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Mimura S, Morishita A, Oura K, Takuma K, Nakahara M, Tadokoro T, Fujita K, Tani J, Kobara H. Galectins and Liver Diseases. Int J Mol Sci 2025; 26:790. [PMID: 39859504 PMCID: PMC11766161 DOI: 10.3390/ijms26020790] [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: 12/18/2024] [Revised: 01/13/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Galectins are widely distributed throughout the animal kingdom, from marine sponges to mammals. Galectins are a family of soluble lectins that specifically recognize β-galactoside-containing glycans and are categorized into three subgroups based on the number and function of their carbohydrate recognition domains (CRDs). The interaction of galectins with specific ligands mediates a wide range of biological activities, depending on the cell type, tissue context, expression levels of individual galectin, and receptor involvement. Galectins affect various immune cell processes through both intracellular and extracellular mechanisms and play roles in processes, such as apoptosis, angiogenesis, and fibrosis. Their importance has increased in recent years because they are recognized as biomarkers, therapeutic agents, and drug targets, with many other applications in conditions such as cardiovascular diseases and cancer. However, little is known about the involvement of galectins in liver diseases. Here, we review the functions of various galectins and evaluate their roles in liver diseases.
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Affiliation(s)
- Shima Mimura
- Departments of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Takamatsu 761-0793, Kagawa Prefecture, Japan
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He J, Li S, Yang Z, Ma J, Qian C, Huang Z, Li L, Yang Y, Chen J, Sun Y, Zhao T, Luo L. Gallbladder-derived retinoic acid signalling drives reconstruction of the damaged intrahepatic biliary ducts. Nat Cell Biol 2025; 27:39-47. [PMID: 39779943 DOI: 10.1038/s41556-024-01568-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 10/25/2024] [Indexed: 01/11/2025]
Abstract
Severe damage to the intrahepatic biliary duct (IHBD) network occurs in multiple human advanced cholangiopathies, such as primary sclerosing cholangitis, biliary atresia and end-stage primary biliary cholangitis. Whether and how a severely damaged IHBD network could reconstruct has remained unclear. Here we show that, although the gallbladder is not directly connected to the IHBD, there is a common hepatic duct (CHD) in between, and severe damage to the IHBD network induces migration of gallbladder smooth muscle cells (SMCs) to coat the CHD in mouse and zebrafish models. These gallbladder-derived, CHD-coating SMCs produce retinoic acid to activate Sox9b in the CHD, which drives proliferation and ingrowth of CHD cells into the inner liver to reconstruct the IHBD network. This study reveals a hitherto unappreciated function of the gallbladder in the recovery of injured liver, and characterizes mechanisms involved in how the gallbladder and liver communicate through inter-organ cell migration to drive tissue regeneration. Carrying out cholecystectomy will thus cause previously unexpected impairments to liver health.
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Affiliation(s)
- Jianbo He
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Shuang Li
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Zhuolin Yang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Jianlong Ma
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chuanfang Qian
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Zhuofu Huang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Linke Li
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Yun Yang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Jingying Chen
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunfan Sun
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianyu Zhao
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lingfei Luo
- State Key laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai, China.
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China.
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Warsop Z, Anand N, Al Maliki H, De Souza S, Kamyab A, Al Hadad A, Alrubaiy L. Up-to-Date Snapshot of Current and Emerging Medical Therapies in Primary Biliary Cholangitis. J Pers Med 2024; 14:1133. [PMID: 39728045 DOI: 10.3390/jpm14121133] [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: 07/09/2024] [Revised: 09/06/2024] [Accepted: 11/21/2024] [Indexed: 12/28/2024] Open
Abstract
Background/Objectives: Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic disease of the liver that symptomatically can present with pruritus and fatigue. Its established first- and second-line therapies are ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) although they provide limited symptom management. Liver transplantation offers a potentially curative therapeutic option in refractory cases progressing to cirrhosis. Novel research published after the current guidelines highlights the importance of providing an up-to-date analysis of treatment options available. Methods: In this study, we conducted a literature search using Pubmed, Ovid Medline, and SCOPUS to provide a narrative review of first-line, second-line, and emerging therapies in PBC. Results: UDCA has been well established as a long-term, safe therapy within the literature although it is possible that treatment dosage can be further optimised in refractory patients. It has a favourable side effect profile. Despite improving biochemical markers, histopathological profile, and overall outcomes, up to 30-40% of patients are refractory to it. Age and sex are highlighted as independent indicators of non-responsiveness. This necessitates effective second-line therapies. Future trials could aim to investigate UDCA as a co-first-line therapy. Further supporting results for OCA were found in the interim extension trial of the seminal POISE study. The long-term phase 4 COBOLT trial is still awaiting results to further assess the complications, adherence, and potential adverse effects. It is a viable option in UDCA-refractory patients. The high incidence rate of dose-related pruritis indicates that alternative second-line options are needed. Bezafibrate is an off-label antilipemic agent that shows promise as a prospective second-line therapy option. The landmark BEZURSO trial alleviated some efficacy and safety concerns, but it remains associated with elevated serum creatinine; thus, it should be considered with caution. Other prospective second-line therapies are budesonide, triple therapy, and novel agents such as seladelpar and elafibranor. Conclusions: UDCA should remain the treatment of choice for PBC, though perhaps not as monotherapy. With further investigation, BF shows promise as a new second-line therapy alongside OCA, which it may outperform.
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Affiliation(s)
- Zakary Warsop
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Nikhil Anand
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Husam Al Maliki
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Shuell De Souza
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Arya Kamyab
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Amin Al Hadad
- Healthpoint Hospital, Abu Dhabi 112308, United Arab Emirates
| | - Laith Alrubaiy
- Healthpoint Hospital, Abu Dhabi 112308, United Arab Emirates
- Department of Medicine Health and Life Sciences, Singleton Bay Campus, Swansea University School of Medicine, Swansea SA2 8PP, UK
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Zhao J, Yue P, Mi N, Li M, Fu W, Zhang X, Gao L, Bai M, Tian L, Jiang N, Lu Y, Ma H, Dong C, Zhang Y, Zhang H, Zhang J, Ren Y, Suzuki A, Wong PF, Tanaka K, Rerknimitr R, Junger HH, Cheung TT, Melloul E, Demartines N, Leung JW, Yao J, Yuan J, Lin Y, Schlitt HJ, Meng W. Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications. MEDICAL REVIEW (2021) 2024; 4:326-365. [PMID: 39135601 PMCID: PMC11317084 DOI: 10.1515/mr-2024-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/06/2024] [Indexed: 08/15/2024]
Abstract
Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.
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Affiliation(s)
- Jinyu Zhao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ping Yue
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningning Mi
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Matu Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Wenkang Fu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xianzhuo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Long Gao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Mingzhen Bai
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Liang Tian
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningzu Jiang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yawen Lu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Haidong Ma
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hengwei Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jinduo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yanxian Ren
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Azumi Suzuki
- Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan
| | - Peng F. Wong
- Department of Vascular Surgery, The James Cook University Hospital, Middlesbrough, UK
| | - Kiyohito Tanaka
- Department of Gastroenterology, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Rungsun Rerknimitr
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn, Bangkok, Thailand
- Excellence Center for Gastrointestinal Endoscopy, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Henrik H. Junger
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Tan T. Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Joseph W. Leung
- Division of Gastroenterology and Hepatology, UC Davis Medical Center and Sacramento VA Medical Center, Sacramento, CA, USA
| | - Jia Yao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hans J. Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Wakil A, Muzahim Y, Awadallah M, Kumar V, Mazzaferro N, Greenberg P, Pyrsopoulos N. Trends of autoimmune liver disease inpatient hospitalization and mortality from 2011 to 2017: A United States nationwide analysis. World J Hepatol 2024; 16:1029-1038. [PMID: 39086532 PMCID: PMC11287613 DOI: 10.4254/wjh.v16.i7.1029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 05/23/2024] [Accepted: 06/25/2024] [Indexed: 07/26/2024] Open
Abstract
BACKGROUND Autoimmune liver diseases (AiLD) encompass a variety of disorders that target either the liver cells (autoimmune hepatitis, AIH) or the bile ducts [(primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC)]. These conditions can progress to chronic liver disease (CLD), which is characterized by fibrosis, cirrhosis, and hepatocellular carcinoma. Recent studies have indicated a rise in hospitalizations and associated costs for CLD in the US, but information regarding inpatient admissions specifically for AiLD remains limited. AIM To examine the trends and mortality of inpatient hospitalization of AiLD from 2011 to 2017. METHODS This study is a retrospective analysis utilizing the National Inpatient Sample (NIS) databases. All subjects admitted between 2011 and 2017 with a diagnosis of AiLD (AIH, PBC, PSC) were identified using the International Classification of Diseases (ICD-9) and ICD-10 codes. primary AiLD admission was defined if the first admission code was one of the AiLD codes. secondary AiLD admission was defined as having the AiLD diagnosis anywhere in the admission diagnosis (25 diagnoses). Subjects aged 21 years and older were included. The national estimates of hospitalization were derived using sample weights provided by NIS. χ 2 tests for categorical data were used. The primary trend characteristics were in-hospital mortality, hospital charges, and length of stay. RESULTS From 2011 to 2017, hospitalization rates witnessed a significant decline, dropping from 83263 admissions to 74850 admissions (P < 0.05). The patients hospitalized were predominantly elderly (median 53% for age > 65), mostly female (median 59%) (P < 0.05), and primarily Caucasians (median 68%) (P < 0.05). Medicare was the major insurance (median 56%), followed by private payer (median 27%) (P < 0.05). The South was the top geographical distribution for these admissions (median 33%) (P < 0.05), with most admissions taking place in big teaching institutions (median 63%) (P < 0.05). Total charges for admissions rose from 66031 in 2011 to 78987 in 2017 (P < 0.05), while the inpatient mortality rate had a median of 4.9% (P < 0.05), rising from 4.67% in 2011 to 5.43% in 2017. The median length of stay remained relatively stable, changing from 6.94 days (SD = 0.07) in 2011 to 6.51 days (SD = 0.06) in 2017 (P < 0.05). Acute renal failure emerged as the most common risk factor associated with an increased death rate, affecting nearly 68% of patients (P < 0.05). CONCLUSION AiLD-inpatient hospitalization showed a decrease in overall trends over the studied years, however there is a significant increase in financial burden on healthcare with increasing in-hospital costs along with increase in mortality of hospitalized patient with AiLD.
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Affiliation(s)
- Ali Wakil
- Department of Gastroenterology and Hepatology, The Brooklyn Hospital Center, Brooklyn, NY 11201, United States
| | - Yasameen Muzahim
- Department of Gastroenterology and Hepatology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, United States
| | - Mina Awadallah
- Department of Gastroenterology and Hepatology, Rutgers the New Jersey Medical School, Newark, NJ 07103, United States
| | - Vikash Kumar
- Department of Gastroenterology and Hepatology, The Brooklyn Hospital Center, Brooklyn, NY 11201, United States
| | - Natale Mazzaferro
- Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ 08854, United States
| | - Patricia Greenberg
- Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ 08854, United States
| | - Nikolaos Pyrsopoulos
- Department of Gastroenterology and Hepatology, Rutgers the New Jersey Medical School, Newark, NJ 07103, United States.
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Bäckström T, Doverskog M, Blackburn TP, Scharschmidt BF, Felipo V. Allopregnanolone and its antagonist modulate neuroinflammation and neurological impairment. Neurosci Biobehav Rev 2024; 161:105668. [PMID: 38608826 DOI: 10.1016/j.neubiorev.2024.105668] [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: 10/19/2023] [Revised: 03/18/2024] [Accepted: 04/07/2024] [Indexed: 04/14/2024]
Abstract
Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.
