14:1410282. [PMID: 39844835 PMCID: PMC11752878 DOI: 10.3389/fcimb.2024.1410282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 12/04/2024] [Indexed: 01/24/2025] Open
Abstract
Background Primary biliary cholangitis (PBC) is a cholestatic, autoimmune liver disease with the presence of characteristic autoantibodies. The aim of the work was to determine the level of antibodies directed against bacterial antigens: Chlamydia pneumoniae (anti-Cpn), Yersinia enterolitica (anti-Y.e), Helicobacter pylori (anti-Hp), Mycoplasma pneumoniae (anti- Mp.) and Escherichia coli (E.coli) in sera of PBC patients. We also performed in vitro studies on the impact of the bacterial peptides on the specific antigen-antibody binding. Method We screened 92 Polish PBC patients and sera samples from healthy donors and pathological controls. Autoantibodies and anti-bacterial antibodies were determined by commercially available ELISA kits. Specific inhibition of antibody binding was also detected by the in house ELISA method. Results Anti-Cpn, anti-Y. enterolitica, anti-Hp, anti-M. pneumoniae and anti-E. coli antibodies were significantly more common in the group of PBC patients than in the pathological and healthy control groups: 74%, 40%, 84%, 39% and 69% respectively. The mean level of anti-Cpn, anti- Y.e, anti-Hp and anti- M.p in the PBC group was significantly higher than those in the healthy group (p < 0.001). and in patients with other liver diseases. In sera of patients with the presence of positive anti-mitochondrial antibodies (AMA), specific for PBC, anti-bacterial antibodies have been found in 80% vs. 50% in sera with AMA negative. We observed inhibition of specific antigen-antibody binding by the bacterial peptide: EClpP (E. coli caseinolytic protease) and adenine glycosylase from E. coli caseinolytic protease P, ClpP Y.e from peptide of Y. enterolitica, Mp PDC from M. pneumonia peptide and adenine glycosylase of E. coli. Bacterial factors influence the specific binding of antibodies to pyruvate dehydrogenase (PDC-E2), gp210 and KLHL12 (kelch-like peptide 12) antigens. Conclusion Microbial mimics may be the major targets of cross-reactivity with human pyruvate dehydrogenase, gp210, and KLHL12 in PBC.
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Affiliation(s)
- Alicja Bauer
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Andrzej Habior
- Clinic of Polish Gastroenterology Foundation, Warsaw, Poland
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Lin YL, Yao T, Wang YW, Yu JS, Zhen C, Lin JF, Chen SB. Association between primary biliary cholangitis with diabetes and cardiovascular diseases: A bidirectional multivariable Mendelian randomization study. Clin Res Hepatol Gastroenterol 2024; 48:102419. [PMID: 38992425 DOI: 10.1016/j.clinre.2024.102419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 07/04/2024] [Accepted: 07/09/2024] [Indexed: 07/13/2024]
Abstract
BACKGROUND AND AIMS Primary biliary cholangitis (PBC) is an autoimmune disease often accompanied by multisystem damage. This study aimed to explore the causal association between genetically predicted PBC and diabetes, as well as multiple cardiovascular diseases (CVDs). METHODS Genome-wide association studies (GWAS) summary data of PBC in 24,510 individuals of European ancestry from the European Association for the Study of the Liver was used to identify genetically predicted PBC. We conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to estimate the impacts of PBC on diabetes (N = 17,685 to 318,014) and 20 CVDs from the genetic consortium (N = 171,875 to 1,030,836). RESULTS SVMR provided evidence that genetically predicted PBC is associated with an increased risk of type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), heart failure (HF), hypertension, atrial fibrillation (AF), stroke, ischemic stroke, and small-vessel ischemic stroke. Additionally, there was no evidence of a causal association between PBC and coronary atherosclerosis. In the MVMR analysis, PBC maintained independent effects on T1D, HF, MI, and small-vessel ischemic stroke in most models. CONCLUSION Our findings revealed the causal effects of PBC on diabetes and 7 CVDs, and no causal relationship was detected between PBC and coronary atherosclerosis.
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Affiliation(s)
- Yun-Lu Lin
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Tao Yao
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Ying-Wei Wang
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Jia-Sheng Yu
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Cheng Zhen
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Jia-Feng Lin
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China
| | - Shui-Bing Chen
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China.
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Floreani A, Gabbia D, De Martin S. Current Perspectives on the Molecular and Clinical Relationships between Primary Biliary Cholangitis and Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:2194. [PMID: 38396870 PMCID: PMC10888596 DOI: 10.3390/ijms25042194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/07/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.g., HBV and HCV, non-response to UDCA, and high alcohol intake, as well as some metabolic-associated factors. Overall, HCC development is significantly more frequent in patients with advanced histological stages, being related to liver cirrhosis. It seems to be of fundamental importance to unravel eventual dysfunctional molecular pathways in PBC patients that may be used as biomarkers for HCC development. In the near future, this will possibly take advantage of artificial intelligence-designed algorithms.
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Affiliation(s)
- Annarosa Floreani
- University of Padova, 35122 Padova, Italy;
- Scientific Consultant IRCCS Negrar, 37024 Verona, Italy
| | - Daniela Gabbia
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy;
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy;
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Villani R, Serviddio G, Avolio C, Cassano T, D'Amico E. Autoimmune liver disease and multiple sclerosis: state of the art and future perspectives. Clin Exp Med 2023; 23:3321-3338. [PMID: 37421590 PMCID: PMC10618321 DOI: 10.1007/s10238-023-01128-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 06/23/2023] [Indexed: 07/10/2023]
Abstract
Clinical observations suggest that the prevalence of autoimmune diseases is changing over time. Both autoimmune liver diseases and multiple sclerosis have shown a significant increase in the last decades. Although the coexistence of autoimmune diseases within individuals and families is a common phenomenon, the extent to which liver disease and multiple sclerosis co-occur is not clear. Case reports and few studies have reported the possible coexistence of multiple sclerosis with thyroid diseases, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. It is unknown whether there is a definite association between multiple sclerosis and autoimmune liver diseases. We reviewed the literature to summarize the available studies on the association between different autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis) and treated or untreated multiple sclerosis.
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Affiliation(s)
- Rosanna Villani
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | - Gaetano Serviddio
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Carlo Avolio
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
| | - Tommaso Cassano
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Emanuele D'Amico
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
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Jensen ASH, Winther-Sørensen M, Burisch J, Bergquist A, Ytting H, Gluud LL, Wewer Albrechtsen NJ. Autoimmune liver diseases and diabetes: A propensity score matched analysis and a proportional meta-analysis. Liver Int 2023; 43:2479-2491. [PMID: 37752719 DOI: 10.1111/liv.15720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/20/2023] [Accepted: 08/24/2023] [Indexed: 09/28/2023]
Abstract
BACKGROUND AND AIMS Patients with some chronic liver diseases have increased risk of diabetes. Whether this is also the case for patients with autoimmune liver diseases is unknown. The study aimed to calculate risk and worldwide prevalence of diabetes in patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). METHODS We performed a case-control study using data from the United Kingdom Biobank (UKB) and compared frequency of type 1 diabetes (T1D) and type 2 diabetes (T2D) in AIH and PBC with age-, sex-, BMI- and ethnicity-matched controls. Next, we performed a systematic review and proportional meta-analysis searching PubMed, Embase, Cochrane Library and Web of Science (inception to 1 May 2022 [AIH]; 20 August 2022 [PBC]; 11 November 2022 [PSC]). The pooled prevalence of diabetes was calculated using an inverse method random effects model. RESULTS Three hundred twenty-eight AIH patients and 345 PBC patients were identified in UKB and risk of T1D and T2D significantly increased compared with matched controls. Our systematic search identified 6914 records including the UKB study. Of these, 77 studies were eligible for inclusion comprising 36 467, 39 924 and 4877 individuals with AIH, PBC and PSC, respectively. The pooled prevalence of T1D was 3.8% (2.6%-5.7%), 1.7% (0.9%-3.1%), 3.1% (1.9%-4.8%) and of T2D 14.8% (11.1%-19.5%), 18.1% (14.6%-22.2%), 6.3% (2.8%-13.3%) in patients with AIH, PBC and PSC, respectively. CONCLUSIONS Patients with autoimmune liver diseases have increased risk of diabetes. Increased awareness of diabetes risk in patients with autoimmune liver diseases is warranted.
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Affiliation(s)
- Anne-Sofie H Jensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Marie Winther-Sørensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Johan Burisch
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre, Denmark
| | - Annika Bergquist
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Henriette Ytting
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark
| | - Lise L Gluud
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
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Sherman MA, Pak K, Pinal-Fernandez I, Flegel WA, Targoff IN, Miller FW, Rider LG, Mammen AL. Autoantibodies Recognizing Specificity Protein 4 Co-occur With Anti-Transcription Intermediary Factor 1 and Are Associated With Distinct Clinical Features and Immunogenetic Risk Factors in Juvenile Myositis. Arthritis Rheumatol 2023; 75:1668-1677. [PMID: 36996276 PMCID: PMC10524257 DOI: 10.1002/art.42512] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 03/17/2023] [Accepted: 03/28/2023] [Indexed: 04/01/2023]
Abstract
OBJECTIVE Autoantibodies recognizing specificity protein 4 (Sp4) were recently discovered in adults with idiopathic inflammatory myopathies (IIM). Anti-Sp4 autoantibodies co-occurred in patients with anti-transcription intermediary factor 1 (anti-TIF1) autoantibody-positive dermatomyositis (DM) and were associated with a reduced risk of cancer. In the present study, the prevalence and clinical features associated with anti-Sp4 autoantibodies in juvenile-onset IIM were investigated. METHODS Serum samples from 336 patients with juvenile myositis in a cross-sectional cohort and 91 healthy controls were screened for anti-Sp4 autoantibodies using enzyme-linked immunosorbent assay. Clinical characteristics, outcomes, and HLA alleles of those with and those without anti-Sp4 autoantibodies were compared. RESULTS Anti-Sp4 autoantibodies were present in 23 patients (7%) with juvenile myositis and were not present in any of the controls. Anti-Sp4 autoantibodies were found among each clinical myositis subgroup. The frequency of TIF1 autoantibody positivity was significantly higher among those with anti-Sp4 autoantibodies (21 [91%] versus 92 [30%], P < 0.001). In the anti-TIF1 autoantibody-positive subgroup, Raynaud's phenomenon (8 [38%] versus 2 [2%], P < 0.001) was more common and peak aspartate aminotransferase was significantly lower in those with anti-Sp4 autoantibodies. None of the patients with anti-Sp4 autoantibodies required a wheelchair. Among White patients, DQA1*04 and DRB1*08 were associated with anti-Sp4 autoantibodies. CONCLUSION Anti-Sp4 autoantibodies were found in patients with juvenile-onset IIM, predominantly those with coexisting anti-TIF1 autoantibodies. Patients with anti-Sp4 autoantibodies represent a phenotypic subset of anti-TIF1 autoantibody-positive myositis characterized by frequent Raynaud's phenomenon and less pronounced muscle involvement, similar to adults with these autoantibodies. Novel immunogenetic risk factors for White patients with IIM were identified among juveniles with anti-Sp4 autoantibodies.
