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Ronca V, Gerussi A, Collins P, Parente A, Oo YH, Invernizzi P. The liver as a central "hub" of the immune system: pathophysiological implications. Physiol Rev 2025; 105:493-539. [PMID: 39297676 DOI: 10.1152/physrev.00004.2023] [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: 05/18/2023] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 01/16/2025] Open
Abstract
The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last part of the review will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver diseases, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.
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Affiliation(s)
- Vincenzo Ronca
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Paul Collins
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
| | - Alessandro Parente
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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Hayashi M, Abe K, Sugaya T, Takahata Y, Fujita M, Takahashi A, Ohira H. A low baseline serum myostatin concentration is associated with poor clinical outcome in patients with primary biliary cholangitis. J Gastroenterol Hepatol 2024; 39:2069-2076. [PMID: 38816894 DOI: 10.1111/jgh.16639] [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: 02/28/2024] [Revised: 04/21/2024] [Accepted: 05/20/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND AND AIM Primary biliary cholangitis (PBC) is an autoimmune-mediated cholestatic liver disease that can progress to biliary cirrhosis and liver-related death. The associations between baseline myostatin levels and clinical outcomes in PBC patients are unknown. We aimed to clarify the influence of myostatin levels on the clinical outcomes of PBC patients. METHODS A total of 119 PBC patients were analyzed in this study. Myostatin levels were measured in stored sera before ursodeoxycholic acid treatment, and their associations with the clinical features and prognosis of PBC patients were analyzed. We analyzed the correlation between serum myostatin and chemokines/cytokines. RESULTS Serum myostatin was significantly lower in PBC patients (2343 pg/mL) than in healthy controls (4059 pg/mL, P < 0.001). The prevalence of patients with low myostatin levels increased according to the severity of histological fibrosis. The serum myostatin concentration was negatively correlated with the IL-6 and leucine-rich α2 glycoprotein levels, but the chemokine concentration was not correlated with the myostatin concentration. Low myostatin in PBC patients was associated with shorter survival without liver-related complications (hazard ratio [HR], 3.598; 95% confidence interval [CI], 1.27-10.1; P = 0.015) and shorter transplant-free survival (HR, 3.129; 95% CI, 1.02-9.56; P = 0.045) independent of pretreatment GLOBE score. Patients with both high pretreatment GLOBE scores and low myostatin levels had poor prognoses (log-rank test: P < 0.001). CONCLUSIONS A low serum myostatin concentration at diagnosis was associated with poor clinical outcomes. Assessment of circulating myostatin levels may improve the prediction of outcomes in patients with PBC.
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Affiliation(s)
- Manabu Hayashi
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Tatsuro Sugaya
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Yosuke Takahata
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Masashi Fujita
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
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Liu Y, Hu Y, Li B, Su R, Han Z, Jin B, Li T, Zheng X, Han Y. Innate lymphoid cell subsets in the pathogenesis of primary biliary cholangitis. J Gastroenterol Hepatol 2024; 39:1431-1441. [PMID: 38606537 DOI: 10.1111/jgh.16547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 02/29/2024] [Accepted: 03/04/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND AND AIM Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by destructive lymphocytic cholangitis and specific anti-mitochondrial antibodies. Innate lymphoid cells (ILCs) have been reported to play a role in liver homeostasis and autoimmunity. METHODS We evaluated the features of peripheral ILC1s and ILC3 in patients with PBC and hepatic ILC1 and ILC3 in two different PBC mouse models (dominant-negative transforming growth factor-beta receptor II [dnTGFβRII] and 2-octynoic acid-bovine serum albumin [2OA-BSA]). RESULTS A total of 115 patients and 18 healthy controls were enrolled in the study. Decreased circulating ILC1/3s were observed in early-stage PBC patients, and the numbers of ILC1/3s were negatively correlated with specific parameters and the proportion of T-helper (Th) 1 and Th17 cells. Reduced numbers of ILC1s were observed in PBC mouse models with different etiologies. ILC1-deficient mice had more severe hepatic inflammation after inducing the 2OA-BSA model. Continuous low-dose injections of lipopolysaccharide (LPS) reduced ILC1 levels in mice, consistent with the lower level of ILC1s in PBC patients with high LPS (> 50 ng/mL), and aggravated hepatic lymphocyte infiltration. CONCLUSION Patients with PBC had decreased ILC1s, which were negatively correlated with CD4+ T cells. Deficient ILC1 populations led to disease exacerbations in mice. Our results indicated that ILC1s may participate in the pathogenesis of PBC.