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Affiliation(s)
| | | | | | | | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
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Hintermann E, Tondello C, Fuchs S, Bayer M, Pfeilschifter JM, Taubert R, Mollenhauer M, Elferink RPJO, Manns MP, Christen U. Blockade of neutrophil extracellular trap components ameliorates cholestatic liver disease in Mdr2 (Abcb4) knockout mice. J Autoimmun 2024; 146:103229. [PMID: 38653165 DOI: 10.1016/j.jaut.2024.103229] [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: 12/27/2023] [Revised: 03/21/2024] [Accepted: 04/09/2024] [Indexed: 04/25/2024]
Abstract
Primary sclerosing cholangitis (PSC) is an (auto)immune-mediated cholestatic liver disease with a yet unclear etiology. Increasing evidence points to an involvement of neutrophils in chronic liver inflammation and cirrhosis but also liver repair. Here, we investigate the role of the neutrophil extracellular trap (NET) component myeloperoxidase (MPO) and the therapeutic potential of DNase I and of neutrophil elastase (NE) inhibitor GW311616A on disease outcome in the multidrug resistance 2 knockout (Mdr2-/-) mouse, a PSC animal model. Initially, we observed the recruitment of MPO expressing cells and the formation of NETs in liver biopsies of PSC patients and in Mdr2-/- livers. Furthermore, sera of Mdr2-/- mice contained perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA)-like reactivity similar to PSC patient sera. Also, hepatic NE activity was significantly higher in Mdr2-/- mice than in wild type littermates. Flow cytometry analyses revealed that during disease development a highly active neutrophil subpopulation established specifically in the liver of Mdr2-/- mice. However, absence of their MPO activity, as in MPO-deficient Mdr2-/- mice, showed no effect on hepatobiliary disease severity. In contrast, clearance of extracellular DNA by DNase I reduced the frequency of liver-resident neutrophils, plasmacytoid dendritic cells (pDCs) and CD103+ conventional DCs and decreased cholangiocyte injury. Combination of DNase I with a pDC-depleting antibody was additionally hepatocyte-protective. Most importantly, GW311616A, an orally bioavailable inhibitor of human NE, attenuated hepatobiliary injury in a TNFα-dependent manner and damped hyperproliferation of biliary epithelial cells. Further, hepatic immigration and activity of CD11b+ DCs as well as the secretion of IFNγ by hepatic CD4 and CD8 T cells were reduced. Our findings delineate neutrophils as important participants in the immune cell crosstalk that drives cholestatic liver disease and identify NET components as potential therapeutic targets.
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Affiliation(s)
- Edith Hintermann
- Pharmazentrum Frankfurt / ZAFES, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany.
| | - Camilla Tondello
- Pharmazentrum Frankfurt / ZAFES, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Sina Fuchs
- Pharmazentrum Frankfurt / ZAFES, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Monika Bayer
- Pharmazentrum Frankfurt / ZAFES, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Josef M Pfeilschifter
- Pharmazentrum Frankfurt / ZAFES, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Martin Mollenhauer
- Department of Cardiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Roland P J Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany
| | - Urs Christen
- Pharmazentrum Frankfurt / ZAFES, Goethe University, University Hospital Frankfurt, Frankfurt am Main, Germany
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Wu Y, Qian Q, Liu Q, Wang R, Pu X, Li Y, Zhang H, You Z, Miao Q, Xiao X, Lian M, Wang Q, Nakamura M, Gershwin ME, Li Z, Ma X, Tang R. Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis. Clin Rev Allergy Immunol 2024; 66:138-148. [PMID: 38554235 DOI: 10.1007/s12016-024-08986-4] [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] [Accepted: 03/08/2024] [Indexed: 04/01/2024]
Abstract
Osteoporosis is a major clinical problem in many autoimmune diseases, including primary biliary cholangitis (PBC), the most common autoimmune liver disease. Osteoporosis is a major cause of fracture and related mortality. However, it remains unclear whether PBC confers a causally risk-increasing effect on osteoporosis. Herein, we aimed to investigate the causal relationship between PBC and osteoporosis and whether the relationship is independent of potential confounders. We performed bidirectional Mendelian randomization (MR) analyses to investigate the association between PBC (8021 cases and 16,489 controls) and osteoporosis in Europeans (the UK Biobank and FinnGen Consortium: 12,787 cases and 726,996 controls). The direct effect of PBC on osteoporosis was estimated using multivariable MR analyses. An independent replication was conducted in East Asians (PBC: 2495 cases and 4283 controls; osteoporosis: 9794 cases and 168,932 controls). Trans-ethnic meta-analysis was performed by pooling the MR estimates of Europeans and East Asians. Inverse-variance weighted analyses revealed that genetic liability to PBC was associated with a higher risk of osteoporosis in Europeans (OR, 1.040; 95% CI, 1.016-1.064; P = 0.001). Furthermore, the causal effect of PBC on osteoporosis persisted after adjusting for BMI, calcium, lipidemic traits, and sex hormones. The causal relationship was further validated in the East Asians (OR, 1.059; 95% CI, 1.023-1.096; P = 0.001). Trans-ethnic meta-analysis confirmed that PBC conferred increased risk on osteoporosis (OR, 1.045; 95% CI, 1.025-1.067; P = 8.17 × 10-6). Our data supports a causal effect of PBC on osteoporosis, and the causality is independent of BMI, calcium, triglycerides, and several sex hormones.
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Affiliation(s)
- Yi Wu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qiwei Qian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qiaoyan Liu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Rui Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Xiting Pu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Yao Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Huayang Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Minoru Nakamura
- Department of Hepatology, Clinical Research Center, Nagasaki University Graduate School of Biomedical Sciences, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura City, Nagasaki, 856-8562, Japan
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Zhiqiang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China.
- Qingdao University, Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao, China.
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.
- Institute of Aging & Tissue Regeneration, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.
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9
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Zubkova E, Kalinin A, Bolotskaya A, Beloglazova I, Menshikov M. Autophagy-Dependent Secretion: Crosstalk between Autophagy and Exosome Biogenesis. Curr Issues Mol Biol 2024; 46:2209-2235. [PMID: 38534758 DOI: 10.3390/cimb46030142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 03/28/2024] Open
Abstract
The cellular secretome is pivotal in mediating intercellular communication and coordinating responses to stressors. Exosomes, initially recognized for their role in waste disposal, have now emerged as key intercellular messengers with significant therapeutic and diagnostic potential. Similarly, autophagy has transcended its traditional role as a waste removal mechanism, emerging as a regulator of intracellular communication pathways and a contributor to a unique autophagy-dependent secretome. Secretory authophagy, initiated by various stress stimuli, prompts the selective release of proteins implicated in inflammation, including leaderless proteins that bypass the conventional endoplasmic reticulum-Golgi secretory pathway. This reflects the significant impact of stress-induced autophagy on cellular secretion profiles, including the modulation of exosome release. The convergence of exosome biogenesis and autophagy is exemplified by the formation of amphisomes, vesicles that integrate autophagic and endosomal pathways, indicating their synergistic interplay. Regulatory proteins common to both pathways, particularly mTORC1, emerge as potential therapeutic targets to alter cellular secretion profiles involved in various diseases. This review explores the dynamic interplay between autophagy and exosome formation, highlighting the potential to influence the secretome composition. While the modulation of exosome secretion and cytokine preconditioning is well-established in regenerative medicine, the strategic manipulation of autophagy is still underexplored, presenting a promising but uncharted therapeutic landscape.
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Affiliation(s)
- Ekaterina Zubkova
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
| | - Alexander Kalinin
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
- Faculty of Fundamental Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Anastasya Bolotskaya
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
- Institute of Clinical Medicine, Sechenov University, 119435 Moscow, Russia
| | - Irina Beloglazova
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
| | - Mikhail Menshikov
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
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10
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Ma D, Ma J, Zhao C, Tai W. Reasons why women are more likely to develop primary biliary cholangitis. Heliyon 2024; 10:e25634. [PMID: 38384574 PMCID: PMC10878884 DOI: 10.1016/j.heliyon.2024.e25634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/29/2024] [Accepted: 01/31/2024] [Indexed: 02/23/2024] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune disease of biliary stasis in which immune factors cause the gradual destruction of small bile ducts, biliary stasis, and eventually the development of liver fibrosis, cirrhosis, and even liver failure. One of the main characteristics of PBC is that it primarily affects middle-aged women, but the precise cause is still unknown. This article analyzes the unique causes and mechanisms of the female predominance of PBC and summarizes the potential causes.The female domination of PBC is reported to be primarily caused by sex hormones, environmental circumstances, and epigenetic changes, each of which has a different subtle impact on patients' gender disparities.
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Affiliation(s)
- Di Ma
- Clinical Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jiaxuan Ma
- Clinical Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chunmei Zhao
- Clinical Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wenlin Tai
- Clinical Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
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11
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Wang Z, Liu Z, Zheng J, Huang L, Jin R, Wang X, Chen D, Xie Y, Feng B. The effects of low-dose IL-2 on Th17/Treg cell imbalance in primary biliary cholangitis mouse models. BMC Gastroenterol 2024; 24:87. [PMID: 38408917 PMCID: PMC10895794 DOI: 10.1186/s12876-024-03176-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 02/15/2024] [Indexed: 02/28/2024] Open
Abstract
BACKGROUND/AIMS Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The imbalance of Th17/Treg cells has been reported in PBC patients. Low-dose IL-2 can alleviate disease severity through modulating CD4 + T cell subsets in patients with autoimmune diseases. Hence, the present study aimed to examine the effects and mechanism of low-dose IL-2 in PBC mouse models. METHODS PBC models were induced in female C57BL/6 mice by two immunizations with 2OA-BSA at two-week intervals, and poly I: C every three days. PBC mouse models were divided into the IL-2 treated and untreated groups and low-dose IL-2 was injected at three different time points. Th17 and Tregs were analyzed by flow cytometry, and the related cytokines were analyzed by ELISA. Liver histopathology was examined by H&E and immunohistochemical staining. RESULTS Twelve weeks after modeling, the serum AMA was positive and the ALP was significantly increased in PBC mouse models (P<0.05). The pathology showed lymphocyte infiltration in the portal area, damage, and reactive proliferation of the small bile duct (P<0.05). The flow cytometric showed the imbalance of Th17/Treg cells in the liver of PBC mouse models, with decreased Treg cells, increased Th17 cells, and Th17/Treg ratio (P < 0.05). After the low-dose IL-2 intervention, biochemical index and liver pathologies showed improvement at 12 weeks. Besides, the imbalance of Th17 and Treg cells recovered. Public database mining showed that Th17 cell differentiation may contribute to poor response in PBC patients. CONCLUSION Low-dose IL-2 can significantly improve liver biochemistry and pathology by reversing the imbalance of Th17 and Treg cells, suggesting that it may be a potential therapeutic target for PBC.
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Affiliation(s)
- Zilong Wang
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Zhicheng Liu
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Jiarui Zheng
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Linxiang Huang
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Rui Jin
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xiaoxiao Wang
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Dongbo Chen
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Yandi Xie
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China.
| | - Bo Feng
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China.
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12
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Chan CW, Chen HW, Wang YW, Lin CI, Chuang YH. IL-21, not IL-17A, exacerbates murine primary biliary cholangitis. Clin Exp Immunol 2024; 215:137-147. [PMID: 37708215 PMCID: PMC10847827 DOI: 10.1093/cei/uxad107] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/23/2023] [Accepted: 09/13/2023] [Indexed: 09/16/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by intrahepatic bile duct injuries, resulting in fibrosis, cirrhosis, and eventually liver failure. T helper (Th) 17 cells are proposed to involve in the pathogenesis of PBC. However, how and which Th17 cell-derived cytokines affect PBC remains unclear. In this study, we investigated the effects of Th17 effector cytokines, including interleukin (IL)-17A, IL-17F, and IL-21 in PBC using a xenobiotic-induced mouse model of autoimmune cholangitis (inducible chemical xenobiotic models of PBC) treated with cytokine-expressing adeno-associated virus. Our results showed that administration of IL-17A, the well-known main cytokine produced by Th17 cells, did not augment liver inflammation or fibrosis. In contrast, we noted IL-17A-treated mice had lower hepatic Th1 cell numbers and higher hepatic CD11b+Ly6G+ polymorphonuclear myeloid-derived suppressor cell numbers. IL-17F did not alter liver inflammation or fibrosis. However, the administration of IL-21 exacerbated liver inflammatory responses and portal cell infiltration. IL-21 markedly increased the numbers of activated CD8+ T cells and liver tissue-resident memory CD8+ T cells. Moreover, IL-21 aggravates liver fibrosis in mice with autoimmune cholangitis. These results emphasized that not IL-17A but IL-21 in Th17 cell-derived cytokines affected the pathogenesis of PBC. IL-21 enhanced liver inflammation and progression to fibrosis by enhancing the numbers and effector activities of CD8+ T cells. Delineation of the effects of different Th17 effector cytokines in PBC offers clues for developing new therapeutic approaches.