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Affiliation(s)
- Matthew A. Sherman
- Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Katherine Pak
- Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Iago Pinal-Fernandez
- Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Willy A. Flegel
- Department of Transfusion Medicine, National Institutes of Health Clinical Center, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Ira N. Targoff
- Veteran’s Affairs Medical Center, University of Oklahoma Health Sciences Center, and Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Frederick W. Miller
- Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland, USA
| | - Lisa G. Rider
- Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland, USA
| | - Andrew L. Mammen
- Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Jensen ASH, Ytting H, Winther-Sørensen M, Burisch J, Bergquist A, Gluud LL, Wewer Albrechtsen NJ. Autoimmune liver diseases and diabetes. Eur J Gastroenterol Hepatol 2023; 35:938-947. [PMID: 37505973 DOI: 10.1097/meg.0000000000002594] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/30/2023]
Abstract
Autoimmune liver diseases include autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. They are chronic, heterogenous diseases affecting the liver which is a key metabolic organ that ensures glucose homeostasis. It is well known that patients with other chronic liver diseases such as cirrhosis and nonalcoholic fatty liver disease (NAFLD) display glucose disturbances like insulin resistance and have an increased risk of diabetes. Previous evidence on glucose disturbances in patients with autoimmune liver disease is scarce but does point towards a potentially increased risk of type 1 diabetes and type 2 diabetes. The underlying mechanisms are unknown but may reflect genetic predisposition, concurrent NAFLD and or cirrhosis development, and treatment (steroid) related impairment of glucose homeostasis. Therefore, increased awareness and surveillance of diabetes development in patients with autoimmune liver disease may be important. Overall, detection and treatment of diabetes generally follow the usual diabetes guidelines; however, in patients with advanced liver cirrhosis, HbA1c may not be a reliable marker of average glucose levels, and treatment with insulin is generally recommended. In addition, it has recently been suggested that sodium-glucose cotransporter 2 inhibitors may be beneficial in treating refractory ascites. Further research on diabetes risk in autoimmune liver disease is warranted.
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Affiliation(s)
- Anne-Sofie H Jensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
| | - Henriette Ytting
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Rigshospitalet
- Institute for Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen
| | - Marie Winther-Sørensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
| | - Johan Burisch
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
| | - Annika Bergquist
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
- Department of Upper GI Diseases, Karolinska University Hospital, Department of Medicine, Karolinska Institutet, Stockholm
| | - Lise Lotte Gluud
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
- Institute for Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen
| | - Nicolai J Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
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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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Yang Y, He X, Rojas M, Leung PSC, Gao L. Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis? Front Immunol 2023; 14:1184252. [PMID: 37325634 PMCID: PMC10266968 DOI: 10.3389/fimmu.2023.1184252] [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: 03/11/2023] [Accepted: 05/16/2023] [Indexed: 06/17/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by cholestasis, biliary injuries, liver fibrosis, and chronic non-suppurative cholangitis. The pathogenesis of PBC is multifactorial and involves immune dysregulation, abnormal bile metabolism, and progressive fibrosis, ultimately leading to cirrhosis and liver failure. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are currently used as first- and second-line treatments, respectively. However, many patients do not respond adequately to UDCA, and the long-term effects of these drugs are limited. Recent research has advanced our understanding the mechanisms of pathogenesis in PBC and greatly facilitated development of novel drugs to target mechanistic checkpoints. Animal studies and clinical trials of pipeline drugs have yielded promising results in slowing disease progression. Targeting immune mediated pathogenesis and anti-inflammatory therapies are focused on the early stage, while anti-cholestatic and anti-fibrotic therapies are emphasized in the late stage of disease, which is characterized by fibrosis and cirrhosis development. Nonetheless, it is worth noting that currently, there exists a dearth of therapeutic options that can effectively impede the progression of the disease to its terminal stages. Hence, there is an urgent need for further research aimed at investigating the underlying pathophysiology mechanisms with potential therapeutic effects. This review highlights our current knowledge of the underlying immunological and cellular mechanisms of pathogenesis in PBC. Further, we also address current mechanism-based target therapies for PBC and potential therapeutic strategies to improve the efficacy of existing treatments.
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Affiliation(s)
- Yushu Yang
- Department of Rheumatology and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - XiaoSong He
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Manuel Rojas
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, Davis, CA, United States
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Patrick S. C. Leung
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Lixia Gao
- Department of Rheumatology and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, Davis, CA, United States
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11
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Yamashita Y, Umemura T, Kimura T, Joshita S, Hirohara J, Nakano T, Komori A, Tanaka A. Prognostic utility of albumin-bilirubin grade in Japanese patients with primary biliary cholangitis. JHEP Rep 2023; 5:100662. [PMID: 36873419 PMCID: PMC9976453 DOI: 10.1016/j.jhepr.2022.100662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 12/07/2022] [Accepted: 12/09/2022] [Indexed: 12/26/2022] Open
Abstract
Background & Aims The albumin-bilirubin (ALBI) score is calculated using serum levels of total bilirubin and albumin as a simple method to assess liver function. This study investigated the ability of baseline ALBI score/grade measurements to assess histological stage and disease progression in individuals with primary biliary cholangitis (PBC) in a large Japanese nationwide cohort. Methods A total of 8,768 Japanese patients with PBC were enrolled between 1980 and 2016 from 469 institutions, among whom 83% received ursodeoxycholic acid (UDCA) only, 9% received UDCA and bezafibrate, and 8% were given neither drug. Baseline clinical and laboratory parameters were retrospectively retrieved and reviewed from a central database. Associations of ALBI score/grade with histological stage, mortality, and need for liver transplantation (LT) were evaluated using Cox proportional hazards models. Results During the median follow-up period of 5.3 years, 1,227 patients died (including 789 from liver-related causes) and 113 underwent LT. ALBI score and ALBI grade were significantly associated with Scheuer's classification (both p <0.0001). ALBI grade 2 or 3 had significant associations with all-cause mortality or need for LT as well as liver-related mortality or need for LT according to Cox proportional hazards regression analysis (hazard ratio 3.453, 95% CI 2.942-4.052 and hazard ratio 4.242, 95% CI 3.421-5.260, respectively; both p <0.0001). Cumulative LT-free survival rates at 5 years in the ALBI grade 1, 2, and 3 groups were 97.2%, 82.4%, and 38.8%, respectively, while respective non-liver-related survival rates were 98.1%, 86.0%, and 42.0% (both p <0.0001, log-rank test). Conclusions This large nationwide study of patients with PBC suggested that baseline measurements of ALBI grade were a simple non-invasive predictor of prognosis in PBC. Impact and implications Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by progressive destruction of intrahepatic bile ducts. This study examined the ability of albumin-bilirubin (ALBI) score/grade to estimate histological findings and disease progression in PBC by means of a large-scale nationwide cohort in Japan. ALBI score/grade were significantly associated with Scheuer's classification stage. Baseline ALBI grade measurements may be a simple non-invasive predictor of prognosis in PBC.
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Key Words
- ALBI, albumin-bilirubin
- ALP, alkaline phosphatase
- AMA, anti-mitochondrial autoantibody
- AUC, area under the ROC curve
- BZF, bezafibrate
- HR, hazard ratio
- LSM, liver stiffness measurement
- LT, liver transplantation
- M2BPGi, Mac-2-binding protein glycosylation isomer
- PBC, primary biliary cholangitis
- Prognosis
- ROC, receiver-operating characteristic
- Transplantation
- UDCA, ursodeoxycholic acid
- ULN, upper limit of normal
- Ursodeoxycholic acid
- pc, corrected p
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Affiliation(s)
- Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.,Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Junko Hirohara
- The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Toshiaki Nakano
- The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Nagasaki, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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12
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Morita-Fujita M, Shindo T, Iemura T, Arai Y, Kanda J, Okada K, Ueda Y, Yoshiyuki O, Anzai N, Mori T, Ishikawa T, Otsuka Y, Yonezawa A, Yuhi N, Imada K, Oba A, Itoh M, Okamoto Y, Kitano T, Ikeda T, Kotani S, Akasaka T, Yago K, Watanabe M, Nohgawa M, Tsuji M, Takeoka T, Yamamoto R, Arima N, Yoshinaga N, Hishizawa M, Yamashita K, Kondo T, Takaori-Kondo A. Epitope mismatch at HLA-DRB1 associates with reduced relapse risk in cord blood transplant for standard-risk hematological malignancy. Transplant Cell Ther 2023:S2666-6367(23)01136-3. [PMID: 36889508 DOI: 10.1016/j.jtct.2023.03.002] [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: 11/23/2022] [Revised: 03/01/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Abstract
BACKGROUND Cord blood transplantation (CBT) is an attractive therapeutic option for patients with hematological malignancies. CBT tolerates HLA mismatches between donors and recipients, but which HLA mismatches generate graft-versus-tumor (GVT) effects is unknown. OBJECTIVE Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, we investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT. STUDY DESIGN A total of 492 patients with hematological malignancies who received single unit, T cell replete CBT were included in this multi-center retrospective study. HLA epitope mismatches (EM) were quantified using HLA matchmaker software from donor and patient HLA-A, B, C and DRB1 allele data. Patients were dichotomized by median EM value and divided into groups transplanted in complete/partial remission (standard stage: 62.4%) and others (advanced stage: 37.6%). RESULTS Median EM numbers in the graft-versus-host direction (GVH-EM) at HLA-class I and HLA-DRB1 were 3 (range, 0-16) and 1 (range, 0-7), respectively. Higher HLA-class I GVH-EM increased non-relapse mortality (NRM) in the advanced stage group (adjusted hazard ratio [HR], 2.12; p=0.021), with no significant advantage for relapse in either stage. On the other hand, higher HLA-DRB1 GVH-EM was associated with better disease-free survival in the standard stage group (adjusted HR, 0.63; p=0.020), which was attributed to lower relapse risk (adjusted HR, 0.46; p=0.014). These associations were also observed even within HLA-DRB1 allele-mismatched transplants in the standard stage group, indicating that EM might have impacts on relapse risk independently of allele mismatch. High HLA-DRB1 GVH-EM did not increase NRM in either stage. CONCLUSIONS High HLA-DRB1 GVH-EM may lead to potent GVT effects and favorable prognosis following CBT especially in the patients transplanted in the standard stage. This approach may facilitate appropriate unit selection and improve the overall prognosis of patients with hematological malignancies who receive CBT.
