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Pawłuszkiewicz K, Ryglowski PJ, Idzik N, Błaszczyszyn K, Kucharczyk E, Gaweł-Dąbrowska D, Siczek M, Widelski J, Paluch E. Rotavirus Infections: Pathophysiology, Symptoms, and Vaccination. Pathogens 2025; 14:480. [PMID: 40430800 DOI: 10.3390/pathogens14050480] [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: 02/21/2025] [Revised: 05/08/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Rotavirus (RV) is the most common cause of severe acute gastroenteritis (AGE) in children under five years of age. This review summarizes current knowledge on RV infections, with a particular focus on viral structure, pathophysiological mechanisms, and age-dependent clinical presentation. Special attention is given to systemic manifestations, including central nervous system involvement, autoimmune responses such as type 1 diabetes and celiac disease, and rare associations with biliary atresia. The mechanisms of RV-induced diarrhea and vomiting are discussed in detail. Clinical severity scoring systems-such as the Vesikari and Clark scales-and dehydration assessment tools-the Clinical Dehydration Scale (CDS) and the Dehydration: Assessing Kids Accurately (DHAKA) score-are compared. The review highlights differences in disease course between children under and over five years, emphasizing that RV is not limited to early childhood. A major section addresses the global effectiveness of vaccination programs, their role in reducing disease burden, coverage challenges, and decreased efficacy in low-income countries. Particular focus is placed on high-risk groups, including preterm and immunocompromised infants.
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Affiliation(s)
- Karolina Pawłuszkiewicz
- Faculty of Medicine, Wroclaw Medical University, Wybrzeże L. Pasteura 1, 50-367 Wrocław, Poland
| | - Piotr Józef Ryglowski
- Faculty of Medicine, Wroclaw Medical University, Wybrzeże L. Pasteura 1, 50-367 Wrocław, Poland
| | - Natalia Idzik
- Faculty of Medicine, Wroclaw Medical University, Wybrzeże L. Pasteura 1, 50-367 Wrocław, Poland
| | - Katarzyna Błaszczyszyn
- Jan Mikulicz-Radecki University Hospital in Wroclaw, Borowska 213, 50-556 Wrocław, Poland
| | - Emilia Kucharczyk
- Faculty of Medicine, Wroclaw Medical University, Wybrzeże L. Pasteura 1, 50-367 Wrocław, Poland
| | - Dagmara Gaweł-Dąbrowska
- Division of Public Health, Faculty of Health Sciences, Wroclaw Medical University, Bujwida 44, 50-345 Wroclaw, Poland
| | - Marta Siczek
- Department of Forensic Medicine, Wroclaw Medical University, J. Mikulicza-Radeckiego 4, 50-345 Wroclaw, Poland
| | - Jarosław Widelski
- Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
| | - Emil Paluch
- Department of Microbiology, Faculty of Medicine, Wroclaw Medical University, St. T. Chałubińskiego 4, 50-376 Wrocław, Poland
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Ram AK, Vats A, Bhatia A, Kumar Y. Evolving Concepts in Etiology of Biliary Atresia: Insights and Perspectives from India. Fetal Pediatr Pathol 2025; 44:236-258. [PMID: 40181637 DOI: 10.1080/15513815.2025.2477704] [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: 08/29/2024] [Revised: 03/01/2025] [Accepted: 03/04/2025] [Indexed: 04/05/2025]
Abstract
Introduction: Biliary atresia (BA) is a potentially fatal newborn cholestatic disease. It is a rapidly advancing fibro-obliterative cholangiopathy that leads to liver failure and death if not treated early. The well-known multihit hypothesis proposes that viral or chemical disruption to the biliary epithelium triggers an immune-mediated inflammatory response, resulting in fibrosis and blockage of the intra and extrahepatic biliary systems. Methods: In recent years, several papers have noticed an upsurge in many aspects of BA, particularly its etiopathogenesis, which has opened a vista of various probable mechanisms currently being examined. This review brings them together with an emphasis on reflecting current scientific views for those interested in this illness. Conclusions: Among the different etiological factors proposed for BA, viruses and immune-mediated injury are the strongest contenders as contributors to the disease onset and pathogenesis.
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Affiliation(s)
- Anil Kumar Ram
- Department of Pathology, University of Kansas Medical Center, Kansas City, USA
| | - Akshit Vats
- Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Alka Bhatia
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Yashwant Kumar
- Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
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Liu M, Zhu Y, Meng W, Zhang C, Chen Y, Shi Q, Song S, Zheng S, Liu Y, Zhou Y, Chen G. Potential therapeutic effect of dimethyl fumarate on Treg/Th17 cell imbalance in biliary atresia. Clin Immunol 2025; 272:110439. [PMID: 39863040 DOI: 10.1016/j.clim.2025.110439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 01/21/2025] [Accepted: 01/22/2025] [Indexed: 01/27/2025]
Abstract
The imbalance between Tregs and proinflammatory Th17 cells in children with biliary atresia (BA) causes immune damage to cholangiocytes. Dimethyl fumarate (DMF), an immunomodulatory drug, regulates the Treg/Th17 balance in diseases like multiple sclerosis (MS). This study explores DMF's effect on Treg/Th17 balance in BA and its potential mechanism. The differential gene expression profiles in liver of BA and choledochal cyst (CC) patients were analyzed by single-cell RNA sequencing (scRNA-seq). Treg and Th17 cell frequencies in BA hilar lymph nodes (LNs) were determined by flow cytometry. CD3+ T cells were isolated from BA hilar LNs and treated with DMF in vitro to observe their differentiation. The effects of DMF were evaluated on BA mouse model, and enzyme-linked immunosorbent assay to measure biochemical markers and cytokine profiles. The Treg/Th17 ratio in the liver was determined by flow cytometry. Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes solute carrier family 7 member 1 (Slc7a11), heme oxygenase - 1 (Hmox1) was validated by q-PCR and Western blot. ScRNA-seq showed CD4+ T cells in BA liver were enriched in antioxidant pathways. The Treg/Th17 ratio in BA hilar LNs was significantly reduced compared to CC. In vitro, DMF promoted Treg differentiation and inhibited Th17 differentiation. In vivo, the Treg/Th17 ratio increased in the liver of the DMF 40 mg/kg group. In the 40 mg/kg DMF group, interleukin-17 A (IL-17 A) expression decreased as seen in pathological staining. DMF increased Nrf2, Hmox1, Slc7a11 mRNA and protein levels in DMF 40 mg/kg group. There is a Treg/Th17 imbalance in BA patients' hilar LNs, which DMF can restore in vitro. DMF improves the survival rate of BA mice and corrects the Treg/Th17 imbalance, possibly via the Nrf2/antioxidant response elements (ARE) pathway.
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Affiliation(s)
- Mengting Liu
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, China
| | - Ye Zhu
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, China
| | - Weida Meng
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Shanghai Xuhui Central Hospital, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
| | - Caiyan Zhang
- Department of Critical Care Medicine, Children's Hospital of Fudan University, Shanghai, China
| | - Yuke Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, China
| | - Qi Shi
- Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Sun Song
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, China
| | - Yun Liu
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Shanghai Xuhui Central Hospital, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yufeng Zhou
- Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, 201102, China.
| | - Gong Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, China.