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Affiliation(s)
- Chun-Wen Chan
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hung-Wen Chen
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Wen Wang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chia-I Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ya-Hui Chuang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
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13
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Wang R, Lin Q, Lu Z, Wen H, Hu F, You J, He Y, Fang Y, Bian Z, Hou Q, Ju Z, Wang Y, Lian M, Xiao X, Sheng L, Guo C, Hua J, Tang R, You Z, Chen X, Gershwin ME, Huang Z, Wang Q, Miao Q, Ma X. Immunosuppression induces regression of fibrosis in primary biliary cholangitis with moderate-to-severe interface hepatitis. J Autoimmun 2024; 143:103163. [PMID: 38301505 DOI: 10.1016/j.jaut.2023.103163] [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: 10/16/2023] [Revised: 12/10/2023] [Accepted: 12/13/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy. METHODS We conducted a multicenter study involving PBC patients with moderate-to-severe interface hepatitis who underwent paired liver biopsies. Firstly, we compared the efficacy of the combination therapy with UDCA monotherapy on improving biochemistry, histology, survival rates, and prognosis. Subsequently we investigated the predictors of a beneficial response. RESULTS This retrospective cohort study with prospectively collected data was conducted in China from January 2009 to April 2023. Of the 198 enrolled patients, 32 underwent UDCA monotherapy, while 166 received combination therapy, consisting of UDCA combined with prednisolone, prednisolone plus mycophenolate mofetil (MMF), or prednisolone plus azathioprine (AZA). The monotherapy group was treated for a median duration of 37.6 months (IQR 27.5-58.1), and the combination therapy group had a median treatment duration of 39.3 months (IQR 34.5-48.8). The combination therapy showed a significantly greater efficacy in reducing fibrosis compared to UDCA monotherapy, with an 8.3-fold increase in the regression rate (from 6.3% to 52.4%, P < 0.001). Other parameters, including biochemistry, survival rates, and prognosis, supported its effectiveness. Baseline IgG >1.3 × ULN and ALP <2.4 × ULN were identified as predictors of regression following the combination therapy. A predictive score named FRS, combining these variables, accurately identified individuals achieving fibrosis regression with a cut-off point of ≥ -0.163. The predictive value was validated internally and externally. CONCLUSION Combination therapy with IS improves outcomes in PBC patients with moderate-to-severe interface hepatitis compared to UDCA monotherapy. Baseline IgG and ALP are the most significant predictors of fibrosis regression. The new predictive score, FRS, incorporating baseline IgG and ALP, can effectively identify individuals who would benefit from the combination therapy.
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Affiliation(s)
- Rui Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qiuxiang Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Zhonghua Lu
- Department of Liver Disease, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, China
| | - Haoyu Wen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Fangqin Hu
- Division of Hepatology, The Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Jia You
- Department of Hepatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yonghong He
- Cholestatic Liver Diseases Center, Department of Gastroenterology, Southwest Hospital of Army Medical University, Chongqing, China
| | - Yuan Fang
- Department of Hepatopathy, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Zhaolian Bian
- Department of Gastroenterology and Hepatology, Nantong Third People's Hospital, The Third Affiliated Hospital of Nantong University, Nantong, China
| | - Qiuchen Hou
- Department of Liver Disease, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, China
| | - Zhaoxia Ju
- Department of Liver Disease, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, China
| | - Yanyan Wang
- Department of Gastroenterology and Hepatology, Nantong Third People's Hospital, The Third Affiliated Hospital of Nantong University, Nantong, China
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Li Sheng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Canjie Guo
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jing Hua
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiaoyu Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China; Division of Infectious Diseases, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China; Institute of Aging & Tissue Regeneration, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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14
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Chen W, Lin F, Feng X, Yao Q, Yu Y, Gao F, Zhou J, Pan Q, Wu J, Yang J, Yu J, Cao H, Li L. MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation. Asian J Pharm Sci 2024; 19:100889. [PMID: 38419761 PMCID: PMC10900800 DOI: 10.1016/j.ajps.2024.100889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 12/13/2023] [Accepted: 01/14/2024] [Indexed: 03/02/2024] Open
Abstract
Primary sclerosing cholangitis (PSC) is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis, with no curative treatment available, and liver transplantation is inevitable for end-stage patients. Human placental mesenchymal stem cell (hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis, inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease. Here, we prepared hpMSC-derived exosomes (ExoMSC) and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2-/- mice and multicellular organoids established from PSC patients. The results showed that ExoMSC ameliorated liver fibrosis in Mdr2-/- mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis, and the percentage of CD4+IL-17A+T cells was reduced both in ExoMSC-treated Mdr2-/- mice (Mdr2-/--Exo) in vivo and ExoMSC-treated Th17 differentiation progressed in vitro. Furthermore, ExoMSC improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids. Thus, our data demonstrate the anti-fibrosis effect of ExoMSC in PSC disease by inhibiting Th17 differentiation, and ameliorating the Th17-induced microenvironment, indicating the promising potential therapeutic role of ExoMSC in liver fibrosis of PSC or Th17-related diseases.
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Affiliation(s)
- Wenyi Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Feiyan Lin
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xudong Feng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qigu Yao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yingduo Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Feiqiong Gao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiahang Zhou
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qiaoling Pan
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jinfeng Yang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China
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15
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Lin W, Wang JX, Liu YJ. Optimal drug regimens for improving ALP biochemical levels in patients with primary biliary cholangitis refractory to UDCA: a systematic review and Bayesian network meta-analysis. Syst Rev 2024; 13:46. [PMID: 38287391 PMCID: PMC10823686 DOI: 10.1186/s13643-024-02460-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 01/12/2024] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND Up to 40% of UDCA-treated patients do not have an adequate clinical response. Farnesoid X receptor agonists, peroxisome proliferator-activated receptor agonists, and fibroblast growth factor 19 analogs were developed as adjunctive therapy. The aim of this network meta-analysis was to compare the efficacy of these drugs as add-on therapy for patients with primary biliary cholangitis (PBC) refractory to UDCA in improving ALP levels. METHODS We searched PubMed, Embase, Web of Science, and the Cochrane Library for eligible studies until 1 December 2023. Randomized controlled trials, cohort studies, and case-control studies comparing the efficacy of different combination treatments and UDCA monotherapy in UDCA-refractory PBC patients were included in the analysis. Cumulative probability was used to rank the included treatments. RESULTS A total of 23 articles were eligible for our network meta-analysis. In terms of improving ALP levels, In terms of improving ALP biochemical levels, bezafibrate combined with UDCA (MD 104.49, 95% CI 60.41, 161.92), fenofibrate combined with UDCA (MD 87.81, 95% CI (52.34, 129.79), OCA combined with UDCA (MD 65.21, 95% CI 8.99, 121.80), seladelpar combined with UDCA (MD 117.39, 95% CI 19.97, 213.95), elafibranor combined with UDCA (MD 140.73, 95% CI 74.34, 209.98), saroglitazar combined with UDCA (MD 132.09, 95% CI 13.99, 247.04) was more effective than UDCA monotherapy. Elafibranor in combination with UDCA was the most likely (32%) to be the optimal drug regimen. CONCLUSION As second-line therapy for UDCA-refractory PBC, PPAR agonists were more effective than any other drugs with other mechanisms in improving ALP biochemical levels, with elafibranor being the best.
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Affiliation(s)
- Wei Lin
- Department of Endoscopy Center, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Jun-Xi Wang
- Department of Endoscopy Center, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Yi-Juan Liu
- Department of Gastroenterology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
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Rigamonti C, Cittone MG, Manfredi GF, De Benedittis C, Paggi N, Baorda F, Di Benedetto D, Minisini R, Pirisi M. Spleen stiffness measurement predicts decompensation and rules out high-risk oesophageal varices in primary biliary cholangitis. JHEP Rep 2024; 6:100952. [PMID: 38192539 PMCID: PMC10772386 DOI: 10.1016/j.jhepr.2023.100952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/17/2023] [Accepted: 10/17/2023] [Indexed: 01/10/2024] Open
Abstract
Background & Aims Primary biliary cholangitis (PBC) may lead to portal hypertension (PH). Spleen stiffness measurement (SSM) by vibration-controlled transient elastography accurately predicts PH. We aimed to assess SSM role in stratifying the risk of liver decompensation in PBC. Methods In this monocentric, prospective, cross-sectional study, we included 114 patients with PBC who underwent liver stiffness measurement (LSM) and SSM. In total, 78 and 33 patients underwent two and three sequential vibration-controlled transient elastography examinations, respectively (longitudinal study). Screening for high-risk oesophageal varices by oesophagogastroduodenoscopy was performed according to guidelines and proposed to all patients with SSM >40 kPa. Results Among the 114 patients, 20 (17%) had LSM ≥10 kPa, whereas 17 (15%) had SSM >40 kPa. None of the patients with SSM ≤40 kPa had high-risk oesophageal varices, compared with three of 14 patients with SSM >40 kPa (21%; three refused endoscopy); any-size oesophageal varices were found in nine of 14 patients (64%). During a median follow-up of 15 months (IQR 10-31 months), five (4%) patients developed liver decompensation. The probability of liver decompensation was significantly higher among patients with both LSM ≥10 kPa and SSM >40 kPa: 41% at 24 months vs. 0% in other patient groups (i.e. LSM <10 kPa and SSM ≤40 kPa, or LSM ≥10 kPa and SSM ≤40 kPa, or LSM <10 kPa and SSM >40 kPa) (p <0.0001). Among the 78 patients undergoing longitudinal evaluation, four of nine patients (44%) with SSM increase during follow-up experienced liver decompensation, whereas none of those with stable LSM and SSM had liver decompensation. Conclusions Both LSM and SSM predict liver decompensation in patients with PBC. SSM ≤40 kPa rules out high-risk oesophageal varices and might be used in combination with LSM to improve the prediction of PH-related complications. Impact and implications Spleen stiffness measurement by vibration-controlled transient elastography accurately predicts portal hypertension in patients with chronic viral hepatitis. The present study is the first to demonstrate that in primary biliary cholangitis the combination of liver stiffness and spleen stiffness measurement can significantly improve risk stratification by predicting liver decompensation. Moreover, when spleen stiffness is combined with liver stiffness measurement and platelet count, it aids in identifying individuals with a low probability of having high-risk oesophageal varices, thereby allowing the avoidance of unnecessary endoscopy examinations. Further validation of our results in larger cohorts of patients with primary biliary cholangitis is needed to implement spleen stiffness measurement in clinical practice.
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Affiliation(s)
- Cristina Rigamonti
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Micol Giulia Cittone
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Giulia Francesca Manfredi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Carla De Benedittis
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Noemi Paggi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Francesca Baorda
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Davide Di Benedetto
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
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Zhang Y, Zheng T, Huang Z, Song B. CT and MR imaging of primary biliary cholangitis: a pictorial review. Insights Imaging 2023; 14:180. [PMID: 37880457 PMCID: PMC10600092 DOI: 10.1186/s13244-023-01517-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 09/03/2023] [Indexed: 10/27/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a rare chronic autoimmune-mediated cholestatic liver disease involving medium and small bile ducts that can lead to liver fibrosis and cirrhosis. To date, the pathogenesis of PBC remains elusive, and there is currently no curative medical treatment. Computed tomography (CT) and magnetic resonance (MR) imaging, as common technical tools that allow non-invasive monitoring of liver tissue in vivo, play crucial roles in the diagnosis, staging, and prognosis prediction in PBC by enabling assessment of abnormalities in liver morphology and parenchyma, irregular configuration of bile ducts, lymphadenopathy, portal hypertension, and complications of cirrhosis. Moreover, CT and MRI can be used to monitor the disease progression after treatment of PBC (e.g. the onset of cirrhotic decompensation or HCC) to guide the clinical decisions for liver transplantation. With the optimization of imaging technology, magnetic resonance elastography (MRE) offers additional information on liver stiffness, allows for the identification of early cirrhosis in PBC and provides a basis for predicting prognosis. Gadoxetic acid-enhanced MRI enables the assessment of liver function in patients with PBC. The purpose of this review is to detail and illustrate the definition, pathological basis, and clinical importance of CT and MRI features of PBC to help radiologists and clinicians enhance their understanding of PBC.Critical Relevance StatementCharacteristic CT and MR imaging manifestations of primary biliary cholangitis may reflect the course of the disease and provide information associated with histological grading and altered cellular function.Key points• Imaging has become highly useful for differentiating PBC from other diseases.• Key pathological alterations of PBC can be captured by CT and MRI.• Characteristic manifestations provide information associated with histological grade and cellular function.• Despite this, the CT or MRI features of PBC are not specific.
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Affiliation(s)
- Yun Zhang
- Department of Radiology, West China Hospital, Sichuan University, No.37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan, China
| | - Tianying Zheng
- Department of Radiology, West China Hospital, Sichuan University, No.37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan, China
| | - Zixing Huang
- Department of Radiology, West China Hospital, Sichuan University, No.37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan, China
- Department of Radiology, West China Tianfu hospital of Sichuan University, Chengdu, China
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, No.37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan, China.