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Affiliation(s)
- Mari Morita-Fujita
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takero Shindo
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Tomoki Iemura
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yasuyuki Arai
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Clinical Laboratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Junya Kanda
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazuya Okada
- Department of Hematology, Kurashiki Central Hospital, Okayama, Japan
| | - Yasunori Ueda
- Department of Hematology, Kurashiki Central Hospital, Okayama, Japan
| | - Onda Yoshiyuki
- Department of Hematology, Takatsuki Red Cross Hospital, Takatsuki, Japan
| | - Naoyuki Anzai
- Department of Hematology, Takatsuki Red Cross Hospital, Takatsuki, Japan
| | - Takuto Mori
- Department of Hematology, Kobe City Medical Center General Hospital, Hyogo, Japan
| | - Takayuki Ishikawa
- Department of Hematology, Kobe City Medical Center General Hospital, Hyogo, Japan
| | - Yasuyuki Otsuka
- Department of Hematology, Kokura Memorial Hospital, Fukuoka, Japan
| | - Akihito Yonezawa
- Department of Hematology, Kokura Memorial Hospital, Fukuoka, Japan
| | - Naoki Yuhi
- Department of Hematology, Osaka Red Cross Hospital, Osaka, Japan
| | - Kazunori Imada
- Department of Hematology, Osaka Red Cross Hospital, Osaka, Japan
| | - Akifumi Oba
- Department of Hematology, Kyoto City Hospital, Kyoto, Japan
| | - Mitsuru Itoh
- Department of Hematology, Kyoto City Hospital, Kyoto, Japan
| | | | | | - Takashi Ikeda
- Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center, Shizuoka, Japan
| | | | | | - Kazuhiro Yago
- Department of Hematology, Shizuoka General Hospital, Shizuoka, Japan
| | - Mitsumasa Watanabe
- Department of Hematology, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan
| | - Masaharu Nohgawa
- Department of Hematology, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan
| | - Masaaki Tsuji
- Department of Hematology and Immunology, Japanese Red Cross Otsu Hospital, Otsu, Japan
| | - Tomoharu Takeoka
- Department of Hematology and Immunology, Japanese Red Cross Otsu Hospital, Otsu, Japan
| | - Ryusuke Yamamoto
- Department of Hematology, Kobe City Medical Center General Hospital, Hyogo, Japan; Department of Hematology, Shinko Hospital, Kobe, Japan
| | | | - Noriyoshi Yoshinaga
- Department of Hematology, Kyoto-Katsura Hospital, Kyoto, Japan; Department of Hematology/Oncology, Shiga General Hospital, Moriyama, Japan
| | | | - Kouhei Yamashita
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tadakazu Kondo
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Hematology, Kobe City Medical Center General Hospital, Hyogo, Japan
| | - Akifumi Takaori-Kondo
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Hitomi Y, Nakamura M. The Genetics of Primary Biliary Cholangitis: A GWAS and Post-GWAS Update. Genes (Basel) 2023; 14:405. [PMID: 36833332 PMCID: PMC9957238 DOI: 10.3390/genes14020405] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/27/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which the small intrahepatic bile ducts are destroyed by autoimmune reactions. Among autoimmune diseases, which are polygenic complex traits caused by the combined contribution of genetic and environmental factors, PBC exhibits the strongest involvement of genetic heritability in disease development. As at December 2022, genome-wide association studies (GWASs) and associated meta-analyses identified approximately 70 PBC susceptibility gene loci in various populations, including those of European and East Asian descent. However, the molecular mechanisms through which these susceptibility loci affect the pathogenesis of PBC are not fully understood. This study provides an overview of current data regarding the genetic factors of PBC as well as post-GWAS approaches to identifying primary functional variants and effector genes in disease-susceptibility loci. Possible mechanisms of these genetic factors in the development of PBC are also discussed, focusing on four major disease pathways identified by in silico gene set analyses, namely, (1) antigen presentation by human leukocyte antigens, (2) interleukin-12-related pathways, (3) cellular responses to tumor necrosis factor, and (4) B cell activation, maturation, and differentiation pathways.
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Affiliation(s)
- Yuki Hitomi
- Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, 2-1001-1 Kubara, Omura 856-8562, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 2-1001-1 Kubara, Omura 856-8562, Japan
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, 2-1001-1 Kubara, Omura 856-8562, Japan
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14
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Mulinacci G, Palermo A, Gerussi A, Asselta R, Gershwin ME, Invernizzi P. New insights on the role of human leukocyte antigen complex in primary biliary cholangitis. Front Immunol 2022; 13:975115. [PMID: 36119102 PMCID: PMC9471323 DOI: 10.3389/fimmu.2022.975115] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/11/2022] [Indexed: 01/04/2023] Open
Abstract
Primary Biliary Cholangitis (PBC) is a rare autoimmune cholangiopathy. Genetic studies have shown that the strongest statistical association with PBC has been mapped in the human leukocyte antigen (HLA) locus, a highly polymorphic area that mostly contribute to the genetic variance of the disease. Furthermore, PBC presents high variability throughout different population groups, which may explain the different geoepidemiology of the disease. A major role in defining HLA genetic contribution has been given by genome-wide association studies (GWAS) studies; more recently, new technologies have been developed to allow a deeper understanding. The study of the altered peptides transcribed by genetic alterations also allowed the development of novel therapeutic strategies in the context of immunotolerance. This review summarizes what is known about the immunogenetics of PBC with a focus on the HLA locus, the different distribution of HLA alleles worldwide, and how HLA modifications are associated with the pathogenesis of PBC. Novel therapeutic strategies are also outlined.
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Affiliation(s)
- Giacomo Mulinacci
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Andrea Palermo
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Rosanna Asselta
- Department of Biomedical Sciences, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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15
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. HLA, gut microbiome and hepatic autoimmunity. Front Immunol 2022; 13:980768. [PMID: 36059527 PMCID: PMC9433828 DOI: 10.3389/fimmu.2022.980768] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022] Open
Abstract
Genetic susceptibility to autoimmune liver diseases is conferred mainly by polymorphisms of genes encoding for the human leukocyte antigens (HLA). The strongest predisposition to autoimmune hepatitis type 1 (AIH-1) is linked to the allele DRB1*03:01, possession of which is associated with earlier disease onset and more severe course. In populations where this allele is very rare, such as in Asia, and in DRB1*03-negative patients, risk of AIH-1 is conferred by DRB1*04, which is associated with later disease onset and milder phenotype. AIH type 2 (AIH-2) is associated with DRB1*07. The pediatric condition referred to as autoimmune sclerosing cholangitis (ASC), is associated with the DRB1*13 in populations of Northern European ancestry. DRB1*1501 is protective from AIH-1, AIH-2 and ASC in Northern European populations. Possession of the DRB1*08 allele is associated with an increased risk of primary biliary cholangitis (PBC) across different populations. DRB1*03:01 and B*08:01 confer susceptibility to primary sclerosing cholangitis (PSC), as well as DRB1*13 and DRB1*15 in Europe. The hepatic blood supply is largely derived from the splanchnic circulation, suggesting a pathophysiological role of the gut microbiome. AIH appears to be associated with dysbiosis, increased gut permeability, and translocation of intestinal microbial products into the circulation; molecular mimicry between microbial and host antigens may trigger an autoaggressive response in genetically-predisposed individuals. In PBC an altered enteric microbiome may affect intestinal motility, immunological function and bile secretion. Patients with PSC have a gut microbial profile different from health as well as from patients with inflammatory bowel disease without PSC.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Faculty of Biomedical Sciences, Epatocentro Ticino and Università della Svizzera Italiana, Lugano, Switzerland
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
- *Correspondence: Benedetta Terziroli Beretta-Piccoli,
| | - Giorgina Mieli-Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
| | - Diego Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
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16
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Ellinghaus D. How genetic risk contributes to autoimmune liver disease. Semin Immunopathol 2022; 44:397-410. [PMID: 35650446 PMCID: PMC9256578 DOI: 10.1007/s00281-022-00950-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/06/2022] [Indexed: 12/16/2022]
Abstract
Genome-wide association studies (GWAS) for autoimmune hepatitis (AIH) and GWAS/genome-wide meta-analyses (GWMA) for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) have been successful over the past decade, identifying about 100 susceptibility loci in the human genome, with strong associations with the HLA locus and many susceptibility variants outside the HLA locus with relatively low risk. However, identifying causative variants and genes and determining their effects on liver cells and their immunological microenvironment is far from trivial. Polygenic risk scores (PRSs) based on current genome-wide data have limited potential to predict individual disease risk. Interestingly, results of mediated expression score regression analysis provide evidence that a substantial portion of gene expression at susceptibility loci is mediated by genetic risk variants, in contrast to many other complex diseases. Genome- and transcriptome-wide comparisons between AIH, PBC, and PSC could help to better delineate the shared inherited component of autoimmune liver diseases (AILDs), and statistical fine-mapping, chromosome X-wide association testing, and genome-wide in silico drug screening approaches recently applied to GWMA data from PBC could potentially be successfully applied to AIH and PSC. Initial successes through single-cell RNA sequencing (scRNA-seq) experiments in PBC and PSC now raise high hopes for understanding the impact of genetic risk variants in the context of liver-resident immune cells and liver cell subpopulations, and for bridging the gap between genetics and disease.
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Affiliation(s)
- David Ellinghaus
- Institute of Clinical Molecular Biology (IKMB), Kiel University and University Medical Center Schleswig-Holstein, Rosalind-Franklin-Str. 12, 24105, Kiel, Germany.
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17
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Park JW, Kim JH, Kim SE, Jung JH, Jang MK, Park SH, Lee MS, Kim HS, Suk KT, Kim DJ. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics. Biomedicines 2022; 10:1288. [PMID: 35740310 PMCID: PMC9220082 DOI: 10.3390/biomedicines10061288] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.
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Affiliation(s)
- Ji-Won Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jung-Hee Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jang Han Jung
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Myoung-Kuk Jang
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sang-Hoon Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Myung-Seok Lee
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Hyoung-Su Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
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Li Y, Liu X, Wang Y, Zhou Y, Hu S, Yang H, Zhong W, Zhao J, Wang X, Chu H, Zheng Y, Zhang J, Zhou L, Wang B. Novel HLA-DRB1 alleles contribute risk for disease susceptibility in primary biliary cholangitis. Dig Liver Dis 2022; 54:228-236. [PMID: 34016546 DOI: 10.1016/j.dld.2021.04.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a complex disease with high heritability. We investigated the association between human leukocyte antigen (HLA)-DRB1 alleles and PBC in families and sporadic cases to evaluate the genetic components of the disease. METHODS We performed whole exome sequencing in three PBC families. We genotyped HLA-DRB1 and calculated the association between HLA-DRB1 alleles and the encoding amino acid sequences with the clinical features. RESULTS Ten variants harboured the HLA-DRB1 gene associated with PBC. DRB1×07:01, 14:01 and 14:05 were highly increased in PBC. Ten coding region polymorphisms were associated with PBC that encode the amino acid variants of HLA-DR β54, β59 and β66 located in the peptide-binding site of the MHC molecule. Glutamine at position 54 was confirmed as a risk amino acid, verifying the results of familial aggregation analysis of PBC families. DISCUSSION Familial aggregation analysis indicated that HLA-DRB1 is a candidate gene for the risk of disease course. Considering that amino acid variations are critical to peptide-binding properties, they underlie the major component of MHC association with PBC.
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Affiliation(s)
- Yanni Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China; Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Xin Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yi Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China; Department of General Surgery, YouAn Hospital, Capital Medical University, Beijing, China
| | - Yi Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shixian Hu
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Hui Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jingwen Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaoyi Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongyu Chu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yanping Zheng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China; Department of Gastroenterology and Hepatology, People's Hospital of Hetian District, Xinjiang Uygur Autonomous Region, China.
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China.
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19
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The genetic architecture of primary biliary cholangitis. Eur J Med Genet 2021; 64:104292. [PMID: 34303876 DOI: 10.1016/j.ejmg.2021.104292] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 07/03/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC) is a rare autoimmune disease of the liver affecting the small bile ducts. From a genetic point of view, PBC is a complex trait and several genetic and environmental factors have been called in action to explain its etiopathogenesis. Similarly to other complex traits, PBC has benefited from the introduction of genome-wide association studies (GWAS), which identified many variants predisposing or protecting toward the development of the disease. While a progressive endeavour toward the characterization of candidate loci and downstream pathways is currently ongoing, there is still a relatively large portion of heritability of PBC to be revealed. In addition, genetic variation behind progression of the disease and therapeutic response are mostly to be investigated yet. This review outlines the state-of-the-art regarding the genetic architecture of PBC and provides some hints for future investigations, focusing on the study of gene-gene interactions, the application of whole-genome sequencing techniques, and the investigation of X chromosome that can be helpful to cover the missing heritability gap in PBC.
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20
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A large-scale investigation into the role of classical HLA loci in multiple types of severe infections, with a focus on overlaps with autoimmune and mental disorders. J Transl Med 2021; 19:230. [PMID: 34059071 PMCID: PMC8165335 DOI: 10.1186/s12967-021-02888-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 05/17/2021] [Indexed: 11/10/2022] Open
Abstract
Background Infections are a major disease burden worldwide. While they are caused by external pathogens, host genetics also plays a part in susceptibility to infections. Past studies have reported diverse associations between human leukocyte antigen (HLA) alleles and infections, but many were limited by small sample sizes and/or focused on only one infection. Methods We performed an immunogenetic association study examining 13 categories of severe infection (bacterial, viral, central nervous system, gastrointestinal, genital, hepatitis, otitis, pregnancy-related, respiratory, sepsis, skin infection, urological and other infections), as well as a phenotype for having any infection, and seven classical HLA loci (HLA-A, B, C, DPB1, DQA1, DQB1 and DRB1). Additionally, we examined associations between infections and specific alleles highlighted in our previous studies of psychiatric disorders and autoimmune disease, as these conditions are known to be linked to infections. Results Associations between HLA loci and infections were generally not strong. Highlighted associations included associations between DQB1*0302 and DQB1*0604 and viral infections (P = 0.002835 and P = 0.014332, respectively), DQB1*0503 and sepsis (P = 0.006053), and DQA1*0301 with “other” infections (a category which includes infections not included in our main categories e.g. protozoan infections) (P = 0.000369). Some HLA alleles implicated in autoimmune diseases showed association with susceptibility to infections, but the latter associations were generally weaker, or with opposite trends (in the case of HLA-C alleles, but not with alleles of HLA class II genes). HLA alleles associated with psychiatric disorders did not show association with susceptibility to infections. Conclusions Our results suggest that classical HLA alleles do not play a large role in the etiology of severe infections. The discordant association trends with autoimmune disease for some alleles could contribute to mechanistic theories of disease etiology. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02888-1.
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21
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Leung KK, Deeb M, Hirschfield GM. Review article: pathophysiology and management of primary biliary cholangitis. Aliment Pharmacol Ther 2020; 52:1150-1164. [PMID: 32813299 DOI: 10.1111/apt.16023] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/13/2020] [Accepted: 07/18/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC), an immune-mediated disease characterised by destruction of intrahepatic bile ducts, results in progressive damage to the biliary tree, cholestasis and ultimately advanced liver disease. In the last decade, advances in practice have improved clinical care, driven novel therapeutic options and improved risk stratification tools. AIMS To provide an overview of the disease characteristics of PBC and review a patient-centred management approach for the clinical team caring for those with PBC. METHODS We reviewed the current literature and guidelines on PBC with a focus on management and therapies. RESULTS A confident diagnosis of PBC is usually made based on serum liver tests and immune serology. Management of PBC should focus on three main 'process' pillars: (a) treat and risk-stratify through use of biochemical and prognostic criteria; (b) manage concurrent symptoms and other associated diseases; and (c) stage disease, monitor progression and prevent complications. With ongoing complexities in management, including a newly licensed therapy (obeticholic acid) and alternative non-licensed treatments and ongoing clinical trials, discussion with PBC expert centres is encouraged. CONCLUSIONS PBC is a dynamic disease wherein current treatment goals have become appropriately ambitious. Goals of care should prioritise prevention of end-stage liver disease and amelioration of patient symptom burden for all.
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Affiliation(s)
- Kristel K Leung
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Maya Deeb
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Gideon M Hirschfield
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
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22
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Huang C, Xing X, Xiang X, Fan X, Men R, Ye T, Yang L. MicroRNAs in autoimmune liver diseases: from diagnosis to potential therapeutic targets. Biomed Pharmacother 2020; 130:110558. [PMID: 32781357 DOI: 10.1016/j.biopha.2020.110558] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 07/21/2020] [Accepted: 07/26/2020] [Indexed: 02/08/2023] Open
Abstract
Autoimmune liver diseases (AILDs) are a group of liver disorders composed of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) characterized by chronic hepatic and biliary inflammation. Although several genetic factors, such as HLA alleles, TNFA, and CTLA-4, have been reported in the pathogenesis of AILDs, many details remain unknown. In recent years, microRNAs (miRNAs) have emerged as crucial components in the diagnosis and therapeutic applications of various autoimmune diseases, including systemic lupus erythematosus (SLE), glomerulonephritis, and AILDs. MiRNAs comprise a class of small, noncoding molecules of 19--25 nucleotides that modulate multiple genes by suppressing or degrading target mRNAs. Altered miRNA profiles have been identified in serum, immune cells, and live tissues from AILD patients. Elevated serum miR-21 and miR-122 levels in AIH patients as well as decreased miR-200c levels in PSC patients indicate their diagnostic utility. Highly expressed miR-122 and miR-378f as well as downregulated miR-4311 and miR-4714-3p in serum samples from refractory PBC patients suggest their potential to evaluate treatment efficacy. Moreover, miRNAs have been reported to participate in AILD development. Increased miR-506 levels may impair bile secretion in PBC by inhibiting Cl-/HCO3-anion exchanger 2 (AE2) and type III inositol 1,4,5-trisphosphate receptor-3 (InsP3R3). Additionally, different miRNA mimics or antagonists, such as atagomiR-155 and miR-223 mimics, have been widely applied in experimental AILD murine models with great efficacy. Here, we provide an overview of miRNAs in AILDs, aiming to summarize their potential roles in diagnosis and therapeutic interventions, and we discuss the challenges and future applications of miRNAs in clinical practice.
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Affiliation(s)
- Chen Huang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xian Xing
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyu Xiang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoli Fan
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Ruoting Men
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Tinghong Ye
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
| | - Li Yang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China.
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Wang C, Zheng X, Tang R, Han C, Jiang Y, Wu J, Shao Y, Gao Y, Yu J, Hu Z, Zang Z, Zhao Y, Dai N, Liu L, Wu X, Nie J, Jiang B, Lin M, Li L, Wei Y, Li Y, Gong Y, Dai Y, Wang L, Ding N, Xu P, Chen S, Jiang P, Wang L, Qiu F, Wu Q, Zhang M, Jawed R, Chen R, Zhang Y, Shi X, Zhu Z, Pei H, Huang L, Tian Y, Zhang K, Qiu H, Zhao W, Gershwin ME, Chen W, Seldin MF, Liu X, Ma X, Sun L. Fine mapping of the MHC region identifies major independent variants associated with Han Chinese primary biliary cholangitis. J Autoimmun 2020; 107:102372. [PMID: 31810856 DOI: 10.1016/j.jaut.2019.102372] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/03/2019] [Accepted: 11/14/2019] [Indexed: 02/08/2023]
Abstract
The genetic association of primary biliary cholangitis with major histocompatibility complex (MHC) has been widely confirmed among different ethnicities. To map specific MHC region variants associated with PBC in a Han Chinese cohort, we imputed HLA antigens and amino acids (AA) in 1126 PBC cases and 1770 healthy control subjects using a Han-MHC reference database. We demonstrate that HLA-DRB1 and/or HLA-DQB1 contributed the strongest signals, and that HLA-DPB1 was a separate independent locus. Regression analyses with classical HLA alleles indicate that HLA-DQB1*03:01 or HLA-DQβ1-Pro55, HLA-DPB1*17:01 or HLA-DPβ1-Asp84 and HLA-DRB1*08:03 could largely explain MHC association with PBC. Forward stepwise regression analyses with HLA amino acid variants localize the major signals to HLA-DRβ1-Ala74, HLA-DQβ1-Pro55 and HLA-DPβ1-Asp84. Electrostatic potential calculations implicated AA variations at HLA-DQβ1 position 55 and HLA-DPβ1 position 84 as critical to peptide binding properties. Furthermore, although several critical Han Chinese AA variants differed from those shown in European populations, the predicted effects on antigen binding are likely to be very similar or identical and underlie the major component of MHC association with PBC.