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Wang W, Zhou Y, Lu Y, Wu B, Peng S, Cai W, Xiao Y. PIgR Autoantibody-abundant Circulating Vesicles Contributes to Biliary Injury in Biliary Atresia. J Pediatr Surg 2025; 60:162116. [PMID: 39733605 DOI: 10.1016/j.jpedsurg.2024.162116] [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: 08/23/2024] [Revised: 12/10/2024] [Accepted: 12/17/2024] [Indexed: 12/31/2024]
Abstract
PURPOSE This study aimed to elucidate the role of polymeric immunoglobulin receptor (pIgR) autoantibodies in the pathogenic progression of biliary atresia (BA). METHODS The presence and levels of plasma pIgR autoantibodies, pIgR antigen expression, and B cell counts were assessed in liver tissues. Serum extracellular vesicles (EVs) were isolated, quantified, and characterized. The functional roles of EVs enriched with pIgR autoantibodies in biliary injury were investigated. RESULTS Infants diagnosed with BA exhibited significantly elevated levels of plasma pIgR autoantibodies, which positively correlated with hepatic inflammation. The expression levels of pIgR autoantibodies demonstrated high accuracy in distinguishing BA from non-BA controls. Notably, the presence of pIgR antigens was specifically observed in cholangiocytes and was associated with an increased number of CD27+ memory B cells within the liver tissue. Furthermore, the concentration of pIgR autoantibodies was found to be higher in EVs derived from BA patients compared to those from control subjects. EVs enriched with pIgR autoantibodies induced biliary injury potentially through activation of the extracellular signal-regulated kinase (ERK) pathway. CONCLUSIONS Our findings suggest that pIgR autoantibody may serve as a potential biomarker for differentiating infants with BA from those without it. Additionally, these results indicate that EVs enriched with pIgR autoantibody could play a significant role in the underlying pathogenesis of BA.
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Affiliation(s)
- Weipeng Wang
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Ying Zhou
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Ying Lu
- Shanghai Institute for Pediatric Research, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Bo Wu
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Shicheng Peng
- Shanghai Institute for Pediatric Research, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Wei Cai
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Shanghai Institute for Pediatric Research, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China.
| | - Yongtao Xiao
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Shanghai Institute for Pediatric Research, Shanghai 200092, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China.
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Miller PN, Baskaran S, Nijagal A. Immunology of Biliary Atresia. Semin Pediatr Surg 2024; 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] [MESH Headings] [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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Mpakosi A, Cholevas V, Tzouvelekis I, Passos I, Kaliouli-Antonopoulou C, Mironidou-Tzouveleki M. Autoimmune Diseases Following Environmental Disasters: A Narrative Review of the Literature. Healthcare (Basel) 2024; 12:1767. [PMID: 39273791 PMCID: PMC11395540 DOI: 10.3390/healthcare12171767] [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: 07/23/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 09/15/2024] Open
Abstract
Environmental disasters are extreme environmental processes such as earthquakes, volcanic eruptions, landslides, tsunamis, floods, cyclones, storms, wildfires and droughts that are the consequences of the climate crisis due to human intervention in the environment. Their effects on human health have alarmed the global scientific community. Among them, autoimmune diseases, a heterogeneous group of disorders, have increased dramatically in many parts of the world, likely as a result of changes in our exposure to environmental factors. However, only a limited number of studies have attempted to discover and analyze the complex association between environmental disasters and autoimmune diseases. This narrative review has therefore tried to fill this gap. First of all, the activation pathways of autoimmunity after environmental disasters have been analyzed. It has also been shown that wildfires, earthquakes, desert dust storms and volcanic eruptions may damage human health and induce autoimmune responses to inhaled PM2.5, mainly through oxidative stress pathways, increased pro-inflammatory cytokines and epithelial barrier damage. In addition, it has been shown that heat stress, in addition to increasing pro-inflammatory cytokines, may also disrupt the intestinal barrier, thereby increasing its permeability to toxins and pathogens or inducing epigenetic changes. In addition, toxic volcanic elements may accelerate the progressive destruction of myelin, which may potentially trigger multiple sclerosis. The complex and diverse mechanisms by which vector-borne, water-, food-, and rodent-borne diseases that often follow environmental diseases may also trigger autoimmune responses have also been described. In addition, the association between post-disaster stress and the onset or worsening of autoimmune disease has been demonstrated. Given all of the above, the rapid restoration of post-disaster health services to mitigate the flare-up of autoimmune conditions is critical.
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Affiliation(s)
- Alexandra Mpakosi
- Department of Microbiology, General Hospital of Nikaia "Agios Panteleimon", 18454 Piraeus, Greece
| | | | - Ioannis Tzouvelekis
- School of Agricultural Technology, Food Technology and Nutrition, Alexander Technological Educational Institute of Thessaloniki, 57400 Thessaloniki, Greece
| | - Ioannis Passos
- Surgical Department, 219, Mobile Army, Surgical Hospital, 68300 Didymoteicho, Greece
| | | | - Maria Mironidou-Tzouveleki
- Department of Pharmacology, School of Medical, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Chen J, Zhang S. The Role of Inflammation in Cholestatic Liver Injury. J Inflamm Res 2023; 16:4527-4540. [PMID: 37854312 PMCID: PMC10581020 DOI: 10.2147/jir.s430730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 10/06/2023] [Indexed: 10/20/2023] Open
Abstract
Cholestasis is a common clinical event in which bile formation and excretion are blocked, leading to retention of bile acids or bile salts; whether it occurs intra- or extrahepatically, primary or secondary, its pathogenesis is still unclear and is influenced by a combination of factors. In a variety of inflammatory and immune cells such as neutrophils, macrophages (intrahepatic macrophages are also known as Kupffer cells), mast cells, NK cells, and even T cells in humoral immunity and B cells in cellular immunity, inflammation can be a "second strike" against cholestatic liver injury. These cells, stimulated by a variety of factors such as bile acids, inflammatory chemokines, and complement, can be activated and accumulate in the cholestatic liver, and with the involvement of inflammatory mediators and modulation by cytokines, can lead to destruction of hepatocytes and bile duct epithelial cells and exacerbate (and occasionally retard) the progression of cholestatic liver disease. In this paper, we summarized the new research advances proposed so far regarding the relationship between inflammation and cholestasis, aiming to provide reference for researchers and clinicians in the field of cholestatic liver injury research.
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Affiliation(s)
- Jie Chen
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Shujun Zhang
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
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9
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Abstract
This article discusses current standard of care in neonatal biliary disease, particularly management of biliary atresia and choledochal cysts. It highlights surgical considerations, guidelines for adjuvant therapies, and promising therapeutic options that are under investigation.
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Affiliation(s)
- Sarah Mohamedaly
- Division of Pediatric Surgery, Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, HSW 1652, Campus Box 0570, San Francisco, CA 94143-0570, USA
| | - Amar Nijagal
- Division of Pediatric Surgery, Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, HSW 1652, Campus Box 0570, San Francisco, CA 94143-0570, USA; The Liver Center, University of California, San Francisco, CA, USA; The Pediatric Liver Center at UCSF Benioff Childrens' Hospitals, San Francisco, CA, USA.
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10
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Antala S, Taylor SA. Biliary Atresia in Children: Update on Disease Mechanism, Therapies, and Patient Outcomes. Clin Liver Dis 2022; 26:341-354. [PMID: 35868678 PMCID: PMC9309872 DOI: 10.1016/j.cld.2022.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Biliary atresia is a rare disease but remains the most common indication for pediatric liver transplantation as there are no effective medical therapies to slow progression after diagnosis. Variable contribution of genetic, immune, and environmental factors contributes to disease heterogeneity among patients with biliary atresia. Developing a deeper understanding of the disease mechanism will help to develop targeted medical therapies and improve patient outcomes.
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Affiliation(s)
- Swati Antala
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
| | - Sarah A. Taylor
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
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11
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Cheng YW, Chuang YC, Huang SW, Liu CC, Wang JR. An auto-antibody identified from phenotypic directed screening platform shows host immunity against EV-A71 infection. J Biomed Sci 2022; 29:10. [PMID: 35130884 PMCID: PMC8822709 DOI: 10.1186/s12929-022-00794-2] [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: 11/19/2021] [Accepted: 02/01/2022] [Indexed: 02/08/2023] Open
Abstract
Background Enterovirus A71 (EV-A71) is a neurotropic virus which may cause severe neural complications, especially in infants and children. The clinical manifestations include hand-foot-and-mouth disease, herpangina, brainstem encephalitis, pulmonary edema, and other severe neurological diseases. Although there are some vaccines approved, the post-marketing surveillance is still unavailable. In addition, there is no antiviral drugs against EV-A71 available. Methods In this study, we identified a novel antibody that could inhibit viral growth through a human single chain variable fragment (scFv) library expressed in mammalian cells and panned by infection with lethal dose of EV-A71. Results We identified that the host protein α-enolase (ENO1) is the target of this scFv, and anti-ENO1 antibody was found to be more in mild cases than severe EV-A71 cases. Furthermore, we examined the antiviral activity in a mouse model. We found that the treatment of the identified 07-human IgG1 antibody increased the survival rate after virus challenge, and significantly decreased the viral RNA and the level of neural pathology in brain tissue. Conclusions Collectively, through a promising intracellular scFv library expression and screening system, we found a potential scFv/antibody which targets host protein ENO1 and can interfere with the infection of EV-A71. The results indicate that the usage and application of this antibody may offer a potential treatment against EV-A71 infection.
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Affiliation(s)
- Yu-Wei Cheng
- The Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.,Leadgene Biomedical, Inc., Tainan, Taiwan
| | - Yung-Chun Chuang
- Leadgene Biomedical, Inc., Tainan, Taiwan.,Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Sheng-Wen Huang
- National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Tainan, Taiwan
| | - Ching-Chuan Liu
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
| | - Jen-Ren Wang
- The Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan. .,Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. .,Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan. .,National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
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12
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Quelhas P, Cerski C, Dos Santos JL. Update on Etiology and Pathogenesis of Biliary Atresia. Curr Pediatr Rev 2022; 19:48-67. [PMID: 35538816 DOI: 10.2174/1573396318666220510130259] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/16/2022] [Accepted: 02/15/2022] [Indexed: 01/31/2023]
Abstract
Biliary atresia is a rare inflammatory sclerosing obstructive cholangiopathy that initiates in infancy as complete choledochal blockage and progresses to the involvement of intrahepatic biliary epithelium. Growing evidence shows that biliary atresia is not a single entity with a single etiology but a phenotype resulting from multifactorial events whose common path is obliterative cholangiopathy. The etiology of biliary atresia has been explained as resulting from genetic variants, toxins, viral infection, chronic inflammation or bile duct lesions mediated by autoimmunity, abnormalities in the development of the bile ducts, and defects in embryogenesis, abnormal fetal or prenatal circulation and susceptibility factors. It is increasingly evident that the genetic and epigenetic predisposition combined with the environmental factors to which the mother is exposed are potential triggers for biliary atresia. There is also an indication that a progressive thickening of the arterial middle layer occurs in this disease, suggestive of vascular remodeling and disappearance of the interlobular bile ducts. It is suggested that the hypoxia/ischemia process can affect portal structures in biliary atresia and is associated with both the extent of biliary proliferation and the thickening of the medial layer.
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Affiliation(s)
- Patrícia Quelhas
- CICS-UBI - Centro de Investigação em Ciências da Saúde, University of Beira Interior, 6200-506 Covilhã, Portugal
| | - Carlos Cerski
- Department of Pathology, University Federal Rio Grande do Sul, 90040-060, Porto Alegre, Brasil
| | - Jorge Luiz Dos Santos
- CICS-UBI - Centro de Investigação em Ciências da Saúde, University of Beira Interior, 6200-506 Covilhã, Portugal
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Siyu P, Junxiang W, Qi W, Yimao Z, Shuguang J. The Role of GLI in the Regulation of Hepatic Epithelial-Mesenchymal Transition in Biliary Atresia. Front Pediatr 2022; 10:861826. [PMID: 35692978 PMCID: PMC9178093 DOI: 10.3389/fped.2022.861826] [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: 01/25/2022] [Accepted: 05/06/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To study the regulatory role of GLI1/GLI2, a nuclear transcription factor of the Sonic hedgehog (Shh) signaling pathway, in epithelial-mesenchymal transition (EMT) related to hepatic fibrosis in patients with biliary atresia (BA). METHODS The messenger RNA (mRNA) and protein expression levels of GLI1/GLI2, Snail/Slug, and other Shh- and EMT-related cytokines were tested in the liver tissues of BA patients and animals. Then, GLI1/GLI2 was silenced and overexpressed in mouse intrahepatic bile duct epithelial cells (mIBECs) and BA animals to investigate changes in the mRNA and protein expression of EMT key factors and liver fibrosis indicators. After silencing and overexpression of GLI1/GLI2, immunofluorescence was used to detect the expression of cytokeratin-19 (CK19) and α-smooth muscle actin (α-SMA) in mIBECs, and hematoxylin and eosin (HE) staining and Masson staining were used to observe the degree of liver fibrosis in the BA animals. RESULTS Compared with the control, the mRNA and protein expression levels of GLI2, Snail, vimentin, and α-SMA were significantly increased and those of E-cadherin were significantly decreased in liver tissue from BA patients and animals. Overexpression of GLI2 increased the mRNA and protein expression levels of Snail, vimentin, and α-SMA and that of E-cadherin was significantly decreased in mIBECs and BA animals. After GLI2 silencing, the opposite pattern was observed. Immunofluorescence detection showed enhanced expression of the bile duct epithelial cell marker CK19 in mIBECs after GLI2 silencing and enhanced expression of the mesenchymal cell marker α-SMA after GLI2 overexpression. HE and Masson staining suggested that the GLI2-overexpressing group had a significantly higher degree of fibrosis. CONCLUSION The Shh signaling pathway plays an important role in fibrogenesis in BA. GLI2 can significantly regulate EMT in mIBECs and livers of BA mice.
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Affiliation(s)
- Pu Siyu
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Wang Junxiang
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Wang Qi
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Zhang Yimao
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Jin Shuguang
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, 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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RRV-induced biliary atresia in neonatal mice involves CD8 + T lymphocyte killer cells and the Notch signaling pathway. Genes Genomics 2021; 43:1289-1299. [PMID: 34410624 DOI: 10.1007/s13258-021-01153-5] [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: 04/22/2021] [Accepted: 08/11/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Persistent inflammation induced by viral infection may contribute to the pathogenesis of biliary atresia (BA). Moreover, CD4+ helper cells and CD8+ killer cells are the main effector cells involved in BA and intrahepatic bile duct injuries. OBJECTIVE Thus, we aimed to explore the dynamics of inflammatory cell infiltration and inflammation-regulated pathways in liver-specific inflammatory responses. METHODS Neonatal Balb/C mice were intraperitoneally infected with 1 × 106 PFU rhesus rotavirus (RRV; BA + group), 1 × 105 PFU RRV (BA- group), or DMEM (control group). Mice were sacrificed 7 or 14 days post-infection and their bile ducts, livers, and spleen-derived tissues were examined via H & E staining. The number of CD4+T lymphocytes helper cells (CD4+Th), CD8+T lymphocytes killer cells (CD8+Tc), natural killer (NK) cells, and macrophages (Mac) in the liver and spleen were quantified by flow cytometry. The expression of inflammatory genes was analyzed via a PCR-array. Western blotting was conducted to quantify the protein expression of Notch receptor active fragments (NICD). Finally, some mice were injected with DAPT (a γ-secretase inhibitor) 12 h post-infection followed by analysis of liver and bile duct tissues after 14 days. RESULTS The numbers of CD4+Th cells were increased in the livers of BA- mice after 14 days (P < 0.05). After RRV infection, the number of CD8+Tc, CD4+Th, NK, and Mac were increased in the livers of BA + mice after 7 and 14 days. Notably, NK cell numbers remained elevated in the BA + group, but the number of Mac first increased and then decreased in both the treatment groups. PCR-array analyses indicated that the expression of many genes related to T cell proliferation and differentiation significantly increased in the livers of BA. The most upregulated gene was Jagged2 (20.34-fold). Increased NICD (Notch receptor active fragments) protein expression was found in the BA + group. Finally, DAPT injection could reduce inflammation, CD8+Tc infiltration, NICD expression, and bile duct damage after RRV infection. We found that CD8+Tc played the most important role in damaging bile ducts and promoting BA. CONCLUSION The DAPT-based intervention could reduce expression of CD8+Tc and bile duct damage in BA mouse livers post-RRV infection. We believe that the Notch signaling pathway regulates CD8+Tc functions and inflammatory dynamics in BA mouse livers.
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Lerner A, Sobolevskaia P, Churilov L, Shoenfeld Y. Alpha-enolase involvement in intestinal and extraintestinal manifestations of celiac disease. J Transl Autoimmun 2021; 4:100109. [PMID: 34189450 PMCID: PMC8219987 DOI: 10.1016/j.jtauto.2021.100109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 01/13/2023] Open
Abstract
Celiac disease is a life-long intestinal autoimmune disease, characterized by the gluten intolerance and chronic enteric inflammation. Traditionally presented by intestinal manifestations, however, a shift toward extra intestinal presentation is taking place. One of the affected organs is the nervous systems presented by neuropsychiatric manifestations, hence the mechanism and pathways are not clear. The presence of neuronal and alpha-enolases and their corresponding antibodies were noticed in the mucosa and serum of celiac disease patients, as well as in other various autoimmune diseases with psycho-neurological manifestations. The aims of the present review are to screen the literature on different isoforms of enolase, mainly alpha enolase, and their specific antibodies and to suggest their potential pathophysiological mechanisms relaying the enolases to intestinal or extraintestinal celiac disease manifestations. The shared aspects between the enolases and celiac disease and the cross-talks between alpha-enolase and tissue transglutaminase suggest new potential pathophysiological mechanisms that might drive celiac disease evolvement.
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Affiliation(s)
- Aaron Lerner
- Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, Israel
| | | | | | - Yehuda Shoenfeld
- Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, Israel
- Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Visiting Professor), Moscow, Russia
- Ariel University, Ariel, Israel
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17
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Luo Y, Brigham D, Bednarek J, Torres R, Wang D, Ahmad S, Mack CL, In conjunction with the Childhood Liver Disease Research Network. 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: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [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: 80] [Impact Index Per Article: 16.0] [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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Gómez-Rial J, Rivero-Calle I, Salas A, Martinón-Torres F. Rotavirus and autoimmunity. J Infect 2020; 81:183-189. [PMID: 32360880 DOI: 10.1016/j.jinf.2020.04.041] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 02/01/2020] [Accepted: 04/24/2020] [Indexed: 01/08/2023]
Abstract
Rotavirus, a major etiological agent of acute diarrhea in children worldwide, has historically been linked to autoimmunity. In the last few years, several physiopathological approaches have been proposed to explain the leading mechanism triggering autoimmunity, from the old concept of molecular mimicry to the emerging theory of bystander activation and break of tolerance. Epidemiological and immunological data indicate a strong link between rotavirus infection and two of the autoimmune pathologies with the highest incidence: celiac disease and diabetes. The role for current oral rotavirus vaccines is now being elucidated, with a so far positive protective association demonstrated.
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Affiliation(s)
- J Gómez-Rial
- Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría (GENVIP), Instituto de Investigación Sanitaria de Santiago (IDIS) and Hospital Clínico Universitario and Universidade de Santiago de Compostela (SERGAS), Travesa da Choupana s/n 15706 Galicia, Spain; Laboratorio de Inmunología, Servicio de Análisis Clínicos, Hospital Clínico Universitario Santiago de Compostela (SERGAS), Travesa da Choupana s/n 15706 Galicia, Spain.
| | - I Rivero-Calle
- Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría (GENVIP), Instituto de Investigación Sanitaria de Santiago (IDIS) and Hospital Clínico Universitario and Universidade de Santiago de Compostela (SERGAS), Travesa da Choupana s/n 15706 Galicia, Spain; Translational Pediatrics and Infectious Diseases, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, Travesa da Choupana s/n 15706 Galicia, Spain
| | - A Salas
- Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría (GENVIP), Instituto de Investigación Sanitaria de Santiago (IDIS) and Hospital Clínico Universitario and Universidade de Santiago de Compostela (SERGAS), Travesa da Choupana s/n 15706 Galicia, Spain; Unidade de Xenética, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigaciones Sanitarias (IDIS), Hospital Clínico Universitario de Santiago (SERGAS), Travesa da Choupana s/n 15706 Galicia, Spain
| | - F Martinón-Torres
- Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría (GENVIP), Instituto de Investigación Sanitaria de Santiago (IDIS) and Hospital Clínico Universitario and Universidade de Santiago de Compostela (SERGAS), Travesa da Choupana s/n 15706 Galicia, Spain; Translational Pediatrics and Infectious Diseases, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, Travesa da Choupana s/n 15706 Galicia, Spain
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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: 65] [Impact Index Per Article: 13.0] [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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Abstract
BACKGROUND Biliary atresia (BA) is the most common cause of obstructive jaundice in infants. Although the Kasai procedure has greatly improved the prognosis, most patients still need liver transplantation (LT) for long-term survival. The pathogenesis of BA has not been fully clarified, and liver fibrosis in BA is far beyond biliary obstructive cirrhosis. DATA SOURCES Literature reviews were underwent through PubMed. Persistent inflammation, immune response, biliary epithelial-mesenchymal transition, matrix deposition, decompensated angiogenesis, and unique biliary structure development all contribute to the fibrosis process. Observed evidences in such fields have been collected and form the backbone of this review. RESULTS Interactions of the multiple pathways accelerate this process. CONCLUSIONS Understanding the mechanisms of the liver fibrosis in BA may pave the way to improved survival after the Kasai procedure.
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Affiliation(s)
- Wen-Jun Shen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Gong Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Min Wang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102, China.
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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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Averbukh LD, Wu GY. Evidence for Viral Induction of Biliary Atresia: A Review. J Clin Transl Hepatol 2018; 6:410-419. [PMID: 30637219 PMCID: PMC6328731 DOI: 10.14218/jcth.2018.00046] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 09/05/2018] [Accepted: 09/07/2018] [Indexed: 12/14/2022] Open
Abstract
Biliary atresia (BA) is a childhood disease which manifests with abnormal narrowing, blockage or complete absence of bile ducts within the liver. Many possible etiologies have been reported for the development of BA, including congenital, perinatal and acquired conditions. Since the 1970's, there has been increasing evidence linking BA development to viral perinatal infections. The viral vectors most commonly implicated include members of the herpesviridae family (cytomegalovirus and Epstein-Barr virus) as well as those of the reoviridae family (reovirus and rotavirus). While extensive work has been done on a murine model of disease, the current review focuses primarily on evidence from human studies of viral vectors in children afflicted with BA.
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Affiliation(s)
- Leon D. Averbukh
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- *Correspondence to: Leon D. Averbukh, Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, 236 Farmington Ave., Farmington, CT 06030, USA. Tel: +1-347-306-4752, E-mail:
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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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Bezerra JA, Wells RG, Mack CL, Karpen SJ, Hoofnagle J, Doo E, Sokol RJ. Biliary Atresia: Clinical and Research Challenges for the Twenty-First Century. Hepatology 2018; 68:1163-1173. [PMID: 29604222 PMCID: PMC6167205 DOI: 10.1002/hep.29905] [Citation(s) in RCA: 228] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 03/08/2018] [Accepted: 03/27/2018] [Indexed: 12/12/2022]
Abstract
Biliary atresia (BA) is a fibroinflammatory disease of the intrahepatic and extrahepatic biliary tree. Surgical hepatic portoenterostomy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research. Investigators discussed recent advances using gestational ultrasound and results of newborn BA screening with serum direct (conjugated) bilirubin that support a prenatal onset of biliary injury. Experimental and human studies implicate the toxic properties of environmental toxins (e.g., biliatresone) and of viruses (e.g., cytomegalovirus) to the biliary system. Among host factors, sequence variants in genes related to biliary development and ciliopathies, a notable lack of a cholangiocyte glycocalyx and of submucosal collagen bundles in the neonatal extrahepatic bile ducts, and an innate proinflammatory bias of the neonatal immune system contribute to an increased susceptibility to damage and obstruction following epithelial injury. These advances form the foundation for a future research agenda focused on identifying the environmental and host factor(s) that cause BA, the potential use of population screening, studies of the mechanisms of prominent fibrosis in young infants, determinations of clinical surrogates of disease progression, and the design of clinical trials that target subgroups of patients with initial drainage following HPE. (Hepatology 2018; 00:000-000).
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Affiliation(s)
- Jorge A. Bezerra
- Liver Care Center of Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Rebecca G. Wells
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Cara L. Mack
- Pediatric Liver Center, Children’s Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Saul J. Karpen
- Emory University School of Medicine and Children’s Healthcare of Atlanta, GA, USA
| | - Jay Hoofnagle
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Edward Doo
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Ronald J. Sokol
- Pediatric Liver Center, Children’s Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
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Clemente MG, Schwarz KB, Antonucci R. Multiple glycolytic enzymes are antigens also in biliary atresia. Immunol Lett 2018; 196:124-125. [PMID: 29432777 DOI: 10.1016/j.imlet.2018.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 02/06/2018] [Indexed: 11/20/2022]
Affiliation(s)
- Maria Grazia Clemente
- Pediatric Liver Center, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Johns Hopkins University School of Medicine, 21205 Baltimore, MD, USA; Pediatric Clinic, Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy.
| | - Kathleen B Schwarz
- Pediatric Liver Center, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Johns Hopkins University School of Medicine, 21205 Baltimore, MD, USA
| | - Roberto Antonucci
- Pediatric Clinic, Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy
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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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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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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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Verkade HJ, Bezerra JA, Davenport M, Schreiber RA, Mieli-Vergani G, Hulscher JB, Sokol RJ, Kelly DA, Ure B, Whitington PF, Samyn M, Petersen C. Biliary atresia and other cholestatic childhood diseases: Advances and future challenges. J Hepatol 2016; 65:631-42. [PMID: 27164551 DOI: 10.1016/j.jhep.2016.04.032] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Revised: 04/26/2016] [Accepted: 04/28/2016] [Indexed: 02/08/2023]
Abstract
Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10-19,000 in Europe and North America. Other diseases such as the genetic conditions, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical progress in these diseases, as well as the research needs. For the various diseases, we formulate current key questions and controversies and identify top priorities to guide future research.
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Affiliation(s)
- Henkjan J Verkade
- Department of Paediatrics, University of Groningen, Beatrix Children's Hospital/University Medical Center, Groningen, The Netherlands.
| | - Jorge A Bezerra
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Mark Davenport
- Department of Paediatric Surgery, King's College Hospital, Denmark Hill, London, UK
| | - Richard A Schreiber
- Department of Paediatrics, University of British Columbia, Vancouver, Canada
| | - Georgina Mieli-Vergani
- Paediatric Liver, GI & Nutrition Centre, King's College London School of Medicine at King's College Hospital, London, UK
| | - Jan B Hulscher
- Department of Paediatric Surgery, University of Groningen, Beatrix Children's Hospital-University Medical Center, Groningen, The Netherlands
| | - Ronald J Sokol
- Section of Paediatric Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, University of Colorado School of Medicine, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA
| | - Deirdre A Kelly
- Liver Unit, Birmingham Children's Hospital NHS Trust, Birmingham, UK
| | - Benno Ure
- Department of Paediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Peter F Whitington
- Department of Paediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Marianne Samyn
- Paediatric Liver, GI & Nutrition Centre, King's College London School of Medicine at King's College Hospital, London, UK
| | - Claus Petersen
- Department of Paediatric Surgery, Hannover Medical School, Hannover, Germany
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Lakshminarayanan B, Davenport M. Biliary atresia: A comprehensive review. J Autoimmun 2016; 73:1-9. [PMID: 27346637 DOI: 10.1016/j.jaut.2016.06.005] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 06/13/2016] [Indexed: 02/08/2023]
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Zhang RZ, Yu JK, Peng J, Wang FH, Liu HY, Lui VCH, Nicholls JM, Tam PKH, Lamb JR, Chen Y, Xia HM. Role of CD56-expressing immature biliary epithelial cells in biliary atresia. World J Gastroenterol 2016; 22:2545-2557. [PMID: 26937142 PMCID: PMC4768200 DOI: 10.3748/wjg.v22.i8.2545] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/04/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the clinical and pathological parameters and expression of the neural cell adhesion molecule (CD56) in patients with biliary atresia (BA).
METHODS: Established clinical laboratory markers of hepatic function, including enzyme activity, protein synthesis, and bilirubin metabolism, were evaluated in patients with BA and compared with those in patients with choledochal cysts and neonatal hepatitis. Pathological changes in tissue morphology and fibrosis were examined by histological and tissue collagen staining. Immunohistochemical staining for the biliary epithelial cell markers CD56 and CK19 together with the Notch signaling related molecules Notch1 and Notch2 was performed in the context of alterations in the structure of intrahepatic biliary ducts.
RESULTS: Differences in some clinical laboratory parameters among the three diseases examined were observed, but they did not correlate with the pathological classification of fibrosis in BA. Immunohistochemical staining showed the presence of CD56-positive immature bile ducts in most patients (74.5%) with BA but not in patients with choledochal cysts or neonatal hepatitis. The number of CD56-expressing cells correlated with disease severity, with more positive cells present in the later stages of liver damage (81.8% vs 18.2%). Furthermore, bile plugs were mainly found in CD56-positive immature biliary ducts. Notch signaling was a key regulatory pathway in biliary duct formation and played a role in tissue fibrosis. Notch1 was co-expressed in CD56-positive cells, whereas Notch2 was found exclusively in blood vessels in the portal area of patients with BA.
CONCLUSION: The maturation of biliary epithelial cells and the expression of Notch may play a role in the pathogenesis of BA.
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Liu YJ, Li K, Yang L, Tang ST, Wang XX, Cao GQ, Li S, Lei HY, Zhang X. Dendritic Cells Regulate Treg-Th17 Axis in Obstructive Phase of Bile Duct Injury in Murine Biliary Atresia. PLoS One 2015; 10:e0136214. [PMID: 26325187 PMCID: PMC4556529 DOI: 10.1371/journal.pone.0136214] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 07/31/2015] [Indexed: 12/05/2022] Open
Abstract
Several cell types are considered to be effector cells in bile duct injury in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here, we identified an increased T helper 17 (Th17) cell population in a BA mode. By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved. Furthermore, we found that in mice with BA, the percentage of CD4+CD25highFoxp3+ T regulatory (Treg) cells decreased along with the increased percentage of Th17 cells. However, the absolute numbers of Treg and Th17 cells were both increased in liver of RRV-injected mice compared to saline-injected mice. The proportion of Th17 cells at 7 days post-infection was decreased if Treg cells isolated from normal adult mice, but not Treg cells from the livers of mice with BA, were intraperitoneally transferred on day 5 of life. In vitro experiments also showed that Treg cells from mice with BA had a diminished suppressive effect on Th17 cell generation. To determine the mechanisms, we investigated the production of cytokines in the liver. The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated. Importantly, in a Treg/Th17 cell suppression assay, IL-6 was demonstrated to paralyze the Treg cells’ suppressive effect on Th17 cells and eventually the unrestrained increase of Th17 cells contributed to bile duct injury. In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.
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Affiliation(s)
- Yong-jun Liu
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kang Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Yang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shao-tao Tang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- * E-mail:
| | - Xin-xing Wang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guo-qing Cao
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hai-yan Lei
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Zhang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Abstract
Biliary atresia is a rare disease of unclear etiology, in which obstruction of the biliary tree causes severe cholestasis leading to cirrhosis and ultimately death if left untreated. Biliary atresia is the leading cause of neonatal cholestasis and the most frequent indication for pediatric liver transplantation. Any infant with persistent jaundice beyond 2 weeks of life needs to be evaluated for biliary atresia with fractionation of the bilirubin into conjugated and unconjugated portions. Early performance of a hepatoportoenterostomy in the first 45 days of life to restore bile flow and lessen further damage to the liver is thought to optimize outcome. Despite surgery, progressive liver scarring occurs, and 80% of patients with biliary atresia will require liver transplantation during childhood.
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Hill R, Quaglia A, Hussain M, Hadzic N, Mieli-Vergani G, Vergani D, Davenport M. Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome. J Pediatr Surg 2015; 50:1297-303. [PMID: 25783388 DOI: 10.1016/j.jpedsurg.2015.02.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 01/14/2015] [Accepted: 02/08/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Biliary atresia (BA), a cholangiopathy of unknown etiology is associated with intrahepatic mononuclear cell infiltrate. An abnormal reaction to viral exposure has been hypothesized in some cases. We aimed to investigate the nature of the CD4+ hepatic infiltrate in defined clinical variants of BA by quantification of inflammatory cell components. METHODS Liver biopsies of infants obtained at Kasai portoenterostomy (KPE) were stained immunohistochemically using monoclonal antibodies to Tbet, GATA-3, FOXP3 and interleukin (IL) 17, identifying Th-1, Th-2, Tregs and Th-17 cells respectively. T cells were counted with the aid of a graticule. Data are reported as median (range) of cells per high-power-field (×400) and compared using nonparametric statistical tests with P≤0.05 regarded as significant. RESULTS Liver biopsies from BA (n=37) and age-matched cholestatic controls (e.g. alpha-1-anti trypsin deficiency, Alagilles syndrome, n=12) were investigated. BA infants were divided into three groups: cytomegalovirus IgM +ve (CMV; n=9); BA splenic malformation (BASM; n=9) and isolated BA (IBA; n=19). All T-cell subsets were present in the portal tracts, with an overrepresentation of Th-1 (P<0.001) and Th-17 (P<0.03), but not Th-2 (P=0.94) or Tregs (P=0.15), compared to controls. Th-1 cells predominated in the CMV group; (18 [7-37] vs. 3 [0-14] [BASM] and vs. 5 [3-23] [IBA]; P<0.01 both), while no subgroup differences were seen for Th-17 cells. The degree of Th-1 cell infiltrate inversely correlated with platelet count (rS=-0.49; P<0.01). Th-17 cells were fewer (6 [2-11] vs. 11 [8-20]; P=0.02) in infants who cleared their jaundice (n=15, <20μmol/L) although this did not translate to improved native liver survival (P=0.17). CONCLUSIONS Th-17 cells infiltrate the liver in BA and are associated with a worse surgical outcome; a Th-1 profile predominates in CMV-associated BA.
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Affiliation(s)
- Richard Hill
- Department of Paediatric Surgery, King's College Hospital, London SE5 9RS, UK
| | - Alberto Quaglia
- Institute of Liver Studies, GI & Nutrition Centre, King's College London School of Medicine at King's College Hospital, London SE5 9RS, UK
| | - Munther Hussain
- Institute of Liver Studies, GI & Nutrition Centre, King's College London School of Medicine at King's College Hospital, London SE5 9RS, UK
| | - Nedim Hadzic
- Paediatric Liver, GI & Nutrition Centre, King's College London School of Medicine at King's College Hospital, London SE5 9RS, UK
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI & Nutrition Centre, King's College London School of Medicine at King's College Hospital, London SE5 9RS, UK
| | - Diego Vergani
- Institute of Liver Studies, GI & Nutrition Centre, King's College London School of Medicine at King's College Hospital, London SE5 9RS, UK
| | - Mark Davenport
- Department of Paediatric Surgery, King's College Hospital, London SE5 9RS, UK.
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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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Abstract
Cholangiocytes (ie, the epithelial cells that line the bile ducts) are an important subset of liver cells. They are actively involved in the modification of bile volume and composition, are activated by interactions with endogenous and exogenous stimuli (eg, microorganisms, drugs), and participate in liver injury and repair. The term cholangiopathies refers to a category of chronic liver diseases that share a central target: the cholangiocyte. The cholangiopathies account for substantial morbidity and mortality given their progressive nature, the challenges associated with clinical management, and the lack of effective medical therapies. Thus, cholangiopathies usually result in end-stage liver disease requiring liver transplant to extend survival. Approximately 16% of all liver transplants performed in the United States between 1988 and 2014 were for cholangiopathies. For all these reasons, cholangiopathies are an economic burden on patients, their families, and society. This review offers a concise summary of the biology of cholangiocytes and describes a conceptual framework for development of the cholangiopathies. We also present the recent progress made in understanding the pathogenesis of and how this knowledge has influenced therapies for the 6 common cholangiopathies-primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis involving the liver, biliary atresia, polycystic liver disease, and cholangiocarcinoma-because the latest scientific progress in the field concerns these conditions. We performed a search of the literature in PubMed for published papers using the following terms: cholangiocytes, biliary epithelia, cholestasis, cholangiopathy, and biliary disease. Studies had to be published in the past 5 years (from June 1, 2009, through May 31, 2014), and non-English studies were excluded.
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Affiliation(s)
| | - Nicholas F LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN.
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Abstract
Biliary atresia is a severe cholangiopathy of early infancy that destroys extrahepatic bile ducts and disrupts bile flow. With a poorly defined disease pathogenesis, treatment consists of the surgical removal of duct remnants followed by hepatoportoenterostomy. Although this approach can improve the short-term outcome, the liver disease progresses to end-stage cirrhosis in most children. Further improvement in outcome will require a greater understanding of the mechanisms of biliary injury and fibrosis. Here, we review progress in the field, which has been fuelled by collaborative studies in larger patient cohorts and the development of cell culture and animal model systems to directly test hypotheses. Advances include the identification of phenotypic subgroups and stages of disease based on clinical, pathological and molecular features. Stronger evidence exists for viruses, toxins and gene sequence variations in the aetiology of biliary atresia, triggering a proinflammatory response that injures the duct epithelium and produces a rapidly progressive cholangiopathy. The immune response also activates the expression of type 2 cytokines that promote epithelial cell proliferation and extracellular matrix production by nonparenchymal cells. These advances provide insight into phenotype variability and might be relevant to the design of personalized trials to block progression of liver disease.
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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: 29] [Impact Index Per Article: 2.9] [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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Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice. J Transl Med 2015; 95:180-92. [PMID: 25531565 DOI: 10.1038/labinvest.2014.148] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 09/21/2014] [Accepted: 10/31/2014] [Indexed: 12/21/2022] Open
Abstract
Recent studies have indicated that perinatal infection with cytomegalovirus (CMV) may promote bile duct damage in biliary atresia (BA) and that the decreased regulatory T cell (Treg) percentage associated with BA may further amplify the bile duct damage. Although a majority of BA patients have had previous CMV infections and lower percentages of Tregs, it is unknown whether an initial exposure to a low dose of CMV could induce exaggerated and progressive biliary injury. A Treg-depleted neonatal mouse was infected with low-dose CMV (LD-CMV) as a model to study BA patients. LD-CMV infection in Treg-depleted mice induced extensive inflammation in both the intrahepatic and extrahepatic bile ducts, accompanied with injury to and atresia of intrahepatic bile ducts and partial obstruction of the extrahepatic bile ducts. Serum total and direct bilirubin amounts were also elevated. Evidence for the involvement of cellular and humoral autoimmune responses in LD-CMV-infection of Treg-depleted mice was also obtained through detection of increased percentages of CD3 and CD8 mononuclear cells and serum autoantibodies reactive to bile duct epithelial proteins, one of which was identified as α-enolase. Depletion of Tregs that can lead to the decreased inhibition of aberrantly activated hepatic T-lymphocytes and generation of autoantibodies may lead to further injury. Increased hepatic expression of Th1-related genes (TNF-α), IFN-γ-activated genes (STAT-1) and Th1 cytokines (TNF-α, lymphotactin, IL-12p40 and MIP -1γ) were also identified. In conclusion, autoimmune-mediated and inflammatory responses induced by LD-CMV infection in Treg-depleted mice results in increased intrahepatic and extrahepatic bile duct injury and contributed to disease progression.
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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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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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High-dose IgG therapy mitigates bile duct-targeted inflammation and obstruction in a mouse model of biliary atresia. Pediatr Res 2014; 76:72-80. [PMID: 24727948 PMCID: PMC4062601 DOI: 10.1038/pr.2014.46] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Accepted: 09/27/2013] [Indexed: 01/22/2023]
Abstract
BACKGROUND A proposed etiology of biliary atresia (BA) entails a virus-induced, progressive immune-mediated injury of the biliary system. Intravenous Ig (IVIg) has demonstrated clinical benefit in several inflammatory diseases. The aim of this study was to determine the therapeutic effects of high-dose IgG treatment in the rhesus rotavirus (RRV)-induced mouse model of BA. METHODS Newborn mice were infected with RRV, and jaundiced mice were given high-dose IgG or albumin control. Survival, histology, direct bilirubin, liver immune cell subsets, and cytokine production were analyzed. RESULTS There was no difference in overall survival between RRV-infected groups, however high-dose IgG resulted in decreased bilirubin, bile duct inflammation, and increased extrahepatic bile duct patency. High-dose IgG decreased vascular cell adhesion molecule-1, resulting in limited migration of immune cells to portal tracts. High-dose IgG significantly decreased CD4(+) T cell production of interleukin (IL)-2, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α and CD8(+) T cell production of IFN-γ, as well as increased levels of regulatory T cells. CONCLUSION High-dose IgG therapy in murine BA dramatically decreased Th1 cell-mediated inflammation and biliary obstruction. This study lends support for consideration of IVIg clinical trials in infants with BA, to diminish the progressive intrahepatic bile duct injury.
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Muraji T. Maternal microchimerism in biliary atresia: are maternal cells effector cells, targets, or just bystanders? CHIMERISM 2014; 5:1-5. [PMID: 24670921 DOI: 10.4161/chim.28576] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The etiology of biliary atresia (BA) is unknown; however, the liver histology is similar to that observed in immune-mediated hepatic disorders. Liver fibrosis in BA progresses even after bile drainage has been achieved by the Kasai operation. Maternal microchimerism has been purported to play a part in the pathogenesis of BA as well as certain autoimmune diseases. However, the role of maternal cells has not yet been determined in BA. Specifically, it is unknown whether these maternal cells function as maternal effector T lymphocytes, or targets or bystanders. We currently hypothesize that the first hit is due to GvHD interaction by engrafted maternal effector T lymphocytes. Furthermore, we suggest that the secondary effects that are manifested by progressive cirrhosis are caused either by maternal chimeric effector T lymphocytes (e.g., GvHD interaction) or targets (e.g., HvGD interaction). Based on our hypothesis, mixed lymphocyte reactions between patients and their mothers might shed light on the etiopathogenesis and prognostic indicators.
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Affiliation(s)
- Toshihiro Muraji
- Department of Pediatric Surgery; Child Health and Cancer Research Center; Ibaraki Children's Hospital; Ibaraki, Japan
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Wang JB, Liu C, Yeh YC, Liu CP, Chang CJ, Chen CY, Chin T. A novel rat model simulating biliary atresia after a Kasai operation. J INVEST SURG 2014; 27:183-90. [PMID: 24476001 DOI: 10.3109/08941939.2013.856969] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
PURPOSE The mechanisms of liver fibrosis in biliary atresia (BA) after a Kasai operation deserve studying to improve the clinical outcomes. This study aimed to create a rat model simulating BA after a Kasai operation. METHODS We inserted a polyethylene tube (PE10) into the common hepatic duct (CHD) and ligated the common bile duct (CBD) in 30 newborn rats and injected 95% ethanol into IHD at postoperative week-one (POW-1). The PE10 was removed at POW-3. The rats were sacrificed at POW-5. The CBD cystojejunostomy was performed on another 10 rats at POW-5. RESULTS The IHD obliteration and CBD dilatation were noted at POW-3 cholangiography before removal of the PE tube. The gross findings at sacrifice in the rats without cystojejunostomy included biliary fibrosis, CBD cyst, and IHD obliteration. The microscopic findings of the liver were like BA. Seven of the 10 rats with CBD cystojejunostomy were jaundice-free at POW-8. The fibrosis grade at POW-8 of the rats with CBD cystojejunostomy was significantly lower in the jaundice-free rats (Ishak fibrosis score, 3.4 ± 0.9 and 1.5 ± 0.3 in the jaundiced rats and jaundice-free rats, respectively, p < .05). CONCLUSION Based on our study, CBD cystojejunostomy five weeks after CBD ligation with ethanol injection into the IHD in newborn rats can provide a model for investigating mechanisms and treatments of liver fibrosis in BA after a Kasai operation.
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Affiliation(s)
- Jen-Bin Wang
- 1Division of Pediatric Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, School of Medicine , Taipei , Taiwan
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Humoral immune mechanism of liver injury in giant cell hepatitis with autoimmune hemolytic anemia. J Pediatr Gastroenterol Nutr 2014; 58:74-80. [PMID: 23969541 DOI: 10.1097/mpg.0b013e3182a98dbe] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA) is presumed to be an autoimmune disease, but the mechanism of liver injury is unknown. We proposed that in CGH-AHA, the humoral limb of autoimmunity is the dominant force driving progressive liver injury. METHODS We studied 6 cases of GCH-AHA and 6 cases of autoimmune hepatitis (AIH) with early childhood onset (3 type 1 and 3 type 2). Liver biopsies were graded for portal and periportal inflammation and for giant cells. Immunohistochemistry characterized cellular inflammation and complement involvement in injury by showing C5b-9 complex in hepatocytes. RESULTS Clinical and biochemical features at presentation were generally similar; however, the absence of autoantibodies and the presence of Coombs positivity did distinguish GCH-AHA from early-onset AIH. Liver biopsy pathology in CGH-AHA showed giant cells and little inflammation, whereas AIH showed the opposite. C5b-9 staining showed high-grade complement-mediated pan-lobular hepatocyte injury in all of the cases with GCH-AHA, whereas little C5b-9 was seen in hepatocytes in cases with AIH. Inflammation in GCH-AHA comprised mainly lobular macrophages and neutrophils, whereas portal and periportal T-cell and B-cell inflammation characterized cases with AIH. Most cases with AIH responded to therapy with prednisone and azathioprine, whereas most cases with GCH-AHA responded only to rituximab. CONCLUSIONS Widespread complement-mediated hepatocyte injury and typical C3a and C5a complement-driven liver inflammation along with Coombs-positive hemolytic anemia in GCH-AHA provide convincing evidence that systemic B-cell autoimmunity plays a central pathologic mechanism in the disease. Our findings support B-cell-directed immunotherapy as a first-line treatment of GCH-AHA.
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Yang Y, Liu YJ, Tang ST, Yang L, Yang J, Cao GQ, Zhang JH, Wang XX, Mao YZ. Elevated Th17 cells accompanied by decreased regulatory T cells and cytokine environment in infants with biliary atresia. Pediatr Surg Int 2013; 29:1249-60. [PMID: 24122073 DOI: 10.1007/s00383-013-3421-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/25/2013] [Indexed: 12/26/2022]
Abstract
PURPOSE The aim of this study was to investigate the role of Th17 and T reg cells in biliary atresia (BA) and to assess the liver cytokine environment in BA patients. METHODS The percentages of Th17 and T reg cells in peripheral blood mononuclear cells (PBMCs) of BA patients and healthy controls (HC) were evaluated. The serum concentrations of IL-17a and IL-23 as well as Foxp3, IL-17a, ROR-γt, IL-6, IL-1β and TGF-β1 m-RNA and protein expressions in liver tissues and the number of Foxp3, IL-17a, ROR-γt, CD4 expressing cells which infiltrated the hepatic tissues were determined. RESULTS The Th17/T reg cell ratio (P < 0.001) and blood concentrations of IL-17a and IL-23 (P < 0.05) were increased in the BA as compared to the HC group. Expressions of Foxp3, ROR-γt, IL-17a, IL-1β, IL-6 as well as TGF-β1 mRNA and proteins were significantly increased in BA as compared to HC livers (P < 0.01, P < 0.05). High levels of IL-17a/ROR-γt-positive and moderate levels of Foxp3-positive cells infiltrated damaged BA bile ducts and the ratio of FoxP3+ T to CD4+ T cells was significantly lower in BA than in HC samples (P < 0.01). CONCLUSION Cytokine-induced imbalance between Th17 and T reg cells in BA livers may be involved in bile duct damage.
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Tucker RM, Feldman AG, Fenner EK, Mack CL. Regulatory T cells inhibit Th1 cell-mediated bile duct injury in murine biliary atresia. J Hepatol 2013; 59:790-6. [PMID: 23685050 PMCID: PMC3855478 DOI: 10.1016/j.jhep.2013.05.010] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 04/30/2013] [Accepted: 05/03/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Biliary atresia (BA) is a pediatric inflammatory disease of the biliary system which leads to cirrhosis and the need for liver transplantation. One theory regarding etiology is that bile duct injury is due to virus-induced autoreactive T cell-mediated inflammation. Regulatory T cell (Treg) abnormalities in BA could result in unchecked bystander inflammation and autoimmunity targeting bile ducts. The aim of this study was to determine if Tregs are dysfunctional in the rotavirus-induced mouse model of BA (murine BA). METHODS Murine BA resulted from infection of BALB/c neonates with Rhesus rotavirus (RRV). RESULTS Liver Tregs from BA mice were decreased in number, activation marker expression, and suppressive function. Adoptive transfer studies revealed that RRV-infected mice that received Tregs had significantly increased survival (84%) compared to controls (12.5%). In addition, ablation of Tregs in older mice, followed by RRV infection, resulted in increased bile duct injury. CONCLUSIONS These studies demonstrate that dysregulation of Tregs is present in murine BA and that diminished Treg function may be implicated in the pathogenesis of human BA.
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Affiliation(s)
| | | | | | - Cara L. Mack
- University of Colorado, Denver,Children’s Hospital Colorado, Denver, CO 80262
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