- Department of Radiology, Sanya People's Hospital, Sanya, Hainan, China.
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18
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Hou C, Ren C, Luan L, Li S. A case report of primary biliary cholangitis combined with ankylosing spondylitis. Medicine (Baltimore) 2023; 102:e35655. [PMID: 37832080 PMCID: PMC10578735 DOI: 10.1097/md.0000000000035655] [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: 06/15/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
RATIONALE A chronic autoimmune liver disease known as primary biliary cholangitis (PBC) that selectively destructs small intrahepatic biliary epithelial cells and may result in biliary cirrhosis and eventually liver transplantation or death. PBC is associated with various other extrahepatic autoimmune diseases; however, the combination of PBC with ankylosing spondylitis has been rarely reported in the literature. Here, we reported a case of PBC with ankylosing spondylitis to improve our understanding of such coexistence and provide new ideas for the treatment of such patients. PATIENT CONCERNS A 54-year-old man was presented to the Department of Rheumatology because of an abnormal liver function test for 7 years, chest and back pain for 1 year, and low back pain for 2 months. DIAGNOSES Primary biliary cholangitis, ankylosing spondylitis, and old pulmonary tuberculosis. INTERVENTIONS The patient refused to use nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, and biologic disease-modifying antirheumatic drugs; thus, he was treated with methylenediphosphonate (99Tc-MDP) and ursodeoxycholic acid (UDCA). OUTCOMES The patient achieved remission with UDCA and 99Tc-MDP therapy. LESSONS In the treatment of PBC combined with other disorders, the characteristics of different diseases should be considered. The patient reported herein was treated with 99Tc-MDP and UDCA, and his condition improved; thus, we consider 99Tc-MDP to be an effective treatment. Furthermore, in line with the current understanding of the pathogenesis of PBC and ankylosing spondylitis, we hypothesize that interleukin-17 inhibitor is an effective treatment for such patients.
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Affiliation(s)
- Chunfeng Hou
- Department of Rheumatology, Jining No.1 People’s Hospital, Jining, China
| | - Chunfeng Ren
- Department of Rheumatology, Jining No.1 People’s Hospital, Jining, China
| | - Luan Luan
- Department of Rheumatology, Jining No.1 People’s Hospital, Jining, China
| | - Shujie Li
- Department of Rheumatology, Jining No.1 People’s Hospital, Jining, China
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Almeqdadi M, Gordon FD. Farnesoid X Receptor Agonists: A Promising Therapeutic Strategy for Gastrointestinal Diseases. GASTRO HEP ADVANCES 2023; 3:344-352. [PMID: 39131134 PMCID: PMC11308038 DOI: 10.1016/j.gastha.2023.09.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 09/22/2023] [Indexed: 08/13/2024]
Abstract
Farnesoid X receptor (FXR) agonists have emerged as a promising therapeutic strategy for the management of various gastrointestinal (GI) diseases, including primary biliary cholangitis, nonalcoholic fatty liver disease, inflammatory bowel disease, alcohol-related liver disease, and primary sclerosing cholangitis. In this review, we discuss the mechanisms of action of FXR agonists, including their metabolic and immunomodulatory effects, and provide an overview of the clinical evidence supporting their use in the treatment of GI diseases. We also highlight the safety, adverse effects, and potential drug interactions associated with FXR agonists. While these agents have demonstrated efficacy in improving liver function, reducing hepatic steatosis, and improving histological endpoints in primary biliary cholangitis and nonalcoholic fatty liver disease, further research is needed to determine their long-term safety and effectiveness in other GI diseases, such as inflammatory bowel disease, alcohol-related liver disease, and primary sclerosing cholangitis. Additionally, the development of next-generation FXR agonists with improved potency and reduced side effects could further enhance their therapeutic potential.
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Affiliation(s)
- Mohammad Almeqdadi
- Division of Transplantation and Hepatobiliary Diseases, Lahey Hospital & Medical Center, Burlington, Massachusetts
| | - Fredric D. Gordon
- Abdominal Transplant Institute, Tufts Medical Center, Boston, Massachusetts
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20
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Gao X, Ma H, Niu J, Li D. FcγRIIB expression increases during primary biliary cholangitis. Mol Immunol 2023; 162:30-37. [PMID: 37634276 DOI: 10.1016/j.molimm.2023.08.001] [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: 05/23/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/29/2023]
Abstract
Primary biliary cholangitis (PBC) is a severe disease with unknown aetiology and poor prognosis owing to ineffective treatment. B-cell antibodies play a regulatory role during immune responses; therefore, their role in PBC should not be overlooked. Fcγ receptors (FcγRs) of IgG and cell surface glycoproteins play an important role in autoimmune and infectious disease prevention. In this study, 60 patients with PBC and 35 healthy controls (HCs) were recruited. The number of B cells and the expression of the FcγRIIB on the peripheral blood mononuclear cells of patients with PBC were evaluated using FACS. The concentrations of soluble FcγRs were determined using ELISA, and intrahepatic FcγRIIB and CD19 expressions in patients with PBC were visualised using IHC. FcγRIIB expression in B cells was significantly higher in patients with PBC than in HCs (P < 0.0001). The soluble FcγRIIB levels in the plasma were higher in patients with PBC than in HCs (P = 0.0009). Notably, these levels were reduced by treatment with ursodeoxycholic acid (P = 0.0236). CD19 and FcγRIIB expression increased in the liver of patients with PBC relative to that in HCs. These findings can provide new insights into PBC pathogenesis and can aid the future development of treatment strategies.
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Affiliation(s)
- Xiuzhu Gao
- Department of Hepatology, First Hospital of Jilin University, Jilin University, 71 Xinmin Street, Changchun, Jilin Province 130021, China
| | - Heming Ma
- Department of Hepatology, First Hospital of Jilin University, Jilin University, 71 Xinmin Street, Changchun, Jilin Province 130021, China
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Jilin University, 71 Xinmin Street, Changchun, Jilin Province 130021, China.
| | - Dong Li
- Department of Hepatology, First Hospital of Jilin University, Jilin University, 71 Xinmin Street, Changchun, Jilin Province 130021, China; Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, China.
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21
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Marginean CM, Pirscoveanu D, Popescu M, Docea AO, Radu A, Popescu AIS, Vasile CM, Mitrut R, Marginean IC, Iacob GA, Firu DM, Mitrut P. Diagnostic Approach and Pathophysiological Mechanisms of Anemia in Chronic Liver Disease—An Overview. GASTROENTEROLOGY INSIGHTS 2023; 14:327-341. [DOI: 10.3390/gastroent14030024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Hematological abnormalities are frequently linked to chronic liver disease of any etiology. About 75% of patients with advanced chronic liver disease experience anemia. The causes of anemia are complex and multifactorial, particularly in cirrhotic patients. Acute and long-term blood loss from the upper gastrointestinal tract, malnutrition, an enlarged spleen brought on by portal hypertension, hemolysis, and coagulation issues are the main causes of anemia. Alcohol, a common cause of chronic liver disease, determines anemia through direct toxicity on the bone marrow, with the suppression of hematopoiesis, through vitamin B6, B12, and folate deficiency due to low intake and malabsorption. In patients with chronic hepatitis C virus infection, antiviral drugs such as pegylated interferon and ribavirin can also cause significant anemia. The use of interferon has been linked to bone marrow toxicity, and hemolytic anemia brought on by ribavirin is a well-known dose-dependent side effect. Within six months of the infection with hepatitis B, hepatitis C, and Epstein–Barr viruses, aplastic anemia associated with hepatitis is seen. This anemia is characterized by pancytopenia brought on by hypocellular bone marrow. Esophageal varices, portal hypertensive gastropathy, and gastric antral vascular ectasia can all cause acute and chronic blood loss. These conditions can progress to iron deficiency anemia, microcytic anemia, and hypochromic anemia. Another common hematologic abnormality in liver cirrhosis is macrocytosis, with multifactorial causes. Vitamin B12 and folate deficiency are frequent in liver cirrhosis, especially of alcoholic etiology, due to increased intestinal permeability, dysbiosis, and malnutrition. Many chronic liver diseases, like viral and autoimmune hepatitis, have a chronic inflammatory substrate. Proinflammatory cytokines, including tumor necrosis factor and interleukin 1, 6, and 10, are the main factors that diminish iron availability in progenitor erythrocytes and subsequent erythropoiesis, leading to the development of chronic inflammatory, normochromic, normocytic anemia.
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Affiliation(s)
- Cristina Maria Marginean
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Denisa Pirscoveanu
- Department of Neurology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihaela Popescu
- Department of Endocrinology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Antonia Radu
- Department of Pharmaceutical Botany, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | | | - Corina Maria Vasile
- Department of Pediatric and Adult Congenital Cardiology, Bordeaux University Hospital, 33600 Pessac, France
| | - Radu Mitrut
- Department of Cardiology, University and Emergency Hospital, 050098 Bucharest, Romania
| | | | - George Alexandru Iacob
- Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dan Mihai Firu
- Department of Medical Semiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Paul Mitrut
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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22
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Rigamonti C, De Benedittis C, Labanca S, Vanni E, Morgando A, Manfredi GF, Azzolina D, Cittone MG, Giannini EG, Saracco GM, Pirisi M. Excellent outcome in patients with primary biliary cholangitis in Northwest Italy followed up for up to 30 years. Eur J Gastroenterol Hepatol 2023; 35:899-906. [PMID: 37395243 DOI: 10.1097/meg.0000000000002582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
OBJECTIVE Primary biliary cholangitis (PBC) is a rare chronic autoimmune cholangiopathy, characterized by a variable course and response to treatment. We aimed to describe long-term outcomes of PBC patients referred to three academic centres in Northwest Italy. METHODS This is an ambispective cohort study of PBC patients (retrospective component: diagnosis before 1 January 2019; prospective component: thereafter), including 302 patients: 101 (33%) followed up in Novara, 86 (28%) in Turin, 115 (38%) in Genoa. Clinical features at diagnosis, biochemical response to therapy and survival were analyzed. RESULTS Among the 302 patients (88% women, median age 55 years, median follow-up 75 months), alkaline phosphatase (ALP) levels significantly decreased during treatment with ursodeoxycholic acid (UDCA, P < 0.0001) and obeticholic acid (P < 0.0001). At multivariate analysis, ALP at diagnosis was predictive of 1-year biochemical response to UDCA [odds ratio 3.57, 95% confidence interval (CI) 1.4-9, P < 0.001]. Estimated median survival free of liver transplantation and hepatic complications was 30 years (95% CI 19-41). Bilirubin level at diagnosis was the only independent risk factor for the combined outcome of death, transplantation or hepatic decompensation (hazard ratio, 1.65, 95% CI 1.66-2.56, P = 0.02). Patients presenting with total bilirubin at diagnosis ≥0.6 times the upper normal limit (ULN) had a significantly lower 10-year survival compared to those with bilirubin <0.6 times ULN (63% vs. 97%, P < 0.0001). CONCLUSION In PBC, both short-term response to UDCA and long-term survival can be predicted by simple conventional biomarkers of disease severity, obtained at diagnosis.
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Affiliation(s)
- Cristina Rigamonti
- Department of Translational Medicine, Università del Piemonte Orientale, Division of Internal Medicine, AOU Maggiore della Carità, Novara
| | - Carla De Benedittis
- Department of Translational Medicine, Università del Piemonte Orientale, Division of Internal Medicine, AOU Maggiore della Carità, Novara
| | - Sara Labanca
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa
| | - Ester Vanni
- SC Gastroenterology, AOU Città della Salute e della Scienza, Turin
| | - Anna Morgando
- SC Gastroenterology, AOU Città della Salute e della Scienza, Turin
| | - Giulia Francesca Manfredi
- Department of Translational Medicine, Università del Piemonte Orientale, Division of Internal Medicine, AOU Maggiore della Carità, Novara
| | - Danila Azzolina
- Department of Environment and Prevention Sciences, University of Ferrara, Ferrara, Italy
| | - Micol Giulia Cittone
- Department of Translational Medicine, Università del Piemonte Orientale, Division of Internal Medicine, AOU Maggiore della Carità, Novara
| | - Edoardo Giovanni Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa
| | | | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Division of Internal Medicine, AOU Maggiore della Carità, Novara
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Zhang D, Liu BW, Liang XQ, Liu FQ. Immunological factors in cirrhosis diseases from a bibliometric point of view. World J Gastroenterol 2023; 29:3899-3921. [PMID: 37426317 PMCID: PMC10324529 DOI: 10.3748/wjg.v29.i24.3899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 05/20/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Cirrhosis results from persistent liver injury that leads to liver fibrosis. Immunological factors play important regulatory roles in the development and progression of cirrhosis. Bibliometrics is one of the most commonly used methods for systematic evaluation of a field of study. To date, there are no bibliometric studies on the role of immunological factors in cirrhosis.
AIM To provide a comprehensive overview of the knowledge structure and research hotspots of immunological factors in cirrhosis.
METHODS We retrieved publications related to immunological factors in cirrhosis between 2003 to 2022 from the Web of Science Core Collection database on December 7, 2022. The search strategy was TS = ((Liver Cirrhosis OR hepatic cirrhosis OR liver fibrosis) AND (Immunologic* Factor* OR Immune Factor* OR Immunomodulator* OR Biological Response Modifier* OR Biomodulator*)). Only original articles and reviews were included. A total of 2873 publications were analyzed using indicators of publication and citation metrics, countries, institutes, authors, journals, references, and keywords by CiteSpace and VOSviewer.
RESULTS A total of 5104 authors from 1173 institutions across 51 countries published 2873 papers on cirrhosis and immunological factors in 281 journals. In the past 20 years, the increasing number of related annual publications and citations indicates that research on immunological factors in cirrhosis has become the focus of attention and has entered a period of accelerated development. The United States (781/27.18%), China (538/18.73%), and Germany (300/10.44%) were the leading countries in this field. Most of the top 10 authors were from the United States (4) and Germany (3), with Gershwin ME contributing the most related articles (42). World Journal of Gastroenterology was the most productive journal, whereas Hepatology was the most co-cited journal. Current research hotspots regarding immunological factors in cirrhosis include fibrosis, cirrhosis, inflammation, liver fibrosis, expression, hepatocellular carcinoma, activation, primary biliary cirrhosis, disease, and hepatic stellate cells. Burst keywords (e.g., epidemiology, gut microbiota, and pathways) represent research frontiers that have attracted the interest of researchers in recent years.
CONCLUSION This bibliometric study comprehensively summarizes the research developments and directions of immunological factors in cirrhosis, providing new ideas for promoting scientific research and clinical applications.
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Affiliation(s)
- Dan Zhang
- Department of Interventional Therapy, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Bo-Wen Liu
- Department of Interventional Therapy, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Xiao-Qing Liang
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Fu-Quan Liu
- Department of Interventional Therapy, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
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Zhang X, Zhou Y, Hu J, Yu X, Xu H, Ba Z, Zhang H, Sun Y, Wang R, Du X, Mou R, Li X, Zhu J, Xie R. Comprehensive analysis identifies cuproptosis-related gene DLAT as a potential prognostic and immunological biomarker in pancreatic adenocarcinoma. BMC Cancer 2023; 23:560. [PMID: 37330494 DOI: 10.1186/s12885-023-11042-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 06/05/2023] [Indexed: 06/19/2023] Open
Abstract
BACKGROUND Cuproptosis is a regulated cell death form associated with tumor progression, clinical outcomes, and immune response. However, the role of cuproptosis in pancreatic adenocarcinoma (PAAD) remains unclear. This study aims to investigate the implications of cuproptosis-related genes (CRGs) in PAAD by integrated bioinformatic methods and clinical validation. METHODS Gene expression data and clinical information were downloaded from UCSC Xena platform. We analyzed the expression, mutation, methylation, and correlations of CRGs in PAAD. Then, based on the expression profiles of CRGs, patients were divided into 3 groups by consensus clustering algorithm. Dihydrolipoamide acetyltransferase (DLAT) was chosen for further exploration, including prognostic analysis, co-expression analysis, functional enrichment analysis, and immune landscape analysis. The DLAT-based risk model was established by Cox and LASSO regression analysis in the training cohort, and then verified in the validation cohort. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) assays were performed to examine the expression levels of DLAT in vitro and in vivo, respectively. RESULTS Most CRGs were highly expressed in PAAD. Among these genes, increased DLAT could serve as an independent risk factor for survival. Co-expression network and functional enrichment analysis indicated that DLAT was engaged in multiple tumor-related pathways. Moreover, DLAT expression was positively correlated with diverse immunological characteristics, such as immune cell infiltration, cancer-immunity cycle, immunotherapy-predicted pathways, and inhibitory immune checkpoints. Submap analysis demonstrated that DLAT-high patients were more responsive to immunotherapeutic agents. Notably, the DLAT-based risk score model possessed high accuracy in predicting prognosis. Finally, the upregulated expression of DLAT was verified by RT-qPCR and IHC assays. CONCLUSIONS We developed a DLAT-based model to predict patients' clinical outcomes and demonstrated that DLAT was a promising prognostic and immunological biomarker in PAAD, thereby providing a new possibility for tumor therapy.
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Affiliation(s)
- Xiaoling Zhang
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yuxin Zhou
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jiahe Hu
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Xuefeng Yu
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Haitao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Zhichang Ba
- Medical Imaging Center, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Haoxin Zhang
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yanan Sun
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Rongfang Wang
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Xinlian Du
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Ruishu Mou
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Xuedong Li
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jiuxin Zhu
- Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
| | - Rui Xie
- Department of Digestive Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
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Bossen L, Lau TS, Nielsen MB, Nielsen MC, Andersen AH, Ott P, Becker S, Glerup H, Svenningsen L, Eivindson M, Kornerup L, Kjeldsen NB, Neumann A, Møller HJ, Jepsen P, Grønbæk H. The association between soluble CD163, disease severity, and ursodiol treatment in patients with primary biliary cholangitis. Hepatol Commun 2023; 7:02009842-202304010-00017. [PMID: 36972379 PMCID: PMC10043550 DOI: 10.1097/hc9.0000000000000068] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 12/09/2022] [Indexed: 03/29/2023] Open
Abstract
INTRODUCTION The macrophage activation marker soluble (s)CD163 is associated with disease severity and prognosis in patients with primary biliary cholangitis (PBC). Ursodeoxycholic acid (UDCA) treatment attenuates fibrosis progression in PBC patients, but its effect on macrophage activation is unclear. We examined the effect of UDCA on macrophage activation, as determined by sCD163 levels. METHODS We included 2 cohorts of PBC patients; 1 cohort with prevalent PBC patients, and 1 cohort of incident PBC patients before start of UDCA treatment and with follow-up after 4 weeks and 6 months. We measured sCD163 and liver stiffness in both cohorts. Further, we measured sCD163 and TNF-α shedding in vitro in monocyte-derived macrophages after UDCA and lipopolysaccharide incubation. RESULTS We included 100 patients with prevalent PBC [93% women, median age 63 y (interquartile range: 51-70)] and 47 patients with incident PBC [77% women, median age 60 y (49-67)]. Prevalent PBC patients had a lower median sCD163 of 3.54 mg/L (2.77-4.72) than incident PBC patients with a median sCD163 of 4.33 mg/L (2.83-5.99) at inclusion. Patients with an incomplete response to UDCA and patients with cirrhosis had higher sCD163 than responders to UDCA and noncirrhosis patients. After 4 weeks and 6 months of UDCA treatment median sCD163 decreased by 4.6% and 9.0%, respectively. In in vitro experiments, UDCA attenuated shedding of TNF-α, but not sCD163, from monocyte-derived macrophages. CONCLUSION In PBC patients, sCD163 levels correlated with liver disease severity and treatment response to UDCA. Further, after 6 months of UDCA treatment, we observed a decrease in sCD163, which may be related to the treatment.
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Affiliation(s)
- Lars Bossen
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Tobias Stemann Lau
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | | | - Peter Ott
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Sabine Becker
- Diagnostic Centre, University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Henning Glerup
- Diagnostic Centre, University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Lise Svenningsen
- Department of Internal Medicine, Horsens Regional Hospital, Horsens, Denmark
| | - Martin Eivindson
- Department of Internal Medicine, Horsens Regional Hospital, Horsens, Denmark
| | - Linda Kornerup
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Internal Medicine, Herning Regional Hospital, Herning, Denmark
| | | | - Anders Neumann
- Department of Internal Medicine, Viborg Regional Hospital, Viborg, Denmark
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Jepsen
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Grønbæk
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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26
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Li Y, Li Z, Chen R, Lian M, Wang H, Wei Y, You Z, Zhang J, Li B, Li Y, Huang B, Chen Y, Liu Q, Lyu Z, Liang X, Miao Q, Xiao X, Wang Q, Fang J, Shi Y, Liu X, Seldin MF, Gershwin ME, Tang R, Ma X. A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression. Nat Commun 2023; 14:1732. [PMID: 36977669 PMCID: PMC10049997 DOI: 10.1038/s41467-023-37213-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.3 locus variant(s) contributes to the pathogenesis of PBC. A genome-wide meta-analysis of 1931 PBC subjects and 7852 controls in two Han Chinese cohorts confirms the strong association between 19p13.3 locus and PBC. By integrating functional annotations, luciferase reporter assay and allele-specific chromatin immunoprecipitation, we prioritize rs2238574, an AT-Rich Interaction Domain 3A (ARID3A) intronic variant, as a potential causal variant at 19p13.3 locus. The risk allele of rs2238574 shows higher binding affinity of transcription factors, leading to an increased enhancer activity in myeloid cells. Genome-editing demonstrates the regulatory effect of rs2238574 on ARID3A expression through allele-specific enhancer activity. Furthermore, knock-down of ARID3A inhibits myeloid differentiation and activation pathway, and overexpression of the gene has the opposite effect. Finally, we find ARID3A expression and rs2238574 genotypes linked to disease severity in PBC. Our work provides several lines of evidence that a non-coding variant regulates ARID3A expression, presenting a mechanistic basis for association of 19p13.3 locus with the susceptibility to PBC.
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Affiliation(s)
- You Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Zhiqiang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
- Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China
| | - Ruiling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Hanxiao Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Yiran Wei
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Jun Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Yikang Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Bingyuan Huang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Yong Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Qiaoyan Liu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Zhuwan Lyu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Xueying Liang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Jingyuan Fang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - YongYong Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
- Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China
| | - Xiangdong Liu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, China
| | - Michael F Seldin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
- Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
- Institute of Aging & Tissue Regeneration, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Rigopoulou EI, Bogdanos DP. Role of autoantibodies in the clinical management of primary biliary cholangitis. World J Gastroenterol 2023; 29:1795-1810. [PMID: 37032725 PMCID: PMC10080701 DOI: 10.3748/wjg.v29.i12.1795] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/04/2023] [Accepted: 03/14/2023] [Indexed: 03/28/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by immune-driven destruction of small intrahepatic bile ducts leading a proportion of patients to hepatic failure over the years. Diagnosis at early stages in concert with ursodeoxycholic acid treatment has been linked with prevention of disease progression in the majority of cases. Diagnosis of PBC in a patient with cholestasis relies on the detection of disease-specific autoantibodies, including anti-mitochondrial antibodies, and disease-specific anti-nuclear antibodies targeting sp100 and gp210. These autoantibodies assist the diagnosis of the disease, and are amongst few autoantibodies the presence of which is included in the diagnostic criteria of the disease. They have also become important tools evaluating disease prognosis. Herein, we summarize existing data on detection of PBC-related autoantibodies and their clinical significance. Moreover, we provide insight on novel autoantibodies and their possible prognostic role in PBC patients.
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Affiliation(s)
- Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa 41110, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa 41110, Greece
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa 41110, Greece
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28
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Wang J, Sun Z, Xie J, Ji W, Cui Y, Ai Z, Liang G. Inflammasome and pyroptosis in autoimmune liver diseases. Front Immunol 2023; 14:1150879. [PMID: 36969233 PMCID: PMC10030845 DOI: 10.3389/fimmu.2023.1150879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 02/23/2023] [Indexed: 03/11/2023] Open
Abstract
Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and IgG4-related sclerosing cholangitis (IgG4-SC) are the four main forms of autoimmune liver diseases (AILDs), which are all defined by an aberrant immune system attack on the liver. Most previous studies have shown that apoptosis and necrosis are the two major modes of hepatocyte death in AILDs. Recent studies have reported that inflammasome-mediated pyroptosis is critical for the inflammatory response and severity of liver injury in AILDs. This review summarizes our present understanding of inflammasome activation and function, as well as the connections among inflammasomes, pyroptosis, and AILDs, thus highlighting the shared features across the four disease models and gaps in our knowledge. In addition, we summarize the correlation among NLRP3 inflammasome activation in the liver-gut axis, liver injury, and intestinal barrier disruption in PBC and PSC. We summarize the differences in microbial and metabolic characteristics between PSC and IgG4-SC, and highlight the uniqueness of IgG4-SC. We explore the different roles of NLRP3 in acute and chronic cholestatic liver injury, as well as the complex and controversial crosstalk between various types of cell death in AILDs. We also discuss the most up-to-date developments in inflammasome- and pyroptosis-targeted medicines for autoimmune liver disorders.
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Affiliation(s)
- Jixuan Wang
- School of First Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Zhiwen Sun
- Department of Liver, Spleen and Stomach Diseases, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jingri Xie
- Department of Liver, Spleen and Stomach Diseases, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Wanli Ji
- School of First Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yang Cui
- School of First Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Zongxiong Ai
- School of First Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
- *Correspondence: Guoying Liang, ; Zongxiong Ai,
| | - Guoying Liang
- Department of Liver, Spleen and Stomach Diseases, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
- *Correspondence: Guoying Liang, ; Zongxiong Ai,
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29
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Quan L, Tan J, Hua L, You X. Genetic predisposition between coronavirus disease 2019 and rheumatic diseases: A 2-sample Mendelian randomization study. Int J Rheum Dis 2023; 26:710-717. [PMID: 36890668 DOI: 10.1111/1756-185x.14624] [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: 01/10/2023] [Revised: 01/30/2023] [Accepted: 02/07/2023] [Indexed: 03/10/2023]
Abstract
OBJECTIVE The causalities between the coronavirus disease 2019 (COVID-19) and the risk of rheumatic diseases remain unclear. The purpose of this study was to investigate the causal effect of COVID-19 on rheumatic disease occurrence. METHODS Single nucleotide polymorphisms (SNPs), acquired from published genome-wide association studies, were used to perform 2-sample Mendelian randomization (MR) on cases diagnosed with COVID-19 (n = 13 464), rheumatic diseases (n = 444 199), juvenile idiopathic arthritis (JIA, n = 15 872), gout (n = 69 374), systemic lupus erythematosus (SLE, n = 3094), ankylosing spondylitis (n = 75 130), primary biliary cholangitis (PBC, n = 11 375) and primary Sjögren's syndrome (n = 95 046). Three MR methods were used in the analysis based on different heterogeneity and pleiotropy using the Bonferroni correction. RESULTS The results revealed a causality between COVID-19 and rheumatic diseases with an odds ratio (OR) of 1.010 (95% confidence interval [CI], 1.006-1.013; P = .014). In addition, we observed that COVID-19 was causally associated with an increased risk of JIA (OR 1.517; 95%CI, 1.144-2.011; P = .004), PBC (OR 1.370; 95%CI, 1.149-1.635; P = .005), but a decreased risk of SLE (OR 0.732; 95%CI, 0.590-0.908; P = .004). Using MR, 8 SNPs were identified to associate with COVID-19 and recognized as significant variables. None of them were previously reported in any other diseases. CONCLUSIONS This is the first study to use MR to explore the impact of COVID-19 on rheumatic diseases. From a genetic perspective, we found that COVID-19 could increase the risk of rheumatic diseases, such as PBC and JIA, but decrease that of SLE, thereby suggesting a potential surge in the disease burden of PBC and JIA following the COVID-19 pandemic.
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Affiliation(s)
- Liuliu Quan
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiangshan Tan
- Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and National Clinical Research Center of Cardiovascular Diseases, Beijing, China
| | - Lu Hua
- Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and National Clinical Research Center of Cardiovascular Diseases, Beijing, China
| | - Xin You
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China
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30
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Buzzao D, Castresana-Aguirre M, Guala D, Sonnhammer ELL. TOPAS, a network-based approach to detect disease modules in a top-down fashion. NAR Genom Bioinform 2022; 4:lqac093. [PMCID: PMC9706483 DOI: 10.1093/nargab/lqac093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/14/2022] [Accepted: 11/15/2022] [Indexed: 12/02/2022] Open
Abstract
A vast scenario of potential disease mechanisms and remedies is yet to be discovered. The field of Network Medicine has grown thanks to the massive amount of high-throughput data and the emerging evidence that disease-related proteins form ‘disease modules’. Relying on prior disease knowledge, network-based disease module detection algorithms aim at connecting the list of known disease associated genes by exploiting interaction networks. Most existing methods extend disease modules by iteratively adding connector genes in a bottom-up fashion, while top-down approaches remain largely unexplored. We have created TOPAS, an iterative approach that aims at connecting the largest number of seed nodes in a top-down fashion through connectors that guarantee the highest flow of a Random Walk with Restart in a network of functional associations. We used a corpus of 382 manually selected functional gene sets to benchmark our algorithm against SCA, DIAMOnD, MaxLink and ROBUST across four interactomes. We demonstrate that TOPAS outperforms competing methods in terms of Seed Recovery Rate, Seed to Connector Ratio and consistency during module detection. We also show that TOPAS achieves competitive performance in terms of biological relevance of detected modules and scalability.
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Affiliation(s)
- Davide Buzzao
- Department of Biochemistry and Biophysics, Stockholm University, Science for Life Laboratory, Box 1031, 171 21 Solna, Sweden
| | | | - Dimitri Guala
- Department of Biochemistry and Biophysics, Stockholm University, Science for Life Laboratory, Box 1031, 171 21 Solna, Sweden
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Chen R, Tang R, Ma X, Gershwin ME. Immunologic Responses and the Pathophysiology of Primary Biliary Cholangitis. Clin Liver Dis 2022; 26:583-611. [PMID: 36270718 DOI: 10.1016/j.cld.2022.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis. A recent X-wide association study reveals a novel risk locus on the X chromosome, which reiterates the importance of Treg cells.
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Affiliation(s)
- Ruiling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
| | - M Eric Gershwin
- Division of Rheumatology-Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
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Conde de la Rosa L, Goicoechea L, Torres S, Garcia-Ruiz C, Fernandez-Checa JC. Role of Oxidative Stress in Liver Disorders. LIVERS 2022; 2:283-314. [DOI: 10.3390/livers2040023] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Oxygen is vital for life as it is required for many different enzymatic reactions involved in intermediate metabolism and xenobiotic biotransformation. Moreover, oxygen consumption in the electron transport chain of mitochondria is used to drive the synthesis of ATP to meet the energetic demands of cells. However, toxic free radicals are generated as byproducts of molecular oxygen consumption. Oxidative stress ensues not only when the production of reactive oxygen species (ROS) exceeds the endogenous antioxidant defense mechanism of cells, but it can also occur as a consequence of an unbalance between antioxidant strategies. Given the important role of hepatocytes in the biotransformation and metabolism of xenobiotics, ROS production represents a critical event in liver physiology, and increasing evidence suggests that oxidative stress contributes to the development of many liver diseases. The present review, which is part of the special issue “Oxidant stress in Liver Diseases”, aims to provide an overview of the sources and targets of ROS in different liver diseases and highlights the pivotal role of oxidative stress in cell death. In addition, current antioxidant therapies as treatment options for such disorders and their limitations for future trial design are discussed.
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Affiliation(s)
- Laura Conde de la Rosa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
| | - Leire Goicoechea
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
| | - Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
| | - Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
- Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - José C. Fernandez-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
- Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Shahini E, Pasculli G, Mastropietro A, Stolfi P, Tieri P, Vergni D, Cozzolongo R, Pesce F, Giannelli G. Network Proximity-Based Drug Repurposing Strategy for Early and Late Stages of Primary Biliary Cholangitis. Biomedicines 2022; 10:1694. [PMID: 35884999 PMCID: PMC9312896 DOI: 10.3390/biomedicines10071694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 06/03/2022] [Accepted: 07/11/2022] [Indexed: 11/30/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic, cholestatic, immune-mediated, and progressive liver disorder. Treatment to preventing the disease from advancing into later and irreversible stages is still an unmet clinical need. Accordingly, we set up a drug repurposing framework to find potential therapeutic agents targeting relevant pathways derived from an expanded pool of genes involved in different stages of PBC. Starting with updated human protein-protein interaction data and genes specifically involved in the early and late stages of PBC, a network medicine approach was used to provide a PBC "proximity" or "involvement" gene ranking using network diffusion algorithms and machine learning models. The top genes in the proximity ranking, when combined with the original PBC-related genes, resulted in a final dataset of the genes most involved in PBC disease. Finally, a drug repurposing strategy was implemented by mining and utilizing dedicated drug-gene interaction and druggable genome information knowledge bases (e.g., the DrugBank repository). We identified several potential drug candidates interacting with PBC pathways after performing an over-representation analysis on our initial 1121-seed gene list and the resulting disease-associated (algorithm-obtained) genes. The mechanism and potential therapeutic applications of such drugs were then thoroughly discussed, with a particular emphasis on different stages of PBC disease. We found that interleukin/EGFR/TNF-alpha inhibitors, branched-chain amino acids, geldanamycin, tauroursodeoxycholic acid, genistein, antioestrogens, curcumin, antineovascularisation agents, enzyme/protease inhibitors, and antirheumatic agents are promising drugs targeting distinct stages of PBC. We developed robust and transparent selection mechanisms for prioritizing already approved medicinal products or investigational products for repurposing based on recognized unmet medical needs in PBC, as well as solid preliminary data to achieve this goal.
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Affiliation(s)
- Endrit Shahini
- National Institute of Research IRCCS “Saverio De Bellis”, Castellana Grotte, 70013 Bari, Italy; (R.C.); (G.G.)
| | - Giuseppe Pasculli
- Department of Computer, Control and Management Engineering Antonio Ruberti (DIAG), Sapienza University of Rome, 00185 Rome, Italy; (G.P.); (A.M.)
| | - Andrea Mastropietro
- Department of Computer, Control and Management Engineering Antonio Ruberti (DIAG), Sapienza University of Rome, 00185 Rome, Italy; (G.P.); (A.M.)
| | - Paola Stolfi
- National Research Council (CNR), Institute for Applied Computing (IAC), 00185 Rome, Italy; (P.S.); (P.T.); (D.V.)
| | - Paolo Tieri
- National Research Council (CNR), Institute for Applied Computing (IAC), 00185 Rome, Italy; (P.S.); (P.T.); (D.V.)
| | - Davide Vergni
- National Research Council (CNR), Institute for Applied Computing (IAC), 00185 Rome, Italy; (P.S.); (P.T.); (D.V.)
| | - Raffaele Cozzolongo
- National Institute of Research IRCCS “Saverio De Bellis”, Castellana Grotte, 70013 Bari, Italy; (R.C.); (G.G.)
| | - Francesco Pesce
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari “A. Moro”, 70121 Bari, Italy;
| | - Gianluigi Giannelli
- National Institute of Research IRCCS “Saverio De Bellis”, Castellana Grotte, 70013 Bari, Italy; (R.C.); (G.G.)
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Zhang S, Tao X, Wang L, Chen H, Zhao L, Sun J, Bian S, Chen Z, Shao T, Yang Y, Li Y, Zhang F. Downregulation of Programmed Death-1 Pathway Promoting CD8 + T Cell Cytotoxicity in Primary Biliary Cholangitis. Dig Dis Sci 2022; 67:2981-2993. [PMID: 34392493 DOI: 10.1007/s10620-021-07165-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 07/07/2021] [Indexed: 01/21/2023]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is an autoimmune disease. CD8 + T cell (CTLs) cytotoxicity played a crucial rule in of PBC with unclear detailed pathogenesis. AIMS The role of the programmed death-1 (PD-1) pathway in CD8 + T cell cytotoxicity in patients with PBC was determined. METHODS We recruited 69 patients with PBC and 57 healthy controls (HCs). PD-1 pathway in peripheral CD8 + T cells and related cytokines were detected, and gene expression levels were detected. Immunofluorescence staining of PD-1/PD-L1 was performed on liver tissue. PD-1 ± CTLs were cocultured with human intrahepatic biliary epithelial cells (HiBECs) to measure CTL cytotoxicity, proliferation and cytokine levels and HiBEC apoptosis. The upstream signaling pathway of PD-1 was detected. RESULTS PBC patients exhibited Tbet gene upregulation and PD-1 downregulation in CTLs, with PD-1 expression reduced in CTLs and PD-L1 reduced in the liver portal region relative to HCs. Higher plasma IL-10, interferon-γ and transforming growth factor-β concentrations were observed in the PBC group than the HC group. In CTL and HiBEC coculture experiment, compared with PD-1- CTLs, PD-1 + CTLs exhibited weaker cytotoxicity, less proliferation and lower cytokine production. When the system was blocked by anti-PD-1 antibodies, these effects were antagonized. CONCLUSIONS PD-1 expression in CD8 + T cells decreased, and PD-1 pathway-related cytokines changed in patients with PBC. PD-1/PD-L1 pathway silencing increased CD8 + T cell proliferation, related cytokine production and CTL cytotoxic effects on HiBECs in coculture experiment. The PD-1/PD-L1 pathway might represent an important pathway in the immunological mechanism underlying PBC.
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Affiliation(s)
- Shuo Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xixi Tao
- Department of Ultrasound, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Li Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Hua Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Liling Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Jinlei Sun
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Sainan Bian
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Zhilei Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Tihong Shao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yunjiao Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yongzhe Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.
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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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The Proinflammatory Cytokines IL-18, IL-21, and IFN-γ Differentially Regulate Liver Inflammation and Anti-Mitochondrial Antibody Level in a Murine Model of Primary Biliary Cholangitis. J Immunol Res 2022; 2022:7111445. [PMID: 35300072 PMCID: PMC8922149 DOI: 10.1155/2022/7111445] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/31/2021] [Accepted: 01/06/2022] [Indexed: 11/18/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a cholestatic liver disease primarily featured by autoimmune-mediated damage of intrahepatic small- and medium-sized bile ducts. Elevated serum proinflammatory cytokines, serum anti-mitochondrial antibodies (AMAs), liver inflammation, and fibrosis are also hallmarks of PBC disease. However, whether the elevated proinflammatory cytokines play a role in autoimmune cholangitis remains unknown. Herein, we utilized the p40-/-IL-2Rα-/- PBC mouse model to investigate the roles of proinflammatory cytokines IL-18, IL-21, and IFN-γ in the onset and progression of PBC. IL-18-/-, IFN-γ-/-, and IL-21-/- mice were crossed with p40-/-IL-2Ra+/- mice, respectively, to produce corresponding cytokine-deficient PBC models. Autoantibody level, liver inflammation, and bile duct injury were analyzed. We found that livers from p40-/-IL-2Rα-/- mice exhibit similar transcriptomic characters of PBC patients. In p40-/-IL-2Rα-/- mice, deletion of IL-18 has no remarkable effect on disease progression, while deletion of IL-21 indicates that it is necessary for AMA production but independent of liver inflammation and cholangitis. IFN-γ is responsible for both AMA production and liver inflammation in our model. Our results demonstrate that different proinflammatory cytokines can regulate different effector functions in PBC pathogenesis and need to be considered in PBC treatment.
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You H, Ma X, Efe C, Wang G, Jeong SH, Abe K, Duan W, Chen S, Kong Y, Zhang D, Wei L, Wang FS, Lin HC, Yang JM, Tanwandee T, Gani RA, Payawal DA, Sharma BC, Hou J, Yokosuka O, Dokmeci AK, Crawford D, Kao JH, Piratvisuth T, Suh DJ, Lesmana LA, Sollano J, Lau G, Sarin SK, Omata M, Tanaka A, Jia J. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis. Hepatol Int 2022; 16:1-23. [PMID: 35119627 PMCID: PMC8843914 DOI: 10.1007/s12072-021-10276-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, Mainland, China
| | - Cumali Efe
- Department of Gastroenterology, Gazi Yaşargil Education and Research Hospital, Diyarbakir, Turkey
| | - Guiqiang Wang
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, Mainland, China
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Clinical Research Institute, Beijing, Mainland, China
| | - Lai Wei
- Hepatobiliary Pancreatic Center, Tsinghua Changgung Hospital, Tsinghua University, Beijing, Mainland, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospial, Beijing, Mainland, China
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jin Mo Yang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rino A. Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Diana A. Payawal
- Department of Medicine, Fatima University Medical Center, Manila, Philippines
| | | | - Jinlin Hou
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Mainland, China
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - A. Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Darrell Crawford
- School of Medicine, University of Queensland, Brisbane, Australia
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand
| | - Dong Jin Suh
- Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
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Liu Y, Tian S, Jia G, Han Z, Guo C, Shang Y, Han Y. Symptoms Burden and Health-related Quality of Life in Chinese Patients with Primary Biliary Cholangitis. J Clin Transl Hepatol 2021; 9:860-867. [PMID: 34966649 PMCID: PMC8666377 DOI: 10.14218/jcth.2020.00119] [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: 11/15/2020] [Revised: 03/04/2021] [Accepted: 04/09/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Primary biliary cholangitis (PBC) is a chronic liver disease that negatively affects the health-related quality of life (HRQoL) of patients. Furthermore, the HRQoL of Chinese patients has been neglected for a long time. The present study aimed to assess the HRQoL of Chinese patients with PBC and explore the clinical variables correlating to the improvement of itch and fatigue. METHODS This was an observational, cross-sectional study. The PBC-40 and itch numerical rating scales were used to evaluate the symptoms and HRQoL of patients. RESULTS A total of 383 patients were recruited, and 86.4% were female, with a median age of 55 years (range: 49-63 years). We found that females had significantly higher scores than males in symptoms (p=0.033) and cognitive domains (p=0.021), and the fatigue domain was higher in elderly patients (p=0.007). Meanwhile, patients whose body mass index was <18.5 had the highest scores in the symptoms (p=0.009), fatigue (p=0.010), and cognitive (p=0.019) domains. Age at participation (odds ratio [OR]=1.068, p=0.015) and albumin level at 12 months after ursodeoxycholic acid treatment (OR=208.807, p=0.025) were independent factors that affected the improvement of the itch and fatigue domains, respectively. CONCLUSIONS The HRQoL of Chinese patients with PBC was significantly impaired depending on sex, age, and body mass index. Age and albumin level were significantly associated with the improvement of itch and fatigue, respectively. Therefore, treatment and support aimed at these two factors can be provided to improve the HRQoL of patients.
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Affiliation(s)
| | | | | | | | | | - Yulong Shang
- Correspondence to: Ying Han and Yulong Shang, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi’an, Shaanxi 710032, China. ORCID: https://orcid.org/0000-0003-3046-9507 (YH) and https://orcid.org/0000-0002-8576-3175 (YS). Tel: +86 29 84771509; Fax: +86 29 82539041; E-mail: (YH) or (YS)
| | - Ying Han
- Correspondence to: Ying Han and Yulong Shang, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Air Force Military Medical University, Xi’an, Shaanxi 710032, China. ORCID: https://orcid.org/0000-0003-3046-9507 (YH) and https://orcid.org/0000-0002-8576-3175 (YS). Tel: +86 29 84771509; Fax: +86 29 82539041; E-mail: (YH) or (YS)
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The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude. Clin Gastroenterol Hepatol 2021; 19:2587-2596. [PMID: 33493696 PMCID: PMC8661127 DOI: 10.1016/j.cgh.2021.01.029] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 01/05/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases' rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude. METHODS We performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees. RESULTS The cohort included 8,590,421 records with 53.3 × 107 years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34-2.60); PSC, 0.74 (95% CI, 0.67-0.82); and AIH, 1.94 (95% CI, 1.83-2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79-2.60) to 4.86 (95% CI, 3.93-6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65-2.43) to 3.28 (95% CI, 2.53-4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60-1.11) to 1.02 (95% CI, 0.64-1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude. CONCLUSIONS We describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation.
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Early histopathologic changes in primary biliary cholangitis: does 'minimal change' primary biliary cholangitis exist? A pathologist's view. Eur J Gastroenterol Hepatol 2021; 33:e7-e12. [PMID: 32804848 DOI: 10.1097/meg.0000000000001876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an autoimmune, slowly progressive, cholestatic liver disease characterized by nonsuppurative destructive cholangitis, and interlobular bile duct destruction. Necroinflammatory activities of the hepatic parenchyma and limiting plates of milder form along with late liver fibrosis may develop. Serum liver tests include elevated serum alkaline phosphatase along with a positive antimitochondrial antibody (AMA) in nearly 95% of patients. Liver biopsies are an important confirmatory and staging tool and are additionally very helpful when AMA is negative. More specifically, the earliest changes in liver biopsy suspicious for PBC can be detected, namely loss of the canals of Hering (CoH), as proposed by various authors recently. CoH loss has been described as an early feature of PBC. We focus on early histologic features of PBC, investigating through the literature the possible role of 'minimal change' supporting the clinical diagnosis of PBC, even in the absence of characteristic granulomatous duct destructive lesions.
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Cyr61 Alleviates Cholangitis by Inhibiting Cytotoxic Effects of CD8 + T Cells on Biliary Epithelial Cells. Curr Med Sci 2021; 41:1205-1213. [PMID: 34787784 DOI: 10.1007/s11596-021-2458-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 03/11/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Primary biliary cholangitis (PBC) is a chronic progressive cholestatic liver disease. In recent years, researchers have found that cysteine-rich angiogenic inducer 61 (Cyr61, also known as CCN1) has a potential role in reducing portal inflammation in patients with PBC. This study aimed to explore the relationship between Cyr61 and PBC to provide new ideas and an experimental basis for the clinical treatment of PBC. METHODS After induction of the overexpression of Cyr61 in a mouse model of PBC using recombinant adenovirus, hematoxylin and eosin staining and pathological scores were used to indicate intrahepatic inflammation and bile duct damage. Real-time PCR was used to detect changes in inflammation-related cytokines in the liver. To further study the mechanism, we assessed whether Cyr61 protects bile duct epithelial cells from cytotoxic effects. RESULTS Serum and hepatic Cyr61 levels were increased in the murine model of PBC. Overexpression of Cyr61 alleviated hepatic inflammation and bile duct injury in vivo. Cyr61 inhibited the cytotoxic effects of CD8+ T cells by acting on biliary epithelial cells (BECs) in vitro. CONCLUSION Our results provide novel insight into the pathogenesis of PBC and suggest that Cyr61 plays a dominant role in the cytotoxic effects on BECs in PBC. Consequently, therapeutic strategies targeting Cyr61 could be a potent therapy for PBC.
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Abbas Z, Asim M, Saeed A, Siddiqui B, Abbas M. The Spectrum of Autoimmune Liver Disorders, Clinical Presentation, and Autoantibodies in Patients From a Tertiary Care Center in Pakistan. Cureus 2021; 13:e19789. [PMID: 34820249 PMCID: PMC8606176 DOI: 10.7759/cureus.19789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2021] [Indexed: 01/10/2023] Open
Abstract
Background The autoimmune illnesses that affect the liver include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and overlap syndrome. In our patients, we aimed to address the complete spectrum of autoimmune liver disorders, clinical presentation, and autoantibodies. Methods The study included all the patients diagnosed with autoimmune liver disorder irrespective of age, gender, and ethnic background presented at the liver clinic of the hospital in the last two years. The diagnosis was based on characteristic clinical and laboratory findings, the presence of one or more characteristic autoantibodies, and/or histological abnormalities. The diagnosis of AIH was further validated by revised International AIH Group criteria using a scoring calculator. The diagnostic criteria for PBC required the presence of chronic elevation of alkaline phosphatase (ALP) with positive antimitochondrial antibody (AMA) or positive PBC-specific anti-nuclear antibodies (ANA) (sp-100, gp-210) tests and/or compatible histology. The patients of AIH-PBC overlap syndrome fulfilled the criteria for AIH in the setting of PBC. Patients having liver involvement in other autoimmune disorders were included in the study. Results The total number of patients was 124; 83 (67%) were females; mean age ± standard error of mean (SEM) was 44.97 ± 1.47 years with a range of 09-84 years. Type-1 AIH was seen in 68 (54.8%) patients, type-2 AIH in 10 (8.1%) patients, PBC in 22 (17.7%) patients, overlap of PBC with AIH in 10 (8.1%) patients, IgG4 disease in four (3.2%) patients, psoriasis-specific immune hepatitis in four (3.2%) patients, celiac disease-related hepatitis in three (2.4%) patients, sarcoidosis in two (1.6%) patients, and ichthyosis-associated hepatitis in one (0.8%) patient. There was a high prevalence of cirrhosis (50%) at the time of presentation; 19% of patients had decompensated liver disease. ANA was positive in 52/68 cases of AIH type-1, but anti-smooth muscle antibody (ASMA) was reactive only in nine cases and anti-soluble liver antigen (SLA) in five cases. There was no female preponderance in type-2 AIH (M:F = 6:4). AMA was reactive in 25 (78%) cases of PBC and overlap syndrome. Antibodies prevalent in PBC (AMA-M2, AMA-M2-3E, sp-100, gp-210, anti-Ro52) were also seen in some cases of AIH, though they did not fulfill the criteria of the overlap syndrome. Conclusion There is an unmet need for the early diagnosis of autoimmune liver diseases and the initiation of appropriate management to prevent complications.
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Affiliation(s)
- Zaigham Abbas
- Gastroenterology and Hepatology, Dr. Ziauddin University Hospital, Karachi, PAK
| | - Muhammad Asim
- Gastroenterology, Dr. Ziauddin University Hospital, Karachi, PAK
| | - Alina Saeed
- Internal Medicine, Dr. Ziauddin University Hospital, Karachi, PAK
| | - Basit Siddiqui
- Gastroenterology, Fazaia Ruth Pfau Medical College, Karachi, Karachi, PAK
| | - Minaam Abbas
- Internal Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, GBR
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Patel AM, Liu YS, Davies SP, Brown RM, Kelly DA, Scheel-Toellner D, Reynolds GM, Stamataki Z. The Role of B Cells in Adult and Paediatric Liver Injury. Front Immunol 2021; 12:729143. [PMID: 34630404 PMCID: PMC8495195 DOI: 10.3389/fimmu.2021.729143] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022] Open
Abstract
B lymphocytes are multitasking cells that direct the immune response by producing pro- or anti-inflammatory cytokines, by presenting processed antigen for T cell activation and co-stimulation, and by turning into antibody-secreting cells. These functions are important to control infection in the liver but can also exacerbate tissue damage and fibrosis as part of persistent inflammation that can lead to end stage disease requiring a transplant. In transplantation, immunosuppression increases the incidence of lymphoma and often this is of B cell origin. In this review we bring together information on liver B cell biology from different liver diseases, including alcohol-related and metabolic fatty liver disease, autoimmune hepatitis, primary biliary and primary sclerosing cholangitis, viral hepatitis and, in infants, biliary atresia. We also discuss the impact of B cell depletion therapy in the liver setting. Taken together, our analysis shows that B cells are important in the pathogenesis of liver diseases and that further research is necessary to fully characterise the human liver B cell compartment.
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Affiliation(s)
- Arzoo M. Patel
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Yuxin S. Liu
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Scott P. Davies
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Rachel M. Brown
- Department of Histopathology, Queen Elizabeth Hospital, Birmingham Women’s and Children’s National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Deirdre A. Kelly
- The Liver Unit, Birmingham Women’s and Children’s Hospital and the University of Birmingham, Birmingham, United Kingdom
| | - Dagmar Scheel-Toellner
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Gary M. Reynolds
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- The Liver Unit, Birmingham Women’s and Children’s Hospital and the University of Birmingham, Birmingham, United Kingdom
| | - Zania Stamataki
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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Interleukin-30 Suppresses Not Only CD4 + T Cells but Also Regulatory T Cells in Murine Primary Biliary Cholangitis. Biomedicines 2021; 9:biomedicines9081031. [PMID: 34440235 PMCID: PMC8392158 DOI: 10.3390/biomedicines9081031] [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: 07/01/2021] [Revised: 08/03/2021] [Accepted: 08/11/2021] [Indexed: 11/30/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic liver autoimmune disease with augmented T helper (Th) 1 and corresponding cytokine IFN-γ immune responses. Using 2-octynoic acid (2-OA) coupled to OVA (2-OA-OVA)-induced mouse models of autoimmune cholangitis (inducible chemical xenobiotic models of PBC), our previous study demonstrated that overexpression of IFN-γ in the model mice enhanced liver inflammation upon disease initiation, but subsequently led to the suppression of chronic inflammation with an increase in interleukin-30 (IL-30) levels. In this study, we investigated whether IL-30 had an immunosuppressive function and whether it could be part of an immune therapeutic regimen for PBC, by treating model mice with murine IL-30-expressing recombinant adeno-associated virus (AAV-mIL-30). We first defined the effects of AAV-mIL-30 in vivo by administering it to a well-known concanavalin A (ConA)-induced hepatitis model of mice and found that AAV-mIL-30 reduced the numbers of activated CD25+CD4+ T cells and the levels of serum IFN-γ and IL-12. In autoimmune cholangitis, decreased numbers of activated CD4+ T cells and Foxp3+ regulatory T cells were noted in the mice treated with AAV-mIL-30 at 3 weeks after the 2-OA-OVA immunization. Treatment with IL-30 did not change the features of autoimmune cholangitis including autoantibodies, cell infiltration, and collagen deposition in the liver at 11 weeks of examination. However, increased levels of cytokines and chemokines were observed. These results suggest that IL-30 suppresses not only CD4+ T cells but also regulatory T cells. Additionally, the administration of IL-30 did not suppress liver inflammation in the murine model of PBC.
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McClure T, Cui W, Asadi K, John T, Testro A. Case of nivolumab-induced sclerosing cholangitis: lessons from long-term follow-up. BMJ Open Gastroenterol 2021; 7:bmjgast-2020-000487. [PMID: 32912846 PMCID: PMC7484867 DOI: 10.1136/bmjgast-2020-000487] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 12/19/2022] Open
Abstract
Nivolumab is an immune checkpoint inhibitor used to treat multiple solid-organ malignancies. While many of its immune-related adverse events are well established, nivolumab-induced sclerosing cholangitis remains poorly characterised, with no defined diagnostic criteria. Moreover, data regarding long-term outcomes are particularly lacking. We present a biopsy-proven case of nivolumab-induced sclerosing cholangitis, which uniquely captures 18 months of follow-up post-treatment. Our case highlights key features of intrahepatic subtype sclerosing cholangitis and suggests durable response to corticosteroid therapy.
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Affiliation(s)
- Tess McClure
- Gastroenterology, Austin Health, Heidelberg, Victoria, Australia .,Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Wanyuan Cui
- Medicine, The University of Melbourne, Melbourne, Victoria, Australia.,Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Khashayar Asadi
- Anatomical Pathology, Austin Health, Heidelberg, Victoria, Australia
| | - Thomas John
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Adam Testro
- Gastroenterology, Austin Health, Heidelberg, Victoria, Australia.,Medicine, The University of Melbourne, Melbourne, Victoria, Australia
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Leitch AC, Ibrahim I, Abdelghany TM, Charlton A, Roper C, Vidler D, Palmer JM, Wilson C, Jones DE, Blain PG, Wright MC. The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver. Toxicology 2021; 459:152854. [PMID: 34271081 PMCID: PMC8366605 DOI: 10.1016/j.tox.2021.152854] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/28/2021] [Accepted: 07/07/2021] [Indexed: 12/14/2022]
Abstract
M8OI was recently found to be contaminating the environment. M8OI was detected in the sera from 5/20 PBC patients and 1/10 controls. M8OI is taken up by human liver hepatocytes. M8OI is sequentially metabolised by CYPs followed by oxidation by dehydrogenases. The final carboxylic acid metabolite COOH7IM is, in part, excreted into human bile. A methylimidizolium ionic liquid (M8OI) was recently found to be contaminating the environment and to be related to and/or potentially a component of an environmental trigger for the autoimmune liver disease primary biliary cholangitis (PBC). The aims of this study were to investigate human exposure to M8OI, hepatic metabolism and excretion. PBC patient and control sera were screened for the presence of M8OI. Human livers were perfused with 50μM M8OI in a closed circuit and its hepatic disposition examined. Metabolism was examined in cultured human hepatocytes and differentiated HepaRG cells by the addition of M8OI and metabolites in the range 10–100 μM. M8OI was detected in the sera from 5/20 PBC patients and 1/10 controls. In perfused livers, M8OI was cleared from the plasma with its appearance – primarily in the form of its hydroxylated (HO8IM) and carboxylated (COOH7IM) products – in the bile. Metabolism was reflected in cultured hepatocytes with HO8IM production inhibited by the cytochrome P450 inhibitor ketoconazole. Further oxidation of HO8IM to COOH7IM was sequentially inhibited by the alcohol and acetaldehyde dehydrogenase inhibitors 4-methyl pyrazole and disulfiram respectively. Hepatocytes from 1 donor failed to metabolise M8OI to COOH7IM over a 24 h period. These results demonstrate exposure to M8OI in the human population, monooxygenation by cytochromes P450 followed by alcohol and acetaldehyde dehydrogenase oxidation to a carboxylic acid that are excreted, in part, via the bile in human liver.
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Affiliation(s)
- Alistair C Leitch
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Ibrahim Ibrahim
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom
| | - Tarek M Abdelghany
- Institute of Translation and Clinical Research, 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
| | - Alex Charlton
- School of Natural and Environmental Sciences, Bedson Building, Newcastle University, NE1 8QB, United Kingdom
| | - Clair Roper
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Dan Vidler
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Jeremy M Palmer
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Colin Wilson
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom
| | - David E Jones
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Peter G Blain
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Matthew C Wright
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom.
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Huang MX, Yang SY, Luo PY, Long J, Liu QZ, Wang J, He Y, Li L, Zhao ZB, Lian ZX. Gut microbiota contributes to sexual dimorphism in murine autoimmune cholangitis. J Leukoc Biol 2021; 110:1121-1130. [PMID: 34047390 DOI: 10.1002/jlb.3ma0321-037r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/29/2021] [Accepted: 05/09/2021] [Indexed: 12/16/2022] Open
Abstract
The data demonstrated that a transgenic murine model of primary biliary cholangitis (PBC), expressing dominant negative TGF-β receptor Ⅱ (dnTGFβRⅡ) under the CD4 promoter, showed similarity to PBC patients that is female-dominant. Female dnTGFβRII mice developed more severe lymphocytic infiltration in the liver and had higher levels of inflammatory cytokines, including IFN-γ and TNF-α, than the male mice. Interestingly, elimination of testosterone through gonadectomy in male dnTGFβRII mice did not influence disease severity, supporting that testosterone is an unessential factor in sustaining liver immune homeostasis. Meanwhile, it was observed that treating dnTGFβRII mice with oral antibiotics markedly reduced the differences in the levels of lymphocytic infiltration and cytokines between males and females, suggesting that the commensal gut microbiome plays a role in determining the observed sexual differences in dnTGFβRII mice. Furthermore, the diversity of gut microbiota composition and their metabolic functions in the male and female groups through metagenomic sequencing analysis were identified. The results revealed a testosterone-independent and commensal gut microbiota-mediated female bias in PBC.
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Affiliation(s)
- Meng-Xing Huang
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
| | - Si-Yu Yang
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
| | - Pan-Yue Luo
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jie Long
- Department of Thoracic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Qing-Zhi Liu
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jinjun Wang
- College of Environmental Science and Engineering, Yangzhou University, Yangzhou, Jiangsu, China
| | - Yi He
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Liang Li
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhi-Bin Zhao
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhe-Xiong Lian
- Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China
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Li H, Guan Y, Han C, Zhang Y, Liu Q, Wei W, Ma Y. The pathogenesis, models and therapeutic advances of primary biliary cholangitis. Biomed Pharmacother 2021; 140:111754. [PMID: 34044277 DOI: 10.1016/j.biopha.2021.111754] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/30/2022] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease characterized by the destruction of intrahepatic small bile ducts and the presence of antimitochondrial antibody (AMA), eventually progresses to liver fibrosis and cirrhosis. Genetic predisposition and environmental factors are involved in the occurrence of PBC, and the epitopes exposure and the imbalance of autoimmune tolerance are the last straw. The apoptosis of biliary epithelial cell (BEC) leads to the release of autoantigen epitopes, which activate the immune system, and the disorder of innate and adaptive immunity eventually leads to the start of disease. Animal models have unique advantages in investigating the pathogenesis and drug exploitation of PBC. Multiple models have been reported, and spontaneous model and induced model have been widely used in relevant research of PBC in recent years. Currently, the only drugs licensed for PBC are ursodesoxycholic acid (UDCA) and obeticholic acid (OCA). In the last few years, as the learned more about the pathogenesis of PBC, more and more targets have been discovered, and multiple targeted drugs are being in developed. In this review, the pathogenesis, murine models and treatment strategies of PBC were summarized, and the current research status was discussed to provide insights for the further study of PBC.
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Affiliation(s)
- Hao Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Yanling Guan
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Chenchen Han
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Yu Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Qian Liu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China.
| | - Yang Ma
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China.
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Mulinacci G, Palermo A, Invernizzi P, Carbone M. Old and novel prognostic biomarkers in primary biliary cholangitis. Expert Opin Orphan Drugs 2021. [DOI: 10.1080/21678707.2021.1927700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- G Mulinacci
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - A Palermo
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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50
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Amir M, Parekh SM. Classic Autoimmune Liver Disorders and Celiac Hepatitis. Clin Liver Dis (Hoboken) 2021; 17:347-352. [PMID: 34136140 PMCID: PMC8177834 DOI: 10.1002/cld.1056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/29/2020] [Accepted: 10/11/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Muhammad Amir
- Division of Digestive Diseases Department of Medicine Emory University School of Medicine Atlanta GA
| | - Samir M Parekh
- Division of Digestive Diseases Department of Medicine Emory University School of Medicine Atlanta GA
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