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Affiliation(s)
- Yansheng Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yinan Hu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Bo Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Rui Su
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Zheyi Han
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Boquan Jin
- Department of Immunology, Fourth Military Medical University, Xi'an, China
| | - Ting Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Xiaohong Zheng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
- Department of Immunology, Fourth Military Medical University, Xi'an, China
| | - Ying Han
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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Godbole N, Kyrönlahti A, Hukkinen M, Pihlajoki M, Heikinheimo M, Pakarinen MP. Bacterial translocation markers and toll-like receptors in biliary atresia following successful portoenterostomy. Acta Paediatr 2023; 112:2210-2217. [PMID: 37378619 DOI: 10.1111/apa.16893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 06/15/2023] [Accepted: 06/27/2023] [Indexed: 06/29/2023]
Abstract
AIM The gut-liver axis may contribute to pathophysiology of cholestatic liver disorders like biliary atresia (BA) by bacterial translocation (BT). Toll-like receptors (TLR) are pattern recognition receptors known to activate innate immunity and secretion of inflammatory cytokines. Herein, we examined BT-associated biomarkers and TLRs in relation to liver injury after successful portoenterostomy (SPE) in BA. METHODS Serum levels of lipopolysaccharide-binding protein (LBP), CD14, LAL, TNF-α, IL-6 and FABP2 along with liver expression of TLRs (TLR1, TLR4, TLR7 and TLR9), LBP and CD14 were measured during median 4.9 (1.7-10.6) years follow-up after SPE in 45 BA patients. RESULTS Serum LBP, CD14, TNF-α and IL-6 all increased after SPE whereas LAL and FABP-2 remained unchanged. Serum LBP correlated positively with CD14 and markers of hepatocyte injury and cholestasis, but not with Metavir fibrosis stage, transcriptional markers for fibrosis (ACTA2) or ductular reaction. Serum CD14 concentration was significantly higher in patients with portal hypertension than without. While liver expression of TLR4 and LBP remained low, TLR7 and TLR1 showed marked BA-specific increases, and TLR7 correlated with Metavir fibrosis stage and ACTA2. CONCLUSION BT does not seem to play a significant role in liver injury after SPE in our series of BA patients.
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Affiliation(s)
- Nimish Godbole
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Antti Kyrönlahti
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Maria Hukkinen
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Marjut Pihlajoki
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Markku Heikinheimo
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, USA
- Faculty of Medicine and Health Technology, Center for Child, Adolescent, and Maternal Health Research, Tampere University, Tampere, Finland
| | - Mikko P Pakarinen
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Women's Health, Karolinska Institute, Stockholm, Sweden
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Lee DU, Ponder R, Sandlow S, Yoo A, Lee KJ, Chou H, Fan GH, Urrunaga NH. The impact of recipient and donor gender-match and mismatch on the post-liver transplant outcomes of patients with primary biliary cholangitis. Dig Liver Dis 2023; 55:1242-1252. [PMID: 37085440 PMCID: PMC10524091 DOI: 10.1016/j.dld.2023.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 03/05/2023] [Accepted: 03/25/2023] [Indexed: 04/23/2023]
Abstract
BACKGROUND & AIMS In this study, we evaluate the effects of donor gender on post-liver transplant (LT) prognosis. We specifically consider patients with primary biliary cholangitis (PBC). METHODS The 2005 to 2019 UNOS transplant registry was used to select patients with PBC. The study cohort was stratified by donor gender. All-cause mortality and graft failure hazards were compared using iterative Cox regression analysis. Subanalyses were performed to evaluate gender mismatch on post-LT prognosis. RESULTS There were 1885 patients with PBC. Of these cases, 965 entries had male donors and 920 had female donors. Median follow-up was 4.82 (25-75% IQR 1.83-8.93) years. Having a male donor was associated with higher all-cause mortality (aHR 1.28 95%CI 1.03-1.58) and graft failure (aHR 1.70 95%CI 1.02-2.82). Corresponding incidence rates were also relatively increased. In the sub-analysis of female recipients (n = 1581), those with gender-mismatch (male donors, n = 769) were associated with higher all-cause mortality (aHR 1.41 95%CI 1.11-1.78) but not graft failure. In the male recipient subanalysis (n = 304), no associations were found between gender-mismatch (female donors, n = 108) and all-cause mortality or graft failure. CONCLUSION This study shows that recipients who have male donors experienced higher rates of all-cause mortality following LT. This finding was consistent in the female recipient-male donor mismatch cohort.
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Affiliation(s)
- David Uihwan Lee
- Division of Gastroenterology and Hepatology, University of Maryland, 620W Lexington St, Baltimore, MD 21201, USA.
| | - Reid Ponder
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Sarah Sandlow
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Ashley Yoo
- Division of Gastroenterology and Hepatology, University of Maryland, 620W Lexington St, Baltimore, MD 21201, USA
| | - Ki Jung Lee
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Harrison Chou
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Gregory Hongyuan Fan
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Nathalie Helen Urrunaga
- Division of Gastroenterology and Hepatology, University of Maryland, 620W Lexington St, Baltimore, MD 21201, USA
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Mulcahy V, Liaskou E, Martin JE, Kotagiri P, Badrock J, Jones RL, Rushbrook SM, Ryder SD, Thorburn D, Taylor-Robinson SD, Clark G, Cordell HJ, Sandford RN, Jones DE, Hirschfield GM, Mells GF. Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells. Hepatol Commun 2023; 7:e0110. [PMID: 37026715 PMCID: PMC10079354 DOI: 10.1097/hc9.0000000000000110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 12/21/2022] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND AIMS In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. METHODS We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response ("responders"), 16 PBC patients with inadequate UDCA response ("nonresponders"), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes ("modules") associated with response status and the most highly connected genes ("hub genes") within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation ("latent factors") across all peripheral blood mononuclear cell subsets. RESULTS Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q<0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders. CONCLUSIONS We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response.
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Affiliation(s)
- Victoria Mulcahy
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
- Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Evaggelia Liaskou
- Centre for Liver and Gastrointestinal Research, National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, UK
- Institute of Immunology & Immunotherapy, University of Birmingham, Birmingham, UK
| | - Jose-Ezequiel Martin
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
- Cancer Molecular Diagnostic Laboratory, Oncology Department, University of Cambridge, Cambridge, UK
| | - Prasanti Kotagiri
- Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Jonathan Badrock
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Rebecca L. Jones
- Leeds Liver Unit, The Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Simon M Rushbrook
- Department of Hepatology, Norwich Medical School, University of East Anglia, Norwich, UK
| | - Stephen D. Ryder
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | - Douglas Thorburn
- The Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
| | | | - Graeme Clark
- Stratified Medicine Core Laboratory (SMCL) Next Generation Sequencing Hub, NIHR Cambridge BRC, Cambridge, UK
| | - Heather J. Cordell
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne, UK
| | - Richard N. Sandford
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - David E. Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK
- NIHR Newcastle BRC, Newcastle University, Newcastle-upon-Tyne, UK
| | - Gideon M. Hirschfield
- Toronto Centre for Liver Disease, University Health Network and Department of Medicine, University of Toronto, Toronto, Canada
| | - George F. Mells
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
- Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Chen Y, Chen S, Chuang Y, Chiang B. Attenuation of the severity and changes in the microbiota in an animal model of primary biliary cholangitis by FOXP3 − regulatory T cells. CLINICAL AND TRANSLATIONAL DISCOVERY 2023; 3. [DOI: 10.1002/ctd2.187] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/16/2023] [Indexed: 01/04/2025]
Abstract
AbstractBackgroundPrimary biliary cholangitis (PBC), an autoimmune liver disease, presents with progressive damage to the intrahepatic bile ducts with infiltrating mononuclear cells and the appearance of anti‐mitochondrial antibodies (AMAs). The initiation of autoimmune liver disease is permissively mediated by dysfunctional regulatory T cells (Treg cells). Naïve CD4+ T cells cultured with splenic B220+ cells without additional cytokines or chemicals can differentiate into specific types of Treg cells (Treg/B cells) without expressing forkhead box P3. In this study, we explored the effects of Treg/B cells on disease severity and changes in intestinal microbiota in a murine model of PBC.MethodsTreg/B cells were administered to 2‐octenoic acid‐induced PBC mice. Enzyme‐linked immunosorbent assay, flow cytometry and histopathological techniques were used to evaluate the severity of PBC and to assess its therapeutic effect. Diversity of the intestinal microbiota was determined using 16S rRNA sequencing. The suppressive mechanisms of Treg/B cells were investigated using the bone marrow‐derived dendritic cells (BMDCs).ResultsTreg/B‐cell treatment significantly decreased the levels of serum AMAs against pyruvate dehydrogenase complex E2, lowered the levels of serum bile acids, attenuated inflammatory cell infiltration, reduced dendritic cell activation, altered the population of T cells in the liver and alleviated liver collagen synthesis in PBC mice. In addition, the Treg/B‐cell treatment changed the faecal microbial diversity in PBC mice. Furthermore, Treg/B‐cell treatment decreased the levels of proinflammatory cytokines and expression of costimulatory molecules in BMDCs. This inhibitory effect was partially mediated by the cytotoxic T‐lymphocyte‐associated antigen 4 pathway.ConclusionTreatment with Treg/B cells in a murine model of PBC attenuated liver inflammation and altered the gut microbiota. Immune regulation of Treg/B cells may be a potential therapeutic strategy for treating autoimmune liver disease.
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Affiliation(s)
- Yi‐Lien Chen
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan
| | - Szu‐Ying Chen
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan
| | - Ya‐Hui Chuang
- Department of Clinical Laboratory Sciences and Medical Biotechnology College of Medicine National Taiwan University Taipei Taiwan
| | - Bor‐Luen Chiang
- Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan
- Department of Medical Research National Taiwan University Hospital Taipei Taiwan
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Li Y, Li Z, Chen R, Lian M, Wang H, Wei Y, You Z, Zhang J, Li B, Li Y, Huang B, Chen Y, Liu Q, Lyu Z, Liang X, Miao Q, Xiao X, Wang Q, Fang J, Shi Y, Liu X, Seldin MF, Gershwin ME, Tang R, Ma X. A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression. Nat Commun 2023; 14:1732. [PMID: 36977669 PMCID: PMC10049997 DOI: 10.1038/s41467-023-37213-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.3 locus variant(s) contributes to the pathogenesis of PBC. A genome-wide meta-analysis of 1931 PBC subjects and 7852 controls in two Han Chinese cohorts confirms the strong association between 19p13.3 locus and PBC. By integrating functional annotations, luciferase reporter assay and allele-specific chromatin immunoprecipitation, we prioritize rs2238574, an AT-Rich Interaction Domain 3A (ARID3A) intronic variant, as a potential causal variant at 19p13.3 locus. The risk allele of rs2238574 shows higher binding affinity of transcription factors, leading to an increased enhancer activity in myeloid cells. Genome-editing demonstrates the regulatory effect of rs2238574 on ARID3A expression through allele-specific enhancer activity. Furthermore, knock-down of ARID3A inhibits myeloid differentiation and activation pathway, and overexpression of the gene has the opposite effect. Finally, we find ARID3A expression and rs2238574 genotypes linked to disease severity in PBC. Our work provides several lines of evidence that a non-coding variant regulates ARID3A expression, presenting a mechanistic basis for association of 19p13.3 locus with the susceptibility to PBC.
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Affiliation(s)
- You Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Zhiqiang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
- Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China
| | - Ruiling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Hanxiao Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Yiran Wei
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Jun Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Yikang Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Bingyuan Huang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Yong Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Qiaoyan Liu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Zhuwan Lyu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Xueying Liang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Jingyuan Fang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - YongYong Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
- Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China
| | - Xiangdong Liu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, China
| | - Michael F Seldin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
- Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
- Institute of Aging & Tissue Regeneration, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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9
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Bozward A, Ce M, Dell'oro L, Oo YH, Ronca V. Breakdown in hepatic tolerance and its relation to autoimmune liver diseases. Minerva Gastroenterol (Torino) 2023; 69:10-22. [PMID: 33793157 DOI: 10.23736/s2724-5985.21.02853-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The liver is a complex immunological organ. It has both immunogenic and tolerogenic capacity. Tolerogenic potential of human liver with its protective firewalls is required to guard the body against the continuous influx of microbial product from the gut via the sinusoids and biliary tree. Immunotolerance and anergic state is maintained by a combined effort of both immune cells, parenchyma cells, epithelial and endothelial cells. Despite this, an unknown trigger can ignite the pathway towards breakdown in hepatic tolerance leading to autoimmune liver diseases. Understanding the initial stimulus which causes the hepatic immune system to switch from the regulatory arm towards self-reactive effector arm remains challenging. Dissecting this pathology using the current technological advances is crucial to develop curative immune based therapy in autoimmune liver diseases. We discuss the hepatic immune cells and non-immune cells which maintain liver tolerance and the evidence of immune system barrier breach which leads to autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis.
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Affiliation(s)
- Amber Bozward
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK
| | - Maurizio Ce
- Department of Health Sciences, University of Milan, Milan, Italy
| | | | - Ye H Oo
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
| | - Vincenzo Ronca
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK - .,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
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10
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Caspase-10 affects the pathogenesis of primary biliary cholangitis by regulating inflammatory cell death. J Autoimmun 2022; 133:102940. [PMID: 36323068 DOI: 10.1016/j.jaut.2022.102940] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/08/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease that involves chronic inflammation and injury to biliary epithelial cells. To identify critical genetic factor(s) in PBC patients, we performed whole-exome sequencing of five female siblings, including one unaffected and four affected sisters, in a multi-PBC family, and identified 61 rare heterozygote variants that segregated only within the affected sisters. Among them, we were particularly interested in caspase-10, for although several caspases are involved in cell death, inflammation and autoimmunity, caspase-10 is little known from this perspective. We generated caspase-10 knockout macrophages, and then investigated the obtained phenotypes in comparison to those of its structurally similar protein, caspase-8. Unlike caspase-8, caspase-10 does not play a role during differentiation into macrophages, but after differentiation, it regulates the process of inflammatory cell deaths such as necroptosis and pyroptosis more strongly. Interestingly, caspase-10 displays better protease activity than caspase-8 in the process of RIPK1 cleavage, and an enhanced ability to form a complex with RIPK1 and FADD in human macrophages. Higher inflammatory cell death affected the fibrotic response of hepatic stellate cells; this effect could be recovered by treatment with UDCA and OCA, which are currently approved for PBC patients. Our findings strongly indicate that the defective roles of caspase-10 in macrophages contribute to the pathogenesis of PBC, thereby suggesting a new therapeutic strategy for PBC treatment.
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11
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Shao T, Leung PSC, Zhang W, Tsuneyama K, Ridgway WM, Young HA, Shuai Z, Ansari AA, Gershwin ME. Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression. Cell Mol Immunol 2022; 19:1130-1140. [PMID: 36042351 PMCID: PMC9508183 DOI: 10.1038/s41423-022-00904-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/11/2022] [Indexed: 11/09/2022] Open
Abstract
The interferon (IFN) signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity. We have generated a unique murine model named ARE-Del, with chronic overexpression of IFNγ, by altering IFNγ metabolism. Importantly, these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis, including high titers of autoantibodies and portal inflammation. We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis. To study this hypothesis, ARE-Del+/- mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied. JAK inhibition resulted in a significant reduction in portal inflammation and bile duct damage, associated with a significant reduction in splenic and hepatic CD4+ T cells and CD8+ T cells. Functionally, ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγ and TNF from splenic CD4+ T cells. Additionally, ruxolitinib treatment also decreased the frequencies of germinal center B (GC B) cells and T follicular helper (Tfh) cells and led to lower serological AMA levels. Of note, liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment. Mechanistically, ruxolitinib inhibited the secretion of IL-6, TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro, indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 pathway. Our data highlight the significance, both immunologically and clinically, of the JAK/STAT signaling pathway in autoimmune cholangitis.
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Affiliation(s)
- Tihong Shao
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
| | - Patrick S C Leung
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
| | - Weici Zhang
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - William M Ridgway
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
| | - Howard A Young
- Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Aftab A Ansari
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA.
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12
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. HLA, gut microbiome and hepatic autoimmunity. Front Immunol 2022; 13:980768. [PMID: 36059527 PMCID: PMC9433828 DOI: 10.3389/fimmu.2022.980768] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022] Open
Abstract
Genetic susceptibility to autoimmune liver diseases is conferred mainly by polymorphisms of genes encoding for the human leukocyte antigens (HLA). The strongest predisposition to autoimmune hepatitis type 1 (AIH-1) is linked to the allele DRB1*03:01, possession of which is associated with earlier disease onset and more severe course. In populations where this allele is very rare, such as in Asia, and in DRB1*03-negative patients, risk of AIH-1 is conferred by DRB1*04, which is associated with later disease onset and milder phenotype. AIH type 2 (AIH-2) is associated with DRB1*07. The pediatric condition referred to as autoimmune sclerosing cholangitis (ASC), is associated with the DRB1*13 in populations of Northern European ancestry. DRB1*1501 is protective from AIH-1, AIH-2 and ASC in Northern European populations. Possession of the DRB1*08 allele is associated with an increased risk of primary biliary cholangitis (PBC) across different populations. DRB1*03:01 and B*08:01 confer susceptibility to primary sclerosing cholangitis (PSC), as well as DRB1*13 and DRB1*15 in Europe. The hepatic blood supply is largely derived from the splanchnic circulation, suggesting a pathophysiological role of the gut microbiome. AIH appears to be associated with dysbiosis, increased gut permeability, and translocation of intestinal microbial products into the circulation; molecular mimicry between microbial and host antigens may trigger an autoaggressive response in genetically-predisposed individuals. In PBC an altered enteric microbiome may affect intestinal motility, immunological function and bile secretion. Patients with PSC have a gut microbial profile different from health as well as from patients with inflammatory bowel disease without PSC.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Faculty of Biomedical Sciences, Epatocentro Ticino and Università della Svizzera Italiana, Lugano, Switzerland
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
- *Correspondence: Benedetta Terziroli Beretta-Piccoli,
| | - Giorgina Mieli-Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
| | - Diego Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
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13
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Wang C, Shi Y, Wang X, Ma H, Liu Q, Gao Y, Niu J. Peroxisome Proliferator-Activated Receptors Regulate Hepatic Immunity and Assist in the Treatment of Primary Biliary Cholangitis. Front Immunol 2022; 13:940688. [PMID: 35880178 PMCID: PMC9307989 DOI: 10.3389/fimmu.2022.940688] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/13/2022] [Indexed: 11/26/2022] Open
Abstract
Fibrates, which are agonists of peroxisome proliferator-activated receptor alpha, have received increasing attention in the treatment of primary biliary cholangitis. Reduced alkaline phosphatase levels and improved clinical outcomes were observed in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid (UDCA) monotherapy4 when treated with bezafibrate or fenofibrate combined with UDCA. In contrast to obeticholic acid, which exacerbates pruritus in patients, fibrates have been shown to relieve pruritus. Clinical trial outcomes show potential for the treatment of primary biliary cholangitis by targeting peroxisome proliferator-activated receptors. It is currently agreed that primary biliary cholangitis is an autoimmune-mediated cholestatic liver disease, and peroxisome proliferator-activated receptor is a nuclear receptor that regulates the functions of multiple immune cells, thus playing an important role in regulating innate and adaptive immunity. Therefore, this review focuses on the immune disorder of primary biliary cholangitis and summarizes the regulation of hepatic immunity when peroxisome proliferator-activated receptors are targeted for treating primary biliary cholangitis.
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Affiliation(s)
- Chang Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Ying Shi
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
| | - Xiaomei Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
| | - Heming Ma
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
| | - Quan Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yanhang Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Yanhang Gao, ; Junqi Niu,
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Yanhang Gao, ; Junqi Niu,
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14
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Increased Monocyte Production of IL-6 after Toll-like Receptor Activation in Children with Autism Spectrum Disorder (ASD) Is Associated with Repetitive and Restricted Behaviors. Brain Sci 2022; 12:brainsci12020220. [PMID: 35203983 PMCID: PMC8870658 DOI: 10.3390/brainsci12020220] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 01/27/2023] Open
Abstract
The prevalence of autism spectrum disorder (ASD) has starkly increased, instigating research into risk factors for ASD. This research has identified immune risk factors for ASD, along with evidence of immune dysfunction and excess inflammation frequently experienced by autistic individuals. Increased innate inflammatory cytokines, including interleukin (IL)-6, are seen repeatedly in ASD; however, the origin of excess IL-6 in ASD has not been identified. Here we explore specific responses of circulating monocytes from autistic children. We isolated CD14+ monocytes from whole blood and stimulated them for 24 h under three conditions: media alone, lipoteichoic acid to activate TLR2, and lipopolysaccharide to activate TLR4. We then measured secreted cytokine concentrations in cellular supernatant using a human multiplex bead immunoassay. We found that after TLR4 activation, CD14+ monocytes from autistic children produce increased IL-6 compared to monocytes from children with typical development. IL-6 concentration also correlated with worsening restrictive and repetitive behaviors. These findings suggest dysfunctional activation of myeloid cells, and may indicate that other cells of this lineage, including macrophages, and microglia in the brain, might have a similar dysfunction. Further research on myeloid cells in ASD is warranted.
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15
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You H, Ma X, Efe C, Wang G, Jeong SH, Abe K, Duan W, Chen S, Kong Y, Zhang D, Wei L, Wang FS, Lin HC, Yang JM, Tanwandee T, Gani RA, Payawal DA, Sharma BC, Hou J, Yokosuka O, Dokmeci AK, Crawford D, Kao JH, Piratvisuth T, Suh DJ, Lesmana LA, Sollano J, Lau G, Sarin SK, Omata M, Tanaka A, Jia J. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis. Hepatol Int 2022; 16:1-23. [PMID: 35119627 PMCID: PMC8843914 DOI: 10.1007/s12072-021-10276-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, Mainland, China
| | - Cumali Efe
- Department of Gastroenterology, Gazi Yaşargil Education and Research Hospital, Diyarbakir, Turkey
| | - Guiqiang Wang
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, Mainland, China
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Clinical Research Institute, Beijing, Mainland, China
| | - Lai Wei
- Hepatobiliary Pancreatic Center, Tsinghua Changgung Hospital, Tsinghua University, Beijing, Mainland, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospial, Beijing, Mainland, China
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jin Mo Yang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rino A. Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Diana A. Payawal
- Department of Medicine, Fatima University Medical Center, Manila, Philippines
| | | | - Jinlin Hou
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Mainland, China
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - A. Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Darrell Crawford
- School of Medicine, University of Queensland, Brisbane, Australia
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand
| | - Dong Jin Suh
- Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
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16
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Liu Y, Cavallaro PM, Kim BM, Liu T, Wang H, Kühn F, Adiliaghdam F, Liu E, Vasan R, Samarbafzadeh E, Farber MZ, Li J, Xu M, Mohad V, Choi M, Hodin RA. A role for intestinal alkaline phosphatase in preventing liver fibrosis. Theranostics 2021; 11:14-26. [PMID: 33391458 PMCID: PMC7681079 DOI: 10.7150/thno.48468] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
Rationale: Liