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Miller PN, Baskaran S, Nijagal A. Immunology of Biliary Atresia. Semin Pediatr Surg 2025; 33:151474. [PMID: 39862687 DOI: 10.1016/j.sempedsurg.2025.151474] [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: 10/01/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025]
Abstract
Biliary atresia is a progressive neonatal cholangiopathy that leads to liver failure. Characterized by inflammation-mediated liver injury, the immune system plays a critical role in the pathogenesis of this disease. Though several types of immune cells and mediators have been implicated in animal models of biliary atresia, emerging literature reflects the complex interplay of components of the immune response that contributes to disease progression in humans. Novel therapies targeting the immune system are needed to mitigate the devastating effects of biliary atresia. This review highlights the current literature on the components of the immune system that have been in implicated in biliary atresia and the rich interplay between the major arms of the immune system- innate and adaptive immunity- to cause the highly morbid consequences of this disease.
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Affiliation(s)
- Phoebe N Miller
- Department of Surgery, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Suruthi Baskaran
- Department of Surgery, University of Texas Health Science Center, 7703 Floyd Curl Drive San Antonio, TX 78229, USA
| | - Amar Nijagal
- Department of Surgery, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA; The Liver Center, University of California San Francisco, San Francisco, CA 94143; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
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Kong YM, Yuan K, Wang CL. Congenital biliary atresia caused by GPC1 gene mutation in Chinese siblings: A case report. World J Clin Cases 2023; 11:629-634. [PMID: 36793631 PMCID: PMC9923852 DOI: 10.12998/wjcc.v11.i3.629] [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: 07/18/2022] [Revised: 10/21/2022] [Accepted: 12/09/2022] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Congenital biliary atresia (CBA) is a serious hepatobiliary disease in children with unknown etiology. Its outcome is often liver transplantation or death. Clarifying the etiology of CBA is of great significance for prognosis, treatment, and genetic counseling.
CASE SUMMARY A male Chinese infant at an age of 6 mo and 24 d was hospitalized because of "yellow skin for more than 6 mo". Soon after birth, the patient developed jaundice, which then progressively intensified. A "laparoscopic exploration" indicated "biliary atresia". After coming to our hospital, genetic testing suggested a GPC1 mutation [loss 1 (exons 6-7)]. The patient recovered and was discharged after living donor liver transplantation. After discharge, the patient was followed up. The condition was controlled by oral drugs, and the patient’s condition was stable.
CONCLUSION CBA is a complex disease with a complex etiology. Clarifying the etiology is of great clinical importance for treatment and prognosis. This case reports CBA caused by a GPC1 mutation, which enriches the genetic etiology of biliary atresia. However, its specific mechanism needs to be confirmed by further research.
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Affiliation(s)
- Yuan-Mei Kong
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ke Yuan
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Chun-Lin Wang
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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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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Luo Y, Brigham D, Bednarek J, Torres R, Wang D, Ahmad S, Mack CL. Unique Cholangiocyte-Targeted IgM Autoantibodies Correlate With Poor Outcome in Biliary Atresia. Hepatology 2021; 73:1855-1867. [PMID: 32767570 PMCID: PMC7867668 DOI: 10.1002/hep.31504] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 06/27/2020] [Accepted: 07/12/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS The etiology of biliary atresia (BA) is not known and is likely multifactorial, including a genetic predisposition, a viral or environmental trigger, an aberrant autoimmune response targeting cholangiocytes, and unique susceptibilities of the neonatal bile ducts to injury. Damaged cholangiocytes may express neo self-antigens and elicit autoreactive T-cell-mediated inflammation and B-cell production of autoantibodies. The aim of this study was to discover autoantibodies in BA that correlated with outcomes. APPROACH AND RESULTS An autoantigen microarray encompassing approximately 9,500 autoantigens was used to screen for serum immunoglobulin M (IgM) and immunoglobulin G (IgG) autoantibodies in patients with BA or other liver disease controls. Validation of candidate autoantibodies by enzyme-linked immunosorbent assay on a second cohort of subjects (6-12 months following Kasai portoenterostomy) and correlations of autoantibodies with outcomes were performed (serum bilirubin levels and need for liver transplant in first 2 years of life). Mean anti-chitinase 3-like 1 (CHI3L1), anti-delta-like ligand (DLL-4), and antisurfactant protein D (SFTPD) IgM autoantibodies in BA were significantly higher compared with controls, and IgM autoantibody levels positively correlated with worse outcomes. Immunofluorescence revealed cholangiocyte-predominant expression of CHI3L1, DLL-4, and SFTPD. The humoral autoantibody response was associated with C3d complement activation and T-cell autoimmunity, based on detection of cholangiocyte-predominant C3d co-staining and peripheral blood autoreactive T cells specific to CHI3L1, DLL-4 and SFTPD, respectively. CONCLUSIONS BA is associated with cholangiocyte-predominant IgM autoantibodies in the first year after Kasai portoenterostomy. Anti-CHI3L1, anti-DLL-4, and anti-SFTPD IgM autoantibody correlations with worse outcomes and the detection of C3d on cholangioctyes and antigen-specific autoreactive T cells suggest that autoimmunity plays a role in the ongoing bile duct injury and progression of disease.
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Affiliation(s)
- Yuhuan Luo
- University of Colorado School of Medicine
| | | | - Joseph Bednarek
- University of Colorado School of Medicine and University of Utah
| | | | - Dong Wang
- University of Colorado School of Medicine
| | - Sara Ahmad
- University of Colorado School of Medicine
| | - Cara L. Mack
- University of Colorado School of Medicine, Children’s Hospital Colorado
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Wang J, Xu Y, Chen Z, Liang J, Lin Z, Liang H, Xu Y, Wu Q, Guo X, Nie J, Lu B, Huang B, Xian H, Wang X, Wu Q, Zeng J, Chai C, Zhang M, Lin Y, Zhang L, Zhao S, Tong Y, Zeng L, Gu X, Chen ZG, Yi S, Zhang T, Delfouneso D, Zhang Y, Nutt SL, Lew AM, Lu L, Bai F, Xia H, Wen Z, Zhang Y. Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia. Cell 2020; 183:1867-1883.e26. [PMID: 33248023 DOI: 10.1016/j.cell.2020.10.048] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 09/01/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023]
Abstract
Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1+effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.
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Affiliation(s)
- Jun Wang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Yanhui Xu
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Zhanghua Chen
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics (IGS), School of Life Sciences, Peking University, Beijing, 100871, China
| | - Jiankun Liang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Zefeng Lin
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Huiying Liang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Yiping Xu
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Qi Wu
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Xuanjie Guo
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Junli Nie
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Bingtai Lu
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Bing Huang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Huifang Xian
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Xiaohui Wang
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hongkong; Chongqing International Institute for Immunology, Hongkong, China
| | - Qiang Wu
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Jixiao Zeng
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Chengwei Chai
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Meixue Zhang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Yuzhen Lin
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Li Zhang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Shanmeizi Zhao
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Yanlu Tong
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Liang Zeng
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Xiaoqiong Gu
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Zhuang-Gui Chen
- Department of Pediatrics and Hepatic Surgery, Liver Transplant Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, China
| | - Shuhong Yi
- Department of Pediatrics and Hepatic Surgery, Liver Transplant Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, China
| | - Tong Zhang
- Department of Pediatrics and Hepatic Surgery, Liver Transplant Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, China
| | - David Delfouneso
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Yan Zhang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China
| | - Stephen L Nutt
- Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Parkville, Melbourne, VIC 3052, Australia
| | - Andrew M Lew
- Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Parkville, Melbourne, VIC 3052, Australia
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hongkong; Chongqing International Institute for Immunology, Hongkong, China
| | - Fan Bai
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics (IGS), School of Life Sciences, Peking University, Beijing, 100871, China; Center for Translational Cancer Research, First Hospital, Peking University, Beijing 100871, China.
| | - Huimin Xia
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China.
| | - Zhe Wen
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China.
| | - Yuxia Zhang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China; The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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Ortiz-Perez A, Donnelly B, Temple H, Tiao G, Bansal R, Mohanty SK. Innate Immunity and Pathogenesis of Biliary Atresia. Front Immunol 2020; 11:329. [PMID: 32161597 PMCID: PMC7052372 DOI: 10.3389/fimmu.2020.00329] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 02/10/2020] [Indexed: 12/12/2022] Open
Abstract
Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have fatal consequences, when not treated in a timely manner. It is the most common indication of pediatric liver transplantation worldwide and the development of new therapies, to alleviate the need of surgical intervention, has been hindered due to its complexity and lack of understanding of the disease pathogenesis. For that reason, significant efforts have been made toward the development of experimental models and strategies to understand the etiology and disease mechanisms and to identify novel therapeutic targets. The only characterized model of BA, using a Rhesus Rotavirus Type A infection of newborn BALB/c mice, has enabled the identification of key cellular and molecular targets involved in epithelial injury and duct obstruction. However, the establishment of an unleashed chronic inflammation followed by a progressive pathological wound healing process remains poorly understood. Like T cells, macrophages can adopt different functional programs [pro-inflammatory (M1) and resolutive (M2) macrophages] and influence the surrounding cytokine environment and the cell response to injury. In this review, we provide an overview of the immunopathogenesis of BA, discuss the implication of innate immunity in the disease pathogenesis and highlight their suitability as therapeutic targets.
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Affiliation(s)
- Ana Ortiz-Perez
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
| | - Bryan Donnelly
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Haley Temple
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Greg Tiao
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Ruchi Bansal
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
| | - Sujit Kumar Mohanty
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
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Abstract
Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. Here, the authors highlight studies pertaining to B cell mechanisms associated with disease pathogenesis and outcomes in autoimmune hepatitis and the immune-mediated cholangiopathies (primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia). The vast majority of investigations focus on autoantibodies and future research endeavors should include deciphering the role of the B cell in T cell activation (through antigen presentation, cytokine/chemokine production, and inhibition of regulation). Targeting B cell mechanisms in the treatment of autoimmune liver diseases is also highlighted.
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Affiliation(s)
- Sarah A. Taylor
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - David N. Assis
- Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Cara L. Mack
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Digestive Health Institute, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
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A Phase I/IIa Trial of Intravenous Immunoglobulin Following Portoenterostomy in Biliary Atresia. J Pediatr Gastroenterol Nutr 2019; 68:495-501. [PMID: 30664564 PMCID: PMC6428610 DOI: 10.1097/mpg.0000000000002256] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver. METHODS A multicenter, prospective, open-labeled, phase I/IIA trial of IVIg was conducted, with 1 g/kg/dose of IVIg infused at 3-5, 30, and 60 days post-HPE, and subjects followed for 360 days post-HPE. Twenty-nine participants completed the study. RESULTS Administration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions; however, 90% of participants had an SAE. Compared with a historical placebo-arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin <1.5 mg/dL at 90, 180, or 360 days post-HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo arm, with a difference at 360 days of -11.9% (IVIg: 58.6%, placebo: 70.5%; 90% UCB: 2.1%; P > 0.05). CONCLUSIONS Although IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360-day survival with the native liver. CLINICAL TRIAL Safety Study of Intravenous Immunoglobulin Post-Portoenterostomy in Biliary Atresia; #NCT01854827.
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Kim S, Moore J, Alonso E, Bednarek J, Bezerra JA, Goodhue C, Karpen SJ, Loomes KM, Magee JC, Ng VL, Sherker AH, Smith C, Spino C, Venkat V, Wang K, Sokol RJ, Mack CL. Correlation of Immune Markers With Outcomes in Biliary Atresia Following Intravenous Immunoglobulin Therapy. Hepatol Commun 2019; 3:685-696. [PMID: 31061956 PMCID: PMC6492477 DOI: 10.1002/hep4.1332] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/11/2019] [Indexed: 12/13/2022] Open
Abstract
Biliary atresia is a progressive fibroinflammatory cholangiopathy of infancy that is associated with activation of innate and adaptive immune responses targeting bile ducts. A recently completed multicenter phase I/IIA trial of intravenous immunoglobulin in biliary atresia did not improve serum total bilirubin levels at 90 days after hepatoportoenterostomy or survival with the native liver at 1 year. A mechanistic aim of this trial was to determine if the peripheral blood immunophenotype was associated with clinical outcomes. Flow cytometry of peripheral blood cell markers (natural killer [NK], macrophage subsets, T‐ and B‐cell subsets, regulatory T cells), neutrophils, and activation markers (clusters of differentiation [CD]38, CD69, CD86, human leukocyte antigen‐DR isotype [HLA‐DR]) was performed on 29 patients with biliary atresia at baseline and at 60, 90, 180, and 360 days after hepatoportoenterostomy. Plasma cytokines and neutrophil products were also measured. Spearman correlations of change of an immune marker from baseline to day 90 with change in serum bilirubin revealed that an increase in total bilirubin correlated with 1) increased percentage of HLA‐DR+CD38+ NK cells and expression of NK cell activation markers CD69 and HLA‐DR, 2) decreased percentage of regulatory T cells, and 3) increased interleukin (IL)‐8 and associated neutrophil products (elastase and neutrophil extracellular traps). Cox modeling revealed that the change from baseline to day 60 of the percentage of HLA‐DR+CD38+ NK cells and plasma IL‐8 levels was associated with an increased risk of transplant or death by day 360. Conclusion: Poor outcomes in biliary atresia correlated with higher peripheral blood NK cells and IL‐8 and lower regulatory T cells. Future studies should include immunotherapies targeting these pathways in order to protect the biliary tree from ongoing damage.
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Affiliation(s)
| | | | - Estella Alonso
- Ann and Robert H. Lurie Children's Hospital of Chicago Chicago IL
| | | | | | | | | | | | | | - Vicky L Ng
- The Hospital for Sick Children, University of Toronto Toronto Canada
| | - Averell H Sherker
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Bethesda MD
| | | | | | | | - Kasper Wang
- Children's Hospital Los Angeles Los Angeles CA
| | - Ronald J Sokol
- Children's Hospital Colorado, University of Colorado School of Medicine Aurora CO
| | - Cara L Mack
- Children's Hospital Colorado, University of Colorado School of Medicine Aurora CO
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Taylor SA, Malladi P, Pan X, Wechsler JB, Hulse KE, Perlman H, Whitington PF. Oligoclonal immunoglobulin repertoire in biliary remnants of biliary atresia. Sci Rep 2019; 9:4508. [PMID: 30872727 PMCID: PMC6418100 DOI: 10.1038/s41598-019-41148-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 03/01/2019] [Indexed: 12/13/2022] Open
Abstract
Biliary atresia (BA) is a neonatal cholestatic liver disease that is the leading cause of pediatric liver transplantation, however, the mechanism of disease remains unknown. There are two major forms of BA: isolated BA (iBA) comprises the majority of cases and is thought to result from an aberrant immune response to an environmental trigger, whereas syndromic BA (BASM) has associated malformations and is thought to arise from a congenital insult. To determine whether B cells in BA biliary remnants are antigen driven, we examined the immunoglobulin (Ig) repertoire of diseased tissue from each BA group. Deep sequencing of the Ig chain DNA was performed on iBA and BASM biliary remnants and lymph nodes obtained from the Childhood Liver Disease Research Network (ChiLDReN) repository. Statistical analysis of the Ig repertoire provided measures of Ig clonality and the Ig phenotype. Our data demonstrate that B cells infiltrate diseased iBA and BASM biliary remnant tissue. The Ig repertoires of iBA and BASM disease groups were oligoclonal supporting a role for an antigen-driven immune response in both sub-types. These findings shift the current understanding of BA and suggest a role for antigen stimulation in early iBA and BASM disease pathogenesis.
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Affiliation(s)
- Sarah A Taylor
- Department of Pediatrics, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States. .,Stanley Manne Children's Research Institute, Chicago, Illinois, United States.
| | - Padmini Malladi
- Stanley Manne Children's Research Institute, Chicago, Illinois, United States
| | - Xiaomin Pan
- Stanley Manne Children's Research Institute, Chicago, Illinois, United States
| | - Joshua B Wechsler
- Department of Pediatrics, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
| | - Kathryn E Hulse
- Department of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Harris Perlman
- Department of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Peter F Whitington
- Department of Pediatrics, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States.,Stanley Manne Children's Research Institute, Chicago, Illinois, United States
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Bednarek J, Traxinger B, Brigham D, Roach J, Orlicky D, Wang D, Pelanda R, Mack CL. Cytokine-Producing B Cells Promote Immune-Mediated Bile Duct Injury in Murine Biliary Atresia. Hepatology 2018; 68:1890-1904. [PMID: 29679373 PMCID: PMC6195851 DOI: 10.1002/hep.30051] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 04/02/2018] [Accepted: 04/14/2018] [Indexed: 12/13/2022]
Abstract
Biliary atresia (BA) is a neonatal T cell-mediated, inflammatory, sclerosing cholangiopathy. In the rhesus rotavirus (RRV)-induced neonatal mouse model of BA (murine BA), mice lacking B cells do not develop BA, and the lack of B cells is associated with loss of T-cell and macrophage activation. The aim of this study was to determine the mechanism of B cell-mediated immune activation (antigen presentation versus cytokine production) in murine BA. Normal neonatal B cells in the liver are predominantly at pro-B and pre-B cellular development. However, BA mice exhibit a significant increase in the number and activation status of mature liver B cells. Adoptively transferred B cells into RRV-infected, B cell-deficient mice were able to reinstate T-cell and macrophage infiltration and biliary injury. Nonetheless, neonatal liver B cells were incompetent at antigen presentation to T cells. Moreover, 3-83 immunoglobulin transgenic mice, in which B cells only present an irrelevant antigen, developed BA, indicating a B-cell antigen-independent mechanism. B cells from BA mice produced a variety of innate and adaptive immune cytokines associated with immune activation. In vitro trans-well studies revealed that BA B cells secreted cytokines that activated T cells based on increased expression of T-cell activation marker cluster of differentiation 69. Conclusion: Neonatal liver B cells are highly activated in murine BA and contribute to immune activation through production of numerous cytokines involved in innate and adaptive immunity; this work provides increased knowledge on the capacity of neonatal B cells to contribute to an inflammatory disease through cytokine-mediated mechanisms, and future studies should focus on targeting B cells as a therapeutic intervention in human BA.
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Affiliation(s)
- Joseph Bednarek
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine
| | - Brianna Traxinger
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine
| | - Dania Brigham
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine
| | - Jonathan Roach
- Department of Surgery, University of Colorado School of Medicine
| | - David Orlicky
- Department of Pathology, University of Colorado School of Medicine
| | - Dong Wang
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine
| | - Roberta Pelanda
- Department of Immunology and Microbiology, University of Colorado School of Medicine
| | - Cara L. Mack
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine
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Pang SY, Dai YM, Zhang RZ, Chen YH, Peng XF, Fu J, Chen ZR, Liu YF, Yang LY, Wen Z, Yu JK, Liu HY. Autoimmune liver disease-related autoantibodies in patients with biliary atresia. World J Gastroenterol 2018; 24:387-396. [PMID: 29391761 PMCID: PMC5776400 DOI: 10.3748/wjg.v24.i3.387] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 12/14/2017] [Accepted: 12/20/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prevalence and clinical significance of autoimmune liver disease (ALD)-related autoantibodies in patients with biliary atresia (BA).
METHODS Sera of 124 BA patients and 140 age-matched non-BA controls were assayed for detection of the following autoantibodies: ALD profile and specific anti-nuclear antibodies (ANAs), by line-blot assay; ANA and anti-neutrophil cytoplasmic antibody (ANCA), by indirect immunofluorescence assay; specific ANCAs and anti-M2-3E, by enzyme linked immunosorbent assay. Associations of these autoantibodies with the clinical features of BA (i.e., cytomegalovirus infection, degree of liver fibrosis, and short-term prognosis of Kasai procedure) were evaluated by Spearman’s correlation coefficient.
RESULTS The overall positive rate of serum autoantibodies in preoperative BA patients was 56.5%. ALD profile assay showed that the positive reaction to primary biliary cholangitis-related autoantibodies in BA patients was higher than that to autoimmune hepatitis-related autoantibodies. Among these autoantibodies, anti-BPO was detected more frequently in the BA patients than in the controls (14.8% vs 2.2%, P < 0.05). Accordingly, 32 (25.8%) of the 124 BA patients also showed a high positive reaction for anti-M2-3E. By comparison, the controls had a remarkably lower frequency of anti-M2-3E (P < 0.05), with 6/92 (8.6%) of patients with other liver diseases and 2/48 (4.2%) of healthy controls. The prevalence of ANA in BA patients was 11.3%, which was higher than that in disease controls (3.3%, P < 0.05), but the reactivity to specific ANAs was only 8.2%. The prevalence of ANCAs (ANCA or specific ANCAs) in BA patients was also remarkably higher than that in the healthy controls (37.9% vs 6.3%, P < 0.05), but showed no difference from that in patients with other cholestasis. ANCA positivity was closely associated with the occurrence of postoperative cholangitis (r = 0.61, P < 0.05), whereas none of the autoantibodies showed a correlation to cytomegalovirus infection or the stages of liver fibrosis.
CONCLUSION High prevalence of autoantibodies in the BA developmental process strongly reveals the autoimmune-mediated pathogenesis. Serological ANCA positivity may be a useful predictive biomarker of postoperative cholangitis.
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MESH Headings
- Antibodies, Antineutrophil Cytoplasmic/blood
- Antibodies, Antineutrophil Cytoplasmic/immunology
- Antibodies, Antinuclear/blood
- Autoantigens/immunology
- Biliary Atresia/blood
- Biliary Atresia/immunology
- Biliary Atresia/surgery
- Biomarkers/blood
- Cholangitis, Sclerosing/blood
- Cholangitis, Sclerosing/immunology
- Cytomegalovirus/isolation & purification
- Cytomegalovirus Infections/blood
- Cytomegalovirus Infections/immunology
- Cytomegalovirus Infections/virology
- Enzyme-Linked Immunosorbent Assay
- Female
- Fluorescent Antibody Technique, Indirect
- Hepatitis, Autoimmune/blood
- Hepatitis, Autoimmune/immunology
- Humans
- Infant
- Liver Cirrhosis/blood
- Liver Cirrhosis/immunology
- Male
- Portoenterostomy, Hepatic/adverse effects
- Portoenterostomy, Hepatic/methods
- Postoperative Complications/blood
- Postoperative Complications/epidemiology
- Postoperative Complications/etiology
- Preoperative Period
- Prognosis
- Retrospective Studies
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Affiliation(s)
- Shu-Yin Pang
- Clinical Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Yu-Mei Dai
- Clinical Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Rui-Zhong Zhang
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Yi-Hao Chen
- Clinical Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Xiao-Fang Peng
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Jie Fu
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Zheng-Rong Chen
- Department of Pathology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Yun-Feng Liu
- Clinical Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Li-Yuan Yang
- Clinical Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Zhe Wen
- Department of Neonatal Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Jia-Kang Yu
- Department of Neonatal Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
| | - Hai-Ying Liu
- Clinical Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
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Kilgore A, Mack CL. Update on investigations pertaining to the pathogenesis of biliary atresia. Pediatr Surg Int 2017; 33:1233-1241. [PMID: 29063959 PMCID: PMC5894874 DOI: 10.1007/s00383-017-4172-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2017] [Indexed: 12/14/2022]
Abstract
Biliary atresia is a devastating biliary disease of neonates that results in liver transplantation for the vast majority. The etiology of biliary atresia is unknown and is likely multifactorial, with components of genetic predisposition, environmental trigger and autoimmunity contributing to disease pathogenesis. This review highlights recent work related to investigations of disease pathogenesis in biliary atresia.
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Affiliation(s)
- Alexandra Kilgore
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO 80045, USA
| | - Cara L. Mack
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO 80045, USA
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Harada K. Immunopathology of Biliary Atresia. PATHOLOGY OF THE BILE DUCT 2017:121-137. [DOI: 10.1007/978-981-10-3500-5_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Affiliation(s)
- Dong Zhao
- Shanghai Jiao Tong University, Shanghai, China
| | - Xi-Dai Long
- Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Shanghai Jiao Tong University, Shanghai, China
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Mack CL. What Causes Biliary Atresia? Unique Aspects of the Neonatal Immune System Provide Clues to Disease Pathogenesis. Cell Mol Gastroenterol Hepatol 2015; 1:267-274. [PMID: 26090510 PMCID: PMC4467898 DOI: 10.1016/j.jcmgh.2015.04.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Biliary atresia (BA) is the most frequent identifiable cause of neonatal cholestasis and the majority of patients will need liver transplantation for survival. Despite surgical intervention with the Kasai portoenterostomy, significant fibrosis and cirrhosis develops early in life. An increased understanding of what causes this inflammatory fibrosing cholangiopathy will lead to therapies aimed at protecting the intrahepatic biliary system from immune-mediated damage. This review focuses on studies pertaining to the role of the adaptive immune response in bile duct injury in BA, including cellular and humoral immunity. The neonatal presentation of BA begs the question of what are potential modifications of unique aspects of the neonatal immune system that "sets the stage" for the progressive biliary disease? Throughout this article, characteristics of the neonatal immune response are outlined and theories as to how alterations of this response could contribute to the pathogenesis of BA are discussed. These include aberrant Th1 and Th17 responses, deficiencies in regulatory T cells, activation of humoral immunity and autoimmunity. In order to advance our understanding of the etiology of BA, future studies should focus on those unique aspects of the neonatal immune system that have gone awry, as detailed throughout this review.
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Affiliation(s)
- Cara L. Mack
- Correspondence Address correspondence to: Cara L. Mack, MD, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Hospital Colorado, University of Colorado School of Medicine, 13123 East 16th Avenue, Mailstop B290, Aurora, Colorado 80045. fax: (720) 777-7277.
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Prevalence of groups A and C rotavirus antibodies in infants with biliary atresia and cholestatic controls. J Pediatr 2015; 166:79-84. [PMID: 25444003 DOI: 10.1016/j.jpeds.2014.09.033] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Revised: 08/11/2014] [Accepted: 09/18/2014] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To analyze the prevalence of acute asymptomatic group A and C rotavirus (RV-A and RV-C) infection in neonates with cholestasis. STUDY DESIGN Participants were infants <180 days of age with cholestasis (serum direct or conjugated bilirubin >20% of total and ≥2 mg/dL) enrolled in the Childhood Liver Disease Research and Education Network during RV season (December-May). Forty infants with biliary atresia (BA), age 62 ± 29 days (range, 4.7-13 weeks) and 38 infants with cholestasis, age 67 ± 44 days (range, 3-15.8 weeks) were enrolled. RESULTS At enrollment, RV-A IgM positivity rates did not differ between infants with BA (10%) vs those without (18%) (P = .349). RV-C IgM was positive in 0% of infants with BA vs 3% in those without BA (P = .49). RV-A IgG was lower in infants with BA: 51 ± 39 vs 56 ± 44 enzyme-linked immunoassay unit, P = .045 but this difference may lack biological relevance as maternal RV-A IgG titers were similar between groups. Infant RV-A IgM titers at 2-6 months follow-up increased markedly vs at presentation in both infants with BA (50 ± 30 vs 9 ± 9) and those without (43 ± 18 vs 16 ± 20 enzyme-linked immunoassay unit) (P < .0001), without differences between groups. CONCLUSIONS RV-A infection in the first 6 months of life is common in infants with cholestasis of any cause. RV-A could have different pathogenetic effects by initiating different hepatic immune responses in infants with vs without BA or could lack pathogenetic significance.
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18
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Fujisawa S, Muraji T, Sakamoto N, Hosaka N, Matsuda S, Kawakami H, Hirai M, Yanai T. Positive C4d staining of the portal vein endothelium in the liver of patients with biliary atresia: a role of humoral immunity in ongoing liver fibrosis. Pediatr Surg Int 2014; 30:877-81. [PMID: 25064226 DOI: 10.1007/s00383-014-3553-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/15/2014] [Indexed: 12/20/2022]
Abstract
PURPOSE This study aimed to clarify the role of complement activation in fibrogenesis in BA. METHODS In total, 27 paraffin-embedded liver biopsy samples were immunohistochemically analyzed using C4d polyclonal antibody, vascular cell adhesion molecule-1 (VCAM-1), and CD45. The liver samples were obtained from 25 patients during Kasai operation, and two additional specimens were obtained from 2 patients by needle biopsy later at the time of liver function deterioration. The degree of liver fibrosis was histologically graded 1-3. RESULTS Among the 25 samples, 9 showed C4d-positive immunostaining localized on the endothelia of a few portal veins in the portal tract. The degree of fibrosis was correlated with C4d staining (p = 0.025). The age at Kasai operation correlated with the degree of fibrosis and the C4d positivity. Two needle biopsy samples were positive for C4d. Among 13 samples submitted for VCAM-1 staining, 2 negative samples were C4d negative and all positive C4d samples were VCAM-1 positive with CD45 mononuclear cell infiltration. CONCLUSION These findings suggest that ongoing cirrhosis could be a result of progressive "vasculopathy" of the portal vein caused by humoral and cell-mediated immune interaction.
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Affiliation(s)
- Sorahiko Fujisawa
- Department of Pediatric Surgery, Ibaraki Children's Hospital, 3-3-1 Futabadai, Mito, Ibaraki, 311-4145, Japan
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EXP CLIN TRANSPLANTExp Clin Transplant 2014; 12. [DOI: 10.6002/ect.25liver.p44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Feldman AG, Tucker RM, Fenner EK, Pelanda R, Mack CL. B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia. PLoS One 2013; 8:e73644. [PMID: 23991203 PMCID: PMC3749125 DOI: 10.1371/journal.pone.0073644] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 07/19/2013] [Indexed: 02/04/2023] Open
Abstract
A leading theory regarding the pathogenesis of biliary atresia (BA) is that bile duct injury is initiated by a virus infection, followed by an autoimmune response targeting bile ducts. In experimental models of autoimmune diseases, B cells have been shown to play an important role. The aim of this study was to determine the role of B cells in the development of biliary obstruction in the Rhesus rotavirus (RRV)-induced mouse model of BA. Wild-type (WT) and B cell-deficient (Ig-α(-/-)) mice received RRV shortly after birth. Ig-α(-/-) RRV-infected mice had significantly increased disease-free survival rate compared to WT RRV-infected BA mice (76.8% vs. 17.5%). In stark contrast to the RRV-infected BA mice, the RRV-infected Ig-α(-/-) mice did not have hyperbilirubinemia or bile duct obstruction. The RRV-infected Ig-α(-/-) mice had significantly less liver inflammation and Th1 cytokine production compared to RRV-infected WT mice. In addition, Ig-α(-/-) mice had significantly increased numbers of regulatory T cells (Tregs) at baseline and after RRV infection compared to WT mice. However, depletion of Tregs in Ig-α(-/-) mice did not induce biliary obstruction, indicating that the expanded Tregs in the Ig-α(-/-) mice were not the sole reason for protection from disease. Conclusion : B cell deficient Ig-α(-/-) mice are protected from biliary obstruction in the RRV-induced mouse model of BA, indicating a primary role of B cells in mediating disease pathology. The mechanism of protection may involve lack of B cell antigen presentation, which impairs T-cell activation and Th1 inflammation. Immune modulators that inhibit B cell function may be a new strategy for treatment of BA.
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Affiliation(s)
- Amy G Feldman
- Department of Pediatrics, Section of Pediatric Gastroenterology, Children's Hospital, Colorado, Aurora, Colorado, USA.
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Abstract
Biliary atresia (BA) is an infantile obstructive cholangiopathy of unknown etiology with suboptimal therapy, which is responsible for 40 to 50% of all pediatric liver transplants. Although the etiology of bile duct injury in BA in unknown, it is postulated that a pre- or perinatal viral infection initiates cholangiocyte apoptosis and release of antigens that trigger a Th1 immune response that leads to further bile duct injury, inflammation, and obstructive fibrosis. Humoral immunity and activation of the innate immune system may also play key roles in this process. Moreover, recent investigations from the murine BA model and human data suggest that regulatory T cells and genetic susceptibility factors may orchestrate autoimmune mechanisms. What controls the coordination of these events, why the disease only occurs in the first few months of life, and why a minority of infants with perinatal viral infections develop BA are remaining questions to be answered.
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Affiliation(s)
- Cara L. Mack
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, and Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado
| | - Amy G. Feldman
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, and Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado
| | - Ronald J. Sokol
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, and Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado
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Wang ZM, Chen YJ. Recent progress in understanding pathogenesis and liver pathology in biliary atresia. Shijie Huaren Xiaohua Zazhi 2012; 20:2576-2582. [DOI: 10.11569/wcjd.v20.i27.2576] [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] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia is an infantile destructive inflammatory cholangiopathy that causes obliteration of both intrahepatic and extrahepatic bile ducts and eventually liver cirrhosis. So far, the exact etiology and pathogenesis of biliary atresia remain unclear, and possible etiologies include congenital and genetic factors, infection, inflammation, immune reaction, maternal factors, and vascular factors. Immunoinflammatory theory has been accepted by most researchers, which is supported by liver pathological changes. This review focuses on the recent progress in understanding pathogenesis and liver pathology in biliary atresia.
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Abstract
The cause of biliary atresia is unknown; in the past few decades, the majority of investigations related to its pathogenesis have centered on viral infections and immunity. The acquired or perinatal form of biliary atresia entails a progressive inflammatory injury of bile ducts, leading to fibrosis and obliteration of both the extrahepatic and intrahepatic bile ducts. Theories of pathogenesis include viral infection, chronic inflammatory or autoimmune-mediated bile duct injury, and abnormalities in bile duct development. This review will focus solely on human studies pertaining to a potential viral trigger of bile duct injury at diagnosis and provide insight into the interplay of the innate and adaptive immune responses in the pathogenesis of disease.
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Lee HC, Chang TY, Yeung CY, Chan WT, Jiang CB, Chen WF, Chan HW, Yang HW, Lin M, Lee YJ. Genetic variability of interleukin 4 gene in Taiwanese children with biliary atresia. Cytokine 2012; 57:402-5. [PMID: 22227092 DOI: 10.1016/j.cyto.2011.12.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Revised: 12/05/2011] [Accepted: 12/14/2011] [Indexed: 01/28/2023]
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LU BRANDYR, BRINDLEY STEPHENM, TUCKER REBECCAM, LAMBERT CHERIEL, MACK CARAL. α-enolase autoantibodies cross-reactive to viral proteins in a mouse model of biliary atresia. Gastroenterology 2010; 139:1753-61. [PMID: 20659472 PMCID: PMC3792016 DOI: 10.1053/j.gastro.2010.07.042] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Revised: 07/02/2010] [Accepted: 07/09/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Biliary atresia (BA) is a neonatal cholangiopathy of unknown etiology. The bile duct injury that occurs in patients with BA might result from a hepatobiliary viral infection followed by an autoimmune response against the bile duct epithelia. We aimed to identify autoantigens recognized by serum antibodies in the Rhesus rotavirus (RRV)-induced mouse model of BA; findings were correlated with BA in humans. METHODS Bile duct epithelial proteins were screened for their reactivity with serum antibodies from the mouse model of BA using immunoblot assays. Unique proteins that reacted with sera antibodies were identified by mass spectrometry and verified using enzyme-linked immunosorbent assay (ELISA) and immunoblot analyses. Candidate autoantibodies in BA patient sera were analyzed by ELISA. RESULTS A bile duct epithelial antigen that reacted strongly with serum immunoglobulin (Ig) G from the mouse model of BA was identified as α-enolase. α-Enolase autoantibody specificity was confirmed by ELISA and immunoblot analyses. Anti-RRV and anti-enolase antibodies cross-reacted with enolase and RRV proteins; we identified regions of sequence homology between RRV and enolase. Serum samples from patients with BA had increased levels of anti-enolase IgM and IgG. CONCLUSIONS We have identified autoantibodies against α-enolase in a mouse model of BA (infected with RRV) and in serum samples from patients, indicating a role of humoral autoimmunity in disease pathogenesis. The cross-reactivity between an anti-enolase antibody and RRV proteins indicates that molecular mimicry might activate humoral autoimmunity in BA patients; further studies are required.
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Affiliation(s)
- BRANDY R. LU
- Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital, University of Colorado Denver School of Medicine, Aurora
| | - STEPHEN M. BRINDLEY
- Section of Allergy and Clinical Immunology, University of Colorado Denver School of Medicine, Aurora, Colorado
| | - REBECCA M. TUCKER
- Section of Allergy and Clinical Immunology, University of Colorado Denver School of Medicine, Aurora, Colorado
| | - CHERIE L. LAMBERT
- Section of Allergy and Clinical Immunology, University of Colorado Denver School of Medicine, Aurora, Colorado
| | - CARA L. MACK
- Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital, University of Colorado Denver School of Medicine, Aurora,Section of Allergy and Clinical Immunology, University of Colorado Denver School of Medicine, Aurora, Colorado
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Muraji T, Suskind DL, Irie N. Biliary atresia: a new immunological insight into etiopathogenesis. Expert Rev Gastroenterol Hepatol 2009; 3:599-606. [PMID: 19929581 DOI: 10.1586/egh.09.61] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Biliary atresia is an idiopathic neonatal cholestatic disease characterized by the destruction of both the intra- and extra-hepatic biliary ducts. There are two clinical manifestations of the disease: an embryonal subtype, which often presents at birth and is associated with congenital malformations, and a 'perinatal' subtype, which is probably an acquired disease due to unknown etiology. Over the last two decades, researchers have focused on activation of the cell-mediated immunity as the mechanism for biliary epithelial cell destruction for the latter subtype. A proposed trigger of this immune response is an initial viral infection, inducing biliary epithelial cells to become antigen-presenting cells and thus instigating immune-mediated destruction of the biliary tract. However, putative viruses have never been confirmed. More recently, a novel hypothesis - that maternal microchimerism may initiate a host immunologic response towards the bile duct epithelia - has been proposed. This paper discusses the etiology of biliary atresia in the context of the current research.
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Affiliation(s)
- Toshihiro Muraji
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Mito, 311-4145, Japan.
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Abstract
Biliary atresia is a mystifying cause of neonatal cholestasis, manifested by progressive inflammation and fibrosis of both the extrahepatic and intrahepatic bile ducts. It is a devastating disease that leads to cirrhosis and the need for liver transplantation in the majority of children. The etiology is unknown, and one theory is that it may involve a primary perinatal hepatobiliary viral infection and a secondary generation of an autoimmune-mediated bile duct injury. This review will outline the evidence from both human and murine studies supporting a potential cholangiotropic viral infection as the initiator of bile duct injury in biliary atresia and the role of the adaptive immune response and autoimmunity in progression of disease. Delineating the pathways of immune and autoimmune-mediated bile duct injury within biliary atresia could stimulate development of new medical interventions aimed at suppressing the specific immune response, decreasing the inflammatory damage to bile ducts, and delaying or negating the need for liver transplantation.
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Affiliation(s)
- Cara L Mack
- Pediatric Liver Center and Liver Transplant Program, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital, University of Colorado at Denver-Health Sciences Center, Denver, Colorado 80218, USA
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Mack CL, Tucker RM, Lu BR, Sokol RJ, Fontenot AP, Ueno Y, Gill RG. Cellular and humoral autoimmunity directed at bile duct epithelia in murine biliary atresia. Hepatology 2006; 44:1231-9. [PMID: 17058262 PMCID: PMC1948978 DOI: 10.1002/hep.21366] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Biliary atresia is an inflammatory fibrosclerosing lesion of the bile ducts that leads to biliary cirrhosis and is the most frequent indication for liver transplantation in children. The pathogenesis of biliary atresia is not known; one theory is that of a virus-induced, subsequent autoimmune-mediated injury of bile ducts. The aim of this study was to determine whether autoreactive T cells and autoantibodies specific to bile duct epithelia are present in the rotavirus (RRV)- induced murine model of biliary atresia and whether the T cells are sufficient to result in bile duct inflammation. In vitro analyses showed significant increases in IFN-gamma-producing T cells from RRV-diseased mice in response to bile duct epithelial autoantigen. Adoptive transfer of the T cells from RRV-diseased mice into naïve syngeneic SCID recipients resulted in bile duct-specific inflammation. This induction of bile duct pathology occurred in the absence of detectable virus, indicating a definite response to bile duct autoantigens. Furthermore, periductal immunoglobulin deposits and serum antibodies reactive to bile duct epithelial protein were detected in RRV-diseased mice. In conclusion, both cellular and humoral components of autoimmunity exist in murine biliary atresia, and the progressive bile duct injury is due in part to a bile duct epithelia-specific T cell-mediated immune response. The role of cellular and humoral autoimmunity in human biliary atresia and possible interventional strategies therefore should be the focus of future research.
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Affiliation(s)
- Cara L Mack
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado at Denver Health Sciences Center and The Children's Hospital, Denver, USA.
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Fischler B, Woxenius S, Nemeth A, Papadogiannakis N. Immunoglobulin deposits in liver tissue from infants with biliary atresia and the correlation to cytomegalovirus infection. J Pediatr Surg 2005; 40:541-6. [PMID: 15793732 DOI: 10.1016/j.jpedsurg.2004.11.035] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
PURPOSE The aim of this report was to study the amount and distribution of immunoglobulin deposits in liver biopsies from infants with biliary atresia (BA) and correlate the results to the cytomegalovirus (CMV) infection status. METHODS Stored liver biopsies from 18 patients with BA and from 6 control patients without liver disease were immunohistochemically stained to detect IgG and IgM deposits. The intensity of the immunoglobulin staining was evaluated by a semiquantitative scoring scale. Ongoing CMV infection was defined as the detection of CMV-IgM in serum and/or the isolation of CMV in the urine and was noted in 9 of the patients with BA. RESULTS When analyzing the immunoglobulin deposits on the hepatocellular canalicular membrane the intensity score for IgM deposits was significantly higher in biopsies from patients with BA infected with CMV than in those without. No canalicular staining was detected in control biopsies. CONCLUSIONS The results support the possibility that immunologic mechanisms are of importance in the pathogenesis of BA and that a CMV infection may trigger such mechanisms.
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Affiliation(s)
- Björn Fischler
- Department of Pediatrics, Huddinge University Hospital, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
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Broomé U, Nemeth A, Hultcrantz R, Scheynius A. Different expression of HLA-DR and ICAM-1 in livers from patients with biliary atresia and Byler's disease. J Hepatol 1997; 26:857-62. [PMID: 9126800 DOI: 10.1016/s0168-8278(97)80253-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS Extrahepatic biliary atresia (EHBA) and chronic progressive intra-hepatic cholestasis (Byler's disease) are two distinct disorders of unknown etiology in the neonate, characterized by profound cholestasis. The aim of the present study was to investigate the inflammatory reaction in liver tissue from patients with EHBA and Byler's disease. METHODS The expression of HLA-DR and ICAM-1 and the number of CD4+, CD8+ and gamma/delta+ T-cells were investigated with immunoperoxidase technique on cryostat sections of liver tissue from patients with EHBA (n=11), Byler's disease (n=7) and (healthy controls (n=5). RESULTS Only mild inflammation was seen, mainly with CD4+ cells, predominantly in the portal tracts in EHBA and throughout the lobuli in Byler's disease. Neither ICAM-1 nor HLA-DR was present on the bile duct cells or hepatocytes in the control patients. The bile duct cells in all EHBA patients expressed both ICAM-1 and HLA-DR. HLA-DR was expressed on the hepatocytes in five EHBA patients, but ICAM-1 was only found on the hepatocytes in two EHBA patients. In Byler's disease the bile duct cells did not express ICAM-1 or HLA-DR, but the hepatocytes from all Byler patients expressed both ICAM-1 and HLA-DR. CONCLUSIONS Although neither EHBA nor Byler's disease is characterized by intense inflammatory cell infiltration, an aberrant expression of ICAM-1 and HLA-DR was found in the liver in both patients with EHBA and patients with Byler's disease. The expression of HLA-DR and ICAM-1, was clearly distinct between the two disorders, indicating that it is not merely an unspecific event secondary to cholestasis.
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Affiliation(s)
- U Broomé
- Department of Medicine, Huddinge and Karolinska Hospital, Stockholm, Sweden
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Goss JA, Shackleton CR, Swenson K, Satou NL, Nuesse BJ, Imagawa DK, Kinkhabwala MM, Seu P, Markowitz JS, Rudich SM, McDiarmid SV, Busuttil RW. Orthotopic liver transplantation for congenital biliary atresia. An 11-year, single-center experience. Ann Surg 1996; 224:276-84; discussion 284-7. [PMID: 8813256 PMCID: PMC1235366 DOI: 10.1097/00000658-199609000-00004] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE The authors analyze a single center's 11-year experience with 190 orthotopic liver transplants for congenital biliary atresia. SUMMARY BACKGROUND DATA Hepatic portoenterostomy generally is the initial treatment for children with congenital biliary atresia. Despite multiple modifications of the hepatic portoenterostomy, two thirds of treated patients still develop recurrent cholestasis, portal hypertension, cholangitis, and cirrhosis. Therefore, the only hope of long-term survival in the majority of children with congenital biliary atresia is definitive correction with orthotopic liver transplantation. METHODS The medical records of 190 consecutive patients undergoing orthotopic liver transplantation for congenital biliary atresia from July 1, 1984 to February 29, 1996 were reviewed. Results were analyzed via Cox multivariate regression analysis to determine the statistical strength of independent associations between pretransplant covariates and patient and graft survival. Actuarial patient and graft survival was determined at 1, 2, and 5 years. The type and incidence of post-transplant complications were determined, as was the quality of long-term graft function. The median follow-up period was 3.21 years. RESULTS The liver grafts were comprised on 155 whole-organ, 24 reduced-size, and 11 living donor organs. Median pretransplant values for recipient age, weight, and total bilirubin were 1.4 years, 12.3 kg, and 13.8 mg/dL, respectively. One hundred sixty-four patients (86%) had undergone prior hepatic portoenterostomy. Eighty-seven patients (46%) were United Network for Organ Sharing (UNOS) status 1 or 2 at the time of liver transplantation. The majority (15/24, 62%) of reduced-size graft recipients were UNOS status I at the time of transplantation. One hundred fifty-nine patients (84%) received a single graft, whereas 31 patients required 37 retransplants. The 1, 2, and 5 year actuarial patient survival rates were 83%, 80% and 78% respectively, whereas graft survival rates were 81%, 77%, and 76%, respectively. Cox multivariate regression analysis demonstrated that pretransplant total bilirubin, UNOS status, and graft type significantly predicted patient survival, whereas recipient age, weight, and previous hepatic portoenterostomy did not. Current median follow-up values for total bilirubin and aspartate aminotransferase levels in the 154 surviving patients were 0.5 mg/dL and 34 international units/L, respectively. CONCLUSION Long-term patient survival after orthotopic liver transplantation for congenital biliary atresia is excellent and is independent of recipient age, weight, or previous hepatic portoenterostomy. Optimal results are obtained in this patient population when liver transplantation is performed before marked hyperbilirubinemia, and when possible, using a living-donor graft.
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Affiliation(s)
- J A Goss
- Department of Surgery, School of Medicine, University of California, Los Angeles, USA
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Abstract
In the neonate with cholestasis, clinical features and standard tests of liver function frequently cannot distinguish between diseases of the hepatocyte and those of the biliary tree. Therefore, a multidisciplinary approach to diagnosis is required. A priority in investigation is the identification of patients requiring surgery. A correct diagnosis regarding the need for surgery can be made in the majority of cases after synthesis of information obtained from abdominal sonography, hepatobiliary scintigraphy, and liver biopsy. Intraoperative cholangiography is performed routinely to precisely delineate the anatomy of the intrahepatic and extrahepatic bile ducts.
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Affiliation(s)
- H J Paltiel
- Department of Radiology, Children's Hospital, Boston, MA 02115
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Richardson SC, Bishop RF, Smith AL. Reovirus serotype 3 infection in infants with extrahepatic biliary atresia or neonatal hepatitis. J Gastroenterol Hepatol 1994; 9:264-8. [PMID: 8054525 DOI: 10.1111/j.1440-1746.1994.tb01721.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Infection with reovirus serotype 3 (reo 3) has been postulated to be associated with extrahepatic biliary atresia (EHBA) in infants, and with neonatal hepatitis (NNH). We have investigated this association by assaying antireo 3 antibodies in sera from infants (aged < 4 months) with EHBA (n = 40), NNH (59), cholestatic liver disease due to other causes (61) and control infants with no liver disease (138). Antireo 3 immunoglobulins (Ig) of the G, A and M classes were measured by enzyme-linked immunosorbent assay. No differences in the prevalence of antireo 3 IgG or IgA were found between any of the four groups. A significantly higher prevalence of positive antireo 3 IgM was found in infants with EHBA (12/40), NNH (12/59) or cholestatic liver disease associated with parenteral nutrition (7/17), alpha-1 antitrypsin deficiency (4/15) or a variety of other causes (15/29) compared with control infants (13/138). These data support an association between reovirus 3 infection and cholestatic liver disease in infants. The nature of this association may differ for EHBA, NNH and cholestatic liver disease due to other causes, and remains to be determined.
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Affiliation(s)
- S C Richardson
- Department of Gastroenterology, Royal Children's Hospital, Parkville, Victoria, Australia
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Abstract
The spectrum of diseases causing neonatal cholestasis presents intriguing problems for future investigation. There are many causes, and the eventual outcome of the specific entity has unique individual features, despite the wide areas of overlap. For example, extrahepatic biliary atresia may be the result of the sporadic occurrence of a virus-induced, progressive obliteration of the extrahepatic bile ducts with some degree of intrahepatic bile duct injury. This same sequence of viral infection with persisting injury may account for sporadic (nonfamilial) cases of neonatal hepatitis, as suggested by the Landing hypothesis. Conversely, the familial forms of cholestasis, either neonatal hepatitis or instances of intrahepatic cholestasis, are most likely genetic diseases that represent specific defects in the hepatic excretory process or in the bile secretory apparatus. The persistent nature of these presumed enzymatic or structural defects may explain the less favorable prognosis. Elucidation of the nature of these inborn errors of liver function may allow a better understanding of biliary physiology, and improved therapy.
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