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Affiliation(s)
- Chan Wang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Xiaodong Zheng
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China, Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China, Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China, 218 Jixi Road, Hefei, Anhui, 230022, China
| | - Ruqi Tang
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China
| | - Chongxu Han
- Department of Laboratory Medicine, Subei People's Hospital, Clinical Medical College, Yangzhou University, 98 Nantong West Road, Yangzhou, Jiangsu, 225001, China
| | - Yuzhang Jiang
- Department of Laboratory Medicine, Huai'an First People's Hospital, Nanjing Medical University, 1 Huanghe West Road, Huai'an, Jiangsu, 223300, China
| | - Jian Wu
- Department of Rheumatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - Youlin Shao
- Department of Hepatology, The Third People's Hospital of Changzhou, 300 Lanling North Road, Changzhou, Jiangsu, 213001, China
| | - Yueqiu Gao
- Department of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Jianjiang Yu
- Department of Laboratory Medicine, Jiangyin People's Hospital, Southeast University, 163 Shoushan Road, Jiangyin, Jiangsu, 214400, China
| | - Zhigang Hu
- Department of Laboratory Medicine, Affiliated Wuxi People's Hospital of Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, 214023, China
| | - Zhidong Zang
- Department of Hepatology, The Second Hospital of Nanjing, Southeast University, 1 Zhongfu Road, Nanjing, jiangsu, 210003, China
| | - Yi Zhao
- Department of Gastrointestinal Endoscopy, Eastern Hepatobiliary Surgery Hospital, 700 Moyu North Road, Shanghai, 201800, China
| | - Na Dai
- Department of Gastroenterology, Jiangsu University Affiliated Kunshan Hospital, 91 Qianjin West Road, Kunshan, Jiangsu, 215300, China
| | - Lei Liu
- Department of Gastroenterology, Yixing People's Hospital, 75 Tongzhenguan Road, Yixing, Jiangsu, 214200, China
| | - Xudong Wu
- Department of Gastroenterology, Yancheng First People's Hospital, 66 Renmin South Road, Yancheng, Jiangsu, 224005, China
| | - Jinshan Nie
- Department of Gastroenterology, Taicang First People's Hospital, Soochow University, 58 Changsheng South Road, Taicang, Jiangsu, 215400, China
| | - Bo Jiang
- Department of Hepatology, Jingjiang Second People's Hospital, 1 Chengxiqiao Jiangping Road, Jingjiang, Jiangsu, 214500, China
| | - Maosong Lin
- Department of Gastroenterology, Taizhou People's Hospital, 210 Yingchun Road, Taizhou, Jiangsu, 225300, China
| | - Li Li
- Department of Laboratory Medicine, Zhongda Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu, 210009, China
| | - Yiran Wei
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China
| | - You Li
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China
| | - Yuhua Gong
- Department of Laboratory Medicine, The Third People's Hospital of Zhenjiang, 300 Daijiamen, Zhenjiang, Jiangsu, 212021, China
| | - Yaping Dai
- Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu, 214000, China
| | - Lan Wang
- Department of Laboratory Medicine, The 81st Hospital of PLA, 34 Yanggongjing Nanjing, Jiangsu, 210002, China
| | - Ningling Ding
- Department of Hepatology, Department of Laboratory Medicine, The Fifth People's Hospital of Suzhou, Soochow University, 10 Guangqian Road, Suzhou, Jiangsu, 215131, China
| | - Ping Xu
- Department of Radiology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu, 215004, China
| | - Sufang Chen
- Department of Hepatology, Department of Laboratory Medicine, The Fifth People's Hospital of Suzhou, Soochow University, 10 Guangqian Road, Suzhou, Jiangsu, 215131, China
| | - Peng Jiang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Lu Wang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Fang Qiu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Qiuyuan Wu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Mingming Zhang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Rohil Jawed
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Ru Chen
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Yu Zhang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Xingjuan Shi
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Zhen Zhu
- Department of Hepatology, The Third People's Hospital of Changzhou, 300 Lanling North Road, Changzhou, Jiangsu, 213001, China
| | - Hao Pei
- Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu, 214000, China
| | - Lihua Huang
- Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu, 214000, China
| | - Ye Tian
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, China
| | - Kui Zhang
- Department of Hepatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - Hong Qiu
- Department of Laboratory Medicine, The 81st Hospital of PLA, 34 Yanggongjing Nanjing, Jiangsu, 210002, China
| | - Weifeng Zhao
- Department of Hepatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility Building, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
| | - Weichang Chen
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - Michael F Seldin
- Department of Biochemistry and Molecular Medicine, University of California at Davis School of Medicine, 4327 Tupper Hall, Davis, CA, 95616, USA
| | - Xiangdong Liu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China.
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China.
| | - Liangdan Sun
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China, Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China, Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China, 218 Jixi Road, Hefei, Anhui, 230022, China.
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Abstract
PURPOSE OF REVIEW Primary biliary cholangitis (PBC) is a female predominant chronic autoimmune disease of the intrahepatic bile ducts and with a long latent period. It is crucial to understand how genetics contribute to the disease. RECENT FINDINGS Geo-epidemiological studies in PBC have provided evidence of familial risk; case-control studies and genome wide association studies have identified various human leukocyte antigen (HLA) and non-HLA alleles that are associated with PBC. However, these alleles are non-PBC specific and most of the identified non-HLA loci were also found to be susceptible genes in other autoimmune diseases and different between study populations. SUMMARY Patients with PBC are often asymptomatic and often left undiagnosed. There are no known HLA and non-HLA alleles specific for PBC. Global effort and novel approaches such as epigenetics directed at identification of genetic risk factors will greatly facilitate accurate and timely diagnosis, which will improve prognosis and increase treatment options.
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Karra VK, Chowdhury SJ, Ruttala R, Gumma PK, Polipalli SK, Chakravarti A, Kar P. HLA-DQA1 & DQB1 variants associated with hepatitis B virus-related chronic hepatitis, cirrhosis & hepatocellular carcinoma. Indian J Med Res 2018; 147:573-580. [PMID: 30168489 PMCID: PMC6118146 DOI: 10.4103/ijmr.ijmr_1644_15] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background & objectives: Clinical outcome after hepatitis B virus (HBV) exposure varies extremely from spontaneous clearance to chronic hepatitis B and often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Host genetic factor plays an important role in the regulation of immune response. This study was aimed to investigate whether HLA class II DQA1 and DQB1 gene polymorphism were associated with chronic hepatitis B infection and in the development of HBV-related LC and HCC. Methods: DQA1 and DQB1 allele polymorphism were studied in 187 patients with HBV-related liver diseases (which included 73 chronic hepatitis B, 84 LC and 30 HCC patients) and 109 controls who had spontaneously recovered from HBV infection using polymerase chain reaction amplification with sequence-specific primers. Results: Our data suggested that DQA1*0101/2/4 [odds ratio (OR)=2.78; Pc=0.003], DQA1*0103 (OR=2.64; Pc=0.0007) and DQB1*0302/3 (OR=2.15; Pc=0.01) were associated with the protection from chronic HBV infection, whereas DQB1*0402 (OR=0.25; Pc=0.001) showed susceptible effect on chronic HBV infection. DQB1*0601 (OR=3.73; Pc=0.006) conferred protective effect from developing LC; similarly, DQB1*0302/3 (OR=5.53; Pc=0.05) and DQB1*0402 (OR=0.00; Pc=0.001) conferred protective effect from developing HCC. However, DQA1*0601 and DQB1*0503 showed susceptible effect on chronic HBV infection; these associations were no longer significant after Bonferroni correction. Interpretation & conclusions: Our results revealed HLA-DQA1*0101/2/4 - DQA1*0103 - DQB1*0302/3 and DQB1*0601 as protective and DQB1*0402 as risk alleles. The study suggests that various subtypes of HLA-DQA1 and DQB1 are associated with both HBV clearance and development of chronic HBV infections.
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Affiliation(s)
- Vijay Kumar Karra
- Department of Medicine, PCR Hepatitis Laboratory, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Soumya Jyoti Chowdhury
- Department of Medicine, PCR Hepatitis Laboratory, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Rajesh Ruttala
- Department of Medicine, PCR Hepatitis Laboratory, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Phani Kumar Gumma
- Department of Medicine, PCR Hepatitis Laboratory, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Sunil Kumar Polipalli
- Department of Medicine, PCR Hepatitis Laboratory, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Anita Chakravarti
- Department of Medical Microbiology, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Premashis Kar
- Department of Medicine, PCR Hepatitis Laboratory, Maulana Azad Medical College, University of Delhi, New Delhi, India
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Darlay R, Ayers KL, Mells GF, Hall LS, Liu JZ, Almarri MA, Alexander GJ, Jones DE, Sandford RN, Anderson CA, Cordell HJ. Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and primary biliary cholangitis. PLoS Genet 2018; 14:e1007833. [PMID: 30507971 PMCID: PMC6292650 DOI: 10.1371/journal.pgen.1007833] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 12/13/2018] [Accepted: 11/13/2018] [Indexed: 12/15/2022] Open
Abstract
Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. The strongest genetic association is with HLA-DQA1*04:01, but at least three additional independent HLA haplotypes contribute to susceptibility. We used dense single nucleotide polymorphism (SNP) data in 2861 PBC cases and 8514 controls to impute classical HLA alleles and amino acid polymorphisms using state-of-the-art methodologies. We then demonstrated through stepwise regression that association in the HLA region can be largely explained by variation at five separate amino acid positions. Three-dimensional modelling of protein structures and calculation of electrostatic potentials for the implicated HLA alleles/amino acid substitutions demonstrated a correlation between the electrostatic potential of pocket P6 in HLA-DP molecules and the HLA-DPB1 alleles/amino acid substitutions conferring PBC susceptibility/protection, highlighting potential new avenues for future functional investigation.
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Affiliation(s)
- Rebecca Darlay
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Kristin L. Ayers
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - George F. Mells
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Lynsey S. Hall
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Jimmy Z. Liu
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
| | - Mohamed A. Almarri
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
- Department of Forensic Science and Criminology, Dubai Police HQ, Dubai, United Arab Emirates
| | - Graeme J. Alexander
- Department of Hepatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, United Kingdom
| | - David E. Jones
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Richard N. Sandford
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Carl A. Anderson
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
| | - Heather J. Cordell
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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27
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Probert PM, Leitch AC, Dunn MP, Meyer SK, Palmer JM, Abdelghany TM, Lakey AF, Cooke MP, Talbot H, Wills C, McFarlane W, Blake LI, Rosenmai AK, Oskarsson A, Figueiredo R, Wilson C, Kass GE, Jones DE, Blain PG, Wright MC. Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis. J Hepatol 2018; 69:1123-1135. [PMID: 30006067 PMCID: PMC6192827 DOI: 10.1016/j.jhep.2018.06.027] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 06/24/2018] [Accepted: 06/26/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC. METHODS Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens. RESULTS A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three separate donors. The chemical was identified as the ionic liquid [3-methyl-1-octyl-1H-imidazol-3-ium]+ (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI, bearing structural similarity to lipoic acid, was also enzymatically incorporated into the E2 component of the pyruvate dehydrogenase complex via the exogenous lipoylation pathway in vitro. CONCLUSIONS These results identify, for the first time, a xenobiotic in the environment that may be related to and/or be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids. LAY SUMMARY Primary biliary cholangitis is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins.
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Affiliation(s)
- Philip M Probert
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Alistair C Leitch
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Michael P Dunn
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Stephanie K Meyer
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Jeremy M Palmer
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Tarek M Abdelghany
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt
| | - Anne F Lakey
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Martin P Cooke
- School of Civil Engineering and Geosciences, Drummond Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
| | - Helen Talbot
- School of Civil Engineering and Geosciences, Drummond Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
| | - Corinne Wills
- School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
| | - William McFarlane
- School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
| | - Lynsay I Blake
- Institute for Sustainability, The Key Building, Newcastle University, Newcastle upon Tyne NE4 5TQ, United Kingdom
| | - Anna K Rosenmai
- Swedish University of Agricultural Sciences, Uppsala, Sweden
| | | | - Rodrigo Figueiredo
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear NE7 7DN, United Kingdom
| | - Colin Wilson
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear NE7 7DN, United Kingdom
| | - George E Kass
- European Food Safety Authority, Via Carlo Magno 1A, 43126 Parma, Italy
| | - David E Jones
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Peter G Blain
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Matthew C Wright
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.
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28
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Leitch AC, Lakey AF, Hotham WE, Agius L, Kass GEN, Blain PG, Wright MC. The ionic liquid 1-octyl-3-methylimidazolium (M8OI) is an activator of the human estrogen receptor alpha. Biochem Biophys Res Commun 2018; 503:2167-2172. [PMID: 30086880 DOI: 10.1016/j.bbrc.2018.08.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 08/01/2018] [Indexed: 12/18/2022]
Abstract
Recent environmental sampling around a landfill site in the UK demonstrated that unidentified xenoestrogens were present at higher levels than control sites; that these xenoestrogens were capable of super-activating (resisting ligand-dependent antagonism) the murine variant 2 ERβ and that the ionic liquid 1-octyl-3-methylimidazolium chloride (M8OI) was present in some samples. To determine whether M8OI was a contributor to the xenoestrogen pool in the soils, activation of human estrogen receptors by M8OI was examined. M8OI activated the human ERα in MCF7 cells in a dose-response manner. These effects were inhibited by the ER antagonist ICI182780; occurred in the absence of any metabolism of M8OI and were confirmed on examination of ER-dependent induction of trefoil factor 1 mRNA in MCF7 cells. M8OI also super-activated the murine variant 2 ERβ in a murine hepatopancreatobiliary cell line. The human ERβ was not activated by M8OI when expressed in HEK293 cells. These data demonstrate that M8OI is a xenoestrogen capable of activating the human ERα and super-activating the murine variant 2 ERβ.
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Affiliation(s)
- Alistair C Leitch
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
| | - Anne F Lakey
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
| | - William E Hotham
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
| | - Loranne Agius
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
| | - George E N Kass
- European Food Safety Authority, Via Carlo Magno 1A, 43126, Parma, Italy.
| | - Peter G Blain
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
| | - Matthew C Wright
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
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29
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Tanaka A, Leung PSC, Gershwin ME. The Genetics and Epigenetics of Primary Biliary Cholangitis. Clin Liver Dis 2018; 22:443-455. [PMID: 30259846 DOI: 10.1016/j.cld.2018.03.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Both genetic background and environmental factors contribute to primary biliary cholangitis (PBC). Recent innovative technologies, such as genome-wide association studies, identified a remarkable number of susceptible nonhuman leukocyte antigen genes contributing to the development of PBC; however, they are primarily indicators of active immunologic responses commonly involved in autoimmune reactions. Thus, recent studies have focused on epigenetic mechanisms that would link genetic predisposition and environmental triggering factors. In PBC, methylation profiling and altered X chromosome architecture have been intensively explored in conjunction with a striking female predominance. Further, microRNAs have been found to be associated with the etiology of PBC.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, UC Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis 95616, CA
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, UC Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis 95616, CA.
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30
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Rosa R, Cristoferi L, Tanaka A, Invernizzi P. Geoepidemiology and (epi-)genetics in primary biliary cholangitis. Best Pract Res Clin Gastroenterol 2018; 34-35:11-15. [PMID: 30343705 DOI: 10.1016/j.bpg.2018.05.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 05/14/2018] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is a rare female preponderant chronic autoimmune cholestatic liver disease, characterized by intrahepatic ductopenia and progressive fibrosis. During last decades incidence and prevalence showed an increasing rate which vary widely worldwide demonstrating an important interaction between environmental and genetic factors. Heritability suggested by familial occurrence and monozygotic twins concordance have been confirmed in more studies. Epigenetics mechanisms such as histone modification and DNA methylation can partially explain predisposition and inheritance of this disease. Nevertheless, an association with specific class II human leukocyte antigen (HLA) variants have been reported, showing an increase risk in susceptibility. More recently, data regarding a strong protective association between PBC and HLA alleles confirmed this association. After recent genome-wide association studies (GWAS), a more intricate interaction between PBC and the HLA region has been shown. Furthermore, GWAS also identified several immune-related-genes implicated. More genome-wide association studies on this disease are needed to reach a complete and systematic knowledge of this disease. In this review we discuss more recent issued data on geoepidemiology of PBC and the role of (epi-)genetic mechanisms in its pathogenesis.
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Affiliation(s)
- Roberto Rosa
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
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31
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Zhang P, Lu Q. Genetic and epigenetic influences on the loss of tolerance in autoimmunity. Cell Mol Immunol 2018; 15:575-585. [PMID: 29503444 PMCID: PMC6079019 DOI: 10.1038/cmi.2017.137] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 10/21/2017] [Indexed: 12/23/2022] Open
Abstract
Immunological tolerance loss is fundamental to the development of autoimmunity; however, the underlying mechanisms remain elusive. Immune tolerance consists of central and peripheral tolerance. Central tolerance, which occurs in the thymus for T cells and bone marrow for B cells, is the primary way that the immune system discriminates self from non-self. Peripheral tolerance, which occurs in tissues and lymph nodes after lymphocyte maturation, controls self-reactive immune cells and prevents over-reactive immune responses to various environment factors. Loss of tolerance results in autoimmune disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D) and primary biliary cirrhosis (PBC). The etiology and pathogenesis of autoimmune diseases are highly complicated. Both genetic predisposition and epigenetic modifications are implicated in the loss of tolerance and autoimmunity. In this review, we will discuss the genetic and epigenetic influences on tolerance breakdown in autoimmunity. Genetic and epigenetic influences on autoimmune diseases, such as SLE, RA, T1D and PBC, will also be briefly discussed.
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Affiliation(s)
- Peng Zhang
- Department of Dermatology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, 410011, Changsha, Hunan, China
| | - Qianjin Lu
- Department of Dermatology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, 410011, Changsha, Hunan, China.
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32
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Genetics and epigenetics in the pathogenesis of primary biliary cholangitis. Clin J Gastroenterol 2017; 11:11-18. [PMID: 29159718 DOI: 10.1007/s12328-017-0799-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 11/05/2017] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic, slowly progressive cholestatic autoimmune liver disease predominantly afflicting women. PBC is characterized by the presence of disease-specific antimitochondrial antibodies and the histological destruction of intrahepatic bile ducts, which eventually lead to cirrhosis and hepatic failure. Fortunately, ursodeoxycholic acid therapy has improved the outcome of the vast majority of PBC cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. PBC patients may also have genetically determined risk factors in non-HLA regions. Meanwhile, exposure to environmental factors, such as infectious diseases and harmful chemicals, can produce epigenetic alterations in some individuals and subsequent PBC onset. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies on this disease and its future prospects in terms of epigenetics.
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33
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Ronca V, Carbone M, Bernuzzi F, Malinverno F, Mousa HS, Gershwin ME, Invernizzi P. From pathogenesis to novel therapies in the treatment of primary biliary cholangitis. Expert Rev Clin Immunol 2017; 13:1121-1131. [DOI: 10.1080/1744666x.2017.1391093] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Vincenzo Ronca
- Department of Medicine, S. Paolo Hospital, University of Milan, Milan, Italy
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Marco Carbone
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Francesca Bernuzzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Federica Malinverno
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Hani S. Mousa
- School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, CB2 0AH, United Kingdom
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Pietro Invernizzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
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34
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Yasunami M, Nakamura H, Tokunaga K, Kawashima M, Nishida N, Hitomi Y, Nakamura M. Principal contribution of HLA-DQ alleles, DQB1*06:04 and DQB1*03:01, to disease resistance against primary biliary cholangitis in a Japanese population. Sci Rep 2017; 7:11093. [PMID: 28894202 PMCID: PMC5593890 DOI: 10.1038/s41598-017-11148-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/21/2017] [Indexed: 01/07/2023] Open
Abstract
Identification of the primary allele(s) in HLA class II associated diseases remains challenging because of a tight linkage between alleles of HLA-DR and -DQ loci. In the present study, we determined the genotypes of seven HLA loci (HLA-A, -B, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1) for 1200 Japanese patients with primary biliary cholangitis and 1196 controls. Observation of recombination derivatives facilitated an evaluation of the effects of individual HLA alleles consisting of disease-prone/disease-resistant HLA haplotypes. Consequently, a primary contribution of DQB1*06:04 (odds ratio: 0.19, p = 1.91 × 10−22), DQB1*03:01 (odds ratio: 0.50, p = 6.76 × 10−10), DRB1*08:03 (odds ratio: 1.75, p = 1.01 × 10−7) and DQB1*04:01 (odds ratio: 1.50, p = 9.20 × 10−6) was suggested. Epistasis of the protective DQB1*06:04 to risk conferred by DRB1*08:03 was demonstrated by subpopulation analysis, implicating the presence of an active immunological mechanism that alleviates pathogenic autoimmune reactions. Further, the contribution of the aforementioned HLA alleles as well as an HLA-DP allele, DPB1*02:01 to the association signals of 304 loci among 4103 SNPs in the HLA region at the genome-wide level of significance (p values less than 5 × 10−8) was demonstrated by the stepwise exclusion of the individuals possessing these HLA alleles from the comparison.
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Affiliation(s)
- Michio Yasunami
- Department of Medical Genomics, Life Science Institute, Saga-Ken Medical Centre Koseikan, Saga, 840-8571, Japan. .,Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, 852-8523, Japan.
| | - Hitomi Nakamura
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, 852-8523, Japan.,Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, 856-8562, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan
| | - Minae Kawashima
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan
| | - Nao Nishida
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan.,The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, 272-8516, Japan
| | - Yuki Hitomi
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, 856-8562, Japan. .,Headquarters of PBC Research in the NHO Study Group for Liver Disease in Japan (NHOSLJ), Omura, 856-8562, Japan. .,Headquarters of gp210 Working Group in Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan (gp210WG), Omura, 856-8562, Japan.
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35
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Genetic Contribution to the Pathogenesis of Primary Biliary Cholangitis. J Immunol Res 2017; 2017:3073504. [PMID: 28255561 PMCID: PMC5309396 DOI: 10.1155/2017/3073504] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 01/12/2017] [Indexed: 12/14/2022] Open
Abstract
Formerly termed primary biliary cirrhosis, primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease characterized by the presence of antimitochondrial antibodies. Ursodeoxycholic acid (UDCA) therapy is the most effective and approved treatment for PBC and leads to a favorable outcome in the vast majority of cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. Individuals in different geographic regions of the world may have varying susceptibility alleles that reflect indigenous triggering antigens. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies (GWAS) on this disease.
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36
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Liberal R, Grant CR. Cirrhosis and autoimmune liver disease: Current understanding. World J Hepatol 2016; 8:1157-1168. [PMID: 27729952 PMCID: PMC5055585 DOI: 10.4254/wjh.v8.i28.1157] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/14/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.
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37
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Clemente MG, Frau F, Bernasconi M, Macis MD, Cicotto L, Pilleri G, De Virgiliis S, Castiglia P, Farci P. Distinctive HLA-II association with primary biliary cholangitis on the Island of Sardinia. United European Gastroenterol J 2016; 5:527-531. [PMID: 28588884 DOI: 10.1177/2050640616665030] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 07/26/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The HLA DRB1*08 allele associated with primary biliary cholangitis (PBC) among Caucasians is of low frequency in the Sardinian population. OBJECTIVE The aim of our study was to type a cohort of PBC patients from the island of Sardinia for HLA class II antigens. METHODS Twenty Sardinian patients affected by PBC, 14 with autoimmune hepatitis (AIH) and 89 healthy controls (HCs) were typed for HLA class II alleles by dot-blot analysis. RESULTS The PBC-associated HLA DRB1*08 allele was detected in none of the studied individuals. The DRB1*0301-DQB1*0201 was the prevalent HLA haplotype, detected in 19 (47.5%) out of 40 PBC haplotypes (OR = 3.0; 95% CI 1.5-6.2) and in 11 (39.3%) out of 28 AIH haplotypes (OR = 2.2; 95% CI 0.94-5.0), but in only 41 (23%) out of 178 HC haplotypes. Moreover, PBC patients showed an increased frequency of homozygosity for the DQB1*0201 allele (35% compared with 6.7% of the HCs; OR = 7.5; 95% CI 2.2-25.7). The frequency of the DRB1*11 allele in the PBC group was about half of that seen in the Sardinian HCs (7.5% vs 15.7%) (p = ns). CONCLUSIONS Our study confirmed the low frequency of the HLA DRB1*08 allele among Sardinians, either in the general population or PBC patients. The high prevalence of the HLA DRB1*0301-DQB1*0201 haplotype is a distinctive genetic feature of PBC among Sardinians. Our study strengthens the hypothesis that still unknown genetic, epigenetic, and environmental factors must be involved in the pathogenesis of different HLA-associated liver diseases, and it represents a pathfinder that warrants exploration in a future extensive study.
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Affiliation(s)
- Maria Grazia Clemente
- Department of Biomedical Sciences and Biotechnologies, University of Cagliari, Cagliari, Italy.,Present address: Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Sassari, Italy
| | - Fulvia Frau
- Department of Biomedical Sciences and Biotechnologies, University of Cagliari, Cagliari, Italy
| | | | - Maria Doloretta Macis
- Department of Biomedical Sciences and Biotechnologies, University of Cagliari, Cagliari, Italy
| | - Lucia Cicotto
- Department of Biomedical Sciences and Biotechnologies, University of Cagliari, Cagliari, Italy
| | - Giampaolo Pilleri
- 2nd Division of Medicine, Azienda Ospedaliera Brotzu, Cagliari, Italy
| | - Stefano De Virgiliis
- Department of Biomedical Sciences and Biotechnologies, University of Cagliari, Cagliari, Italy
| | - Paolo Castiglia
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Patrizia Farci
- Department of Medical Sciences "Mario Aresu", University of Cagliari, Cagliari, Italy.,Present address: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Abstract
Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases-suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized.
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Affiliation(s)
- Aliya F. Gulamhusein
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905
| | - Brian D. Juran
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905
| | - Konstantinos N. Lazaridis
- Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. Phone: (507) 538-4877. Fax: (507) 284-0762
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Reshetnyak VI. Primary biliary cirrhosis: Clinical and laboratory criteria for its diagnosis. World J Gastroenterol 2015; 21:7683-7708. [PMID: 26167070 PMCID: PMC4491957 DOI: 10.3748/wjg.v21.i25.7683] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 04/07/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic granulomatous, and destructive inflammatory lesion of small intralobular and septal bile ducts, which is likely to be caused by an autoimmune mechanism with a the presence of serum antimitochondrial antibodies and a potential tendency to progress to cirrhosis. Despite the fact that the etiology of this disease has been unknown so far, there has been a considerable body of scientific evidence that can reveal the clinical and laboratory signs of PBC and the individual components of its pathogenesis and elaborate diagnostic criteria for the disease and its symptomatic therapy. Deficiencies in autoimmune tolerance are critical factors for the initiation and perpetuation of the disease. The purpose of this review is to summarize the data available in the literature and the author's findings on clinical and laboratory criteria for the diagnosis of PBC. This review describes the major clinical manifestations of the disease and the mechanisms of its development. It presents the immunological, biochemical, and morphological signs of PBC and their significance for its diagnosis. A great deal of novel scientific evidence for the problem of PBC has been accumulated. However, the inadequate efficiency of therapy for the disease lends impetus to the quest for its etiological factors and to further investigations of its pathogenetic mechanisms and, on this basis, to searches for new methods for its early diagnosis.
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Tang R, Chen H, Miao Q, Bian Z, Ma W, Feng X, Seldin MF, Invernizzi P, Gershwin ME, Liao W, Ma X. The cumulative effects of known susceptibility variants to predict primary biliary cirrhosis risk. Genes Immun 2015; 16:193-8. [PMID: 25569263 PMCID: PMC5553973 DOI: 10.1038/gene.2014.76] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 09/25/2014] [Accepted: 10/02/2014] [Indexed: 12/12/2022]
Abstract
Multiple genetic variants influence the risk for development of primary biliary cirrhosis (PBC). To explore the cumulative effects of known susceptibility loci on risk, we utilized a weighted genetic risk score (wGRS) to evaluate whether genetic information can predict susceptibility. The wGRS was created using 26 known susceptibility loci and investigated in 1840 UK PBC and 5164 controls. Our data indicate that the wGRS was significantly different between PBC and controls (P=1.61E-142). Moreover, we assessed predictive performance of wGRS on disease status by calculating the area under the receiver operator characteristic curve. The area under curve for the purely genetic model was 0.72 and for gender plus genetic model was 0.82, with confidence limits substantially above random predictions. The risk of PBC using logistic regression was estimated after dividing individuals into quartiles. Individuals in the highest disclosed risk group demonstrated a substantially increased risk for PBC compared with the lowest risk group (odds ratio: 9.3, P=1.91E-084). Finally, we validated our findings in an analysis of an Italian PBC cohort. Our data suggested that the wGRS, utilizing genetic variants, was significantly associated with increased risk for PBC with consistent discriminant ability. Our study is a first step toward risk prediction for PBC.
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Affiliation(s)
- Ruqi Tang
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
| | - Haoyan Chen
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Qi Miao
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
| | - Zhaolian Bian
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
| | - Wansu Ma
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA
| | - Xiaomei Feng
- Division of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Michael F. Seldin
- Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA, USA
- Department of Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Pietro Invernizzi
- Clinical Immunology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
| | - M. Eric Gershwin
- Department of Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Wilson Liao
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Xiong Ma
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, China
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41
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Impact of Aging on Liver Histological Findings of Autoimmune Liver Diseases. Diseases 2014. [DOI: 10.3390/diseases2040308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Ali AH, Carey EJ, Lindor KD. Diagnosis and management of primary biliary cirrhosis. Expert Rev Clin Immunol 2014; 10:1667-78. [DOI: 10.1586/1744666x.2014.979792] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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43
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Mechanisms of tissue injury in autoimmune liver diseases. Semin Immunopathol 2014; 36:553-68. [PMID: 25082647 DOI: 10.1007/s00281-014-0439-3] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 06/24/2014] [Indexed: 02/06/2023]
Abstract
Autoimmune diseases affecting the liver are mainly represented by autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The characteristic morphologic patterns of injury are a chronic hepatitis pattern of damage in AIH, destruction of small intrahepatic bile ducts in PBC and periductal fibrosis and inflammation involving larger bile ducts in PSC. The factors responsible for initiation and perpetuation of the injury in all the three autoimmune liver diseases are not understood completely but are likely to be environmental triggers on the background of genetic variation in immune regulation. In this review, we summarise the current understanding of the mechanisms underlying the breakdown of self-tolerance in autoimmune liver diseases.
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Umemura T, Katsuyama Y, Yoshizawa K, Kimura T, Joshita S, Komatsu M, Matsumoto A, Tanaka E, Ota M. Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan. PLoS One 2014; 9:e100565. [PMID: 24956105 PMCID: PMC4067340 DOI: 10.1371/journal.pone.0100565] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 05/25/2014] [Indexed: 12/31/2022] Open
Abstract
Although we earlier demonstrated that the human leukocyte antigen (HLA) DRB1*04:05 allele was associated with susceptibility to autoimmune hepatitis (AIH) in Japan, the precise relationship of HLA haplotype and the role of amino acid alignment with disease susceptibility and progression has not been fully clarified. We reinvestigated HLA class I A, B, and C and HLA class II DRB1, DQB1, and DPB1 alleles and haplotypes in a larger new cohort of 156 Japanese patients with type 1 AIH and compared them with the published data of 210 healthy subjects. The DRB1*04:05-DQB1*04:01 haplotype was significantly associated with AIH susceptibility (30% vs. 11%, P = 1.2×10−10; odds ratio [OR] = 3.51) and correlated with elevated serum IgG (3042 vs. 2606 mg/dL, P = 0.041) and anti-smooth muscle antigen positivity (77% vs. 34%, P = 0.000006). No associations with HLA-DPB1 alleles were found. The HLA A*24:02 and C*01:02 alleles were associated with disease susceptibility (corrected P = 0.0053 and 0.036, respectively), but this likely constituents of a long ranged haplotype including DRB1*04:05-DQB1*04:01 haplotype. Conversely, the DRB1*15:01-DQB1*06:02 haplotype was associated with protection from both disease onset (5% vs. 13%, P = 0.00057; OR = 0.38) and the development of hepatocellular carcinoma (25% vs. 5%, P = 0.017; OR = 6.81). The frequency of the DRB1*08:03-DQB1*06:01 haplotype was significantly higher in patients who developed hepatic failure (22% vs. 6%, P = 0.034; OR = 4.38). In conclusion, this study established the role of HLA haplotypes in determining AIH susceptibility and progression in the Japanese population. Additional sequencing of the entire HLA region is required to more precisely identify the genetic components of AIH.
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Affiliation(s)
- Takeji Umemura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | | | - Kaname Yoshizawa
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan; Department of Gastroenterology, NHO Ueda Medical Center, Ueda, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Michiharu Komatsu
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masao Ota
- Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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Zimmer V, Lammert F. Role of genetics in diagnosis and therapy of acquired liver disease. Mol Aspects Med 2014; 37:15-34. [DOI: 10.1016/j.mam.2013.10.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 10/07/2013] [Accepted: 10/15/2013] [Indexed: 02/08/2023]
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Li M, Zheng H, Tian QB, Rui MN, Liu DW. HLA-DR polymorphism and primary biliary cirrhosis: evidence from a meta-analysis. Arch Med Res 2014; 45:270-9. [PMID: 24657596 DOI: 10.1016/j.arcmed.2014.03.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Accepted: 02/26/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS We undertook this study to review and quantitatively analyze the association between human leukocyte antigen (HLA) DR polymorphisms and susceptibility of primary biliary cirrhosis (PBC). METHODS All relevant publications on the association between HLA-DR polymorphisms and PBC were searched through June 2013. Odds ratios (OR) and confidence intervals (CI) for the comparisons between case and control group were calculated. Statistical analysis was performed using Stata 11.0 software. RESULTS Nineteen articles (or 20 studies including the substudies) were identified. For DR*7 allele, the ORs (95% CIs) were 1.530 (1.310, 1.788), 1.757 (1.285, 2.403) and 1.495 (1.211, 1.845) in overall, Asian and European populations, respectively. For DR*8 alleles, the ORs (95% CIs) were 3.158 (1.822, 5.475), 2.803 (2.420, 3.247) and 3.056 (2.573, 3.629) in Asian, American and European subgroups, respectively. The subgroup analysis for DR*11 and DR*13 showed a significant association in Asian and European population. For DR*12 and *15 alleles, the overall ORs (95% CIs) were 0.551 (0.404, 0.753) and 0.721 (0.607, 0.857). However, in subgroup analysis for DR*12 allele, the association was only found in Asian population. In addition, statistical significance exists in American and European populations in the subgroup analysis for DR*15 allele. CONCLUSION Our meta-analysis suggested that HLA-DR *7 and *8 allele polymorphisms contributed to the susceptibility of PBC, whereas DR*11, *12, *13 and *15 allele polymorphisms are protective factors in certain population.
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Affiliation(s)
- Man Li
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Hao Zheng
- Department of Ultrasonography, Hebei Chest Hospital, Shijiazhuang, China
| | - Qing-bao Tian
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Mei-na Rui
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Dian-wu Liu
- Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China.
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Zhao DT, Liao HY, Zhang X, Liu YM, Zhao Y, Zhang HP, Sun LM, Ma YX, Yan HP. Human leucocyte antigen alleles and haplotypes and their associations with antinuclear antibodies features in Chinese patients with primary biliary cirrhosis. Liver Int 2014; 34:220-6. [PMID: 23809616 DOI: 10.1111/liv.12236] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 05/28/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Genetic factors are critical in determining susceptibility to PBC. Among human leuocyte antigen (HLA) genes, an association between the DRB1*08 allele and PBC has been reported in many populations, but not in Chinese patients. METHODS We investigated HLA-A, B, DRB1, and DQB1 alleles and haplotypes in 145 PBC patients and 500 healthy subjects. Patients were also stratified according to autoantibody features, and associations between these and HLA alleles were analyzed. RESULTS Significant associations existed between HLA-DRB1*08:03 (22.1% vs. 9.0%, Pc < 0.0001, OR = 2.86), DQ2 (41.4% vs. 25.4%, Pc < 0.0001, OR = 2.07) and DQB1*06:01 (31.0% vs. 17.8%, Pc = 0.014, OR = 2.08) alleles and PBC. DRB1*08:03-DQB1*06:01 (22.1% vs. 8.2%, P < 0.0001, OR = 3.17) and DRB1*07:01-DQB1*02:02 haplotypes (28.3% vs. 17.6%, P = 0.005, OR = 1.85) were also associated with PBC susceptibility. In contrast, the DQB1*03:01 allele (21.4% vs. 39.2%, Pc < 0.0001, OR = 0.42) and DRB1*12:02-DQB1*03:01 haplotype (6.9% vs. 14.6%, P = 0.015, OR = 0.43) were significantly decreased in PBC patients compared with controls. DRB1*14:54 and DQ5(1) protected against antinuclear antibody (ANA) (OR = 0.25) and anti-gp210 antibody (OR = 0.39) production, respectively, while HLA-B*44:03 predisposed patients to anti-gp210 antibody (OR = 5.70) production. CONCLUSION These results suggest that Chinese patients with PBC have a distinct genetic background in eastern Asia, and we confirmed the role of HLA genes in determining PBC susceptibility and autoantibody features in the Chinese population.
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Affiliation(s)
- Dan-Tong Zhao
- Clinical Research Center for Autoimmune Liver Disease, Beijing You'an Hospital, Capital Medical University, Beijing, China
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Qin B, Wang J, Chen J, Liang Y, Yang Z, Zhong R. Association of human leukocyte antigen class II with susceptibility to primary biliary cirrhosis: a systematic review and meta-analysis. PLoS One 2013; 8:e79580. [PMID: 24265779 PMCID: PMC3827176 DOI: 10.1371/journal.pone.0079580] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 09/27/2013] [Indexed: 12/26/2022] Open
Abstract
Purpose Several previous studies suggested that HLA-ClassII may be associated with susceptibility to primary biliary cirrhosis (PBC), but data from individual studies remain controversial. Therefore, a systematic review and meta-analysis is needed to comprehensively evaluate the association between HLA-ClassII and PBC risk. Methods All published reports of an association between HLA class II and PBC risk were searched in PubMed, EMBASE (updated to 22 May 2012). ORs with 95% confidence intervals (CIs) were extracted from each included study and the meta-analysis was performed using the fixed- or random-effects model. Results A total of 3,732 PBC patients and 11,031 controls from 34 studies were included in the meta-analysis. An assessment of study quality revealed that the majority of studies included (18 studies) were of high quality. The serological group DR8 was found to be a risk factor for PBC (OR = 2.82, 95%CI: 1.84–4.30). At the allelic level, HLA-DR*08 and HLA-DR*0801 were identified as risk factors for PBC (OR = 2.30, 95%CI: 1.76-3.00; OR = 3.23, 95%CI: 2.22–4.70, respectively), whereas HLA-DR*11 and HLA-DR*13 were potent protective factors (OR = 0.31, 95%CI: 0.27-0.38; OR = 0.62, 95%CI: 0.48-0.81, respectively). HLA-DQB1 and HLA-DQB1*0402 conferred a predisposition to PBC development (OR = 3.47, 95%CI: 2.35–5.13), whereas HLA-DQB1*0604 was protective against PBC (OR = 0.3, 95%CI: 0.18–0.58). No HLA-DPB1 allele was observed to be associated with PBC susceptibility (P > 0.05). Conclusions The present study revealed that HLA-ClassII components are closely associated with the development of PBC.
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Affiliation(s)
- Baodong Qin
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jiaqi Wang
- Department of Stomatology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jia Chen
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yan Liang
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zaixing Yang
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
- * E-mail: (ZXY); (RQZ)
| | - Renqian Zhong
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
- * E-mail: (ZXY); (RQZ)
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Ninomiya M, Kondo Y, Funayama R, Nagashima T, Kogure T, Kakazu E, Kimura O, Ueno Y, Nakayama K, Shimosegawa T. Distinct microRNAs expression profile in primary biliary cirrhosis and evaluation of miR 505-3p and miR197-3p as novel biomarkers. PLoS One 2013; 8:e66086. [PMID: 23776611 PMCID: PMC3680413 DOI: 10.1371/journal.pone.0066086] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 05/03/2013] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS MicroRNAs are small endogenous RNA molecules with specific expression patterns that can serve as biomarkers for numerous diseases. However, little is known about the expression profile of serum miRNAs in PBC. METHODS First, we employed Illumina deep sequencing for the initial screening to indicate the read numbers of miRNA expression in 10 PBC, 5 CH-C, 5 CH-B patients and 5 healthy controls. Comparing the differentially expressed miRNAs in the 4 groups, analysis of variance was performed on the number of sequence reads to evaluate the statistical significance. Hierarchical clustering was performed using an R platform and we have found candidates for specific miRNAs in the PBC patients. Second, a quantitative reverse transcription PCR validation study was conducted in 10 samples in each group. The expression levels of the selected miRNAs were presented as fold-changes (2(-ΔΔCt)). Finally, computer analysis was conducted to predict target genes and biological functions with MiRror 2.0 and DAVID v6.7. RESULTS We obtained about 12 million 32-mer short RNA reads on average per sample and the mapping rates to miRBase were 16.60% and 81.66% to hg19. In the statistical significance testing, the expression levels of 81 miRNAs were found to be differentially expressed in the 4 groups. The heat map and hierarchical clustering demonstrated that the miRNA profiles from PBC clustered with those of CH-B, CH-C and healthy controls. Additionally, the circulating levels of hsa-miR-505-3p, 197-3p, and 500a-3p were significantly decreased in PBC compared with healthy controls and the expression levels of hsa-miR-505-3p, 139-5p and 197-3p were significantly reduced compared with the viral hepatitis group. CONCLUSIONS Our results indicate that sera from patients with PBC have a unique miRNA expression profile and that the down-regulated expression of hsa-miR-505-3p and miR-197-3p can serve as clinical biomarkers of PBC.
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Affiliation(s)
- Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
| | - Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
| | - Ryo Funayama
- Division of Cell Proliferation, Tohoku University School of Medicine, Sendai, Japan
| | - Takeshi Nagashima
- Division of Cell Proliferation, Tohoku University School of Medicine, Sendai, Japan
| | - Takayuki Kogure
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
| | - Eiji Kakazu
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
| | - Osamu Kimura
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Keiko Nakayama
- Division of Cell Proliferation, Tohoku University School of Medicine, Sendai, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Hospital, Sendai, Japan
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Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2013; 8:303-30. [PMID: 23347352 DOI: 10.1146/annurev-pathol-020712-164014] [Citation(s) in RCA: 225] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony-stimulating factor-stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention.
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Affiliation(s)
- Gideon M Hirschfield
- Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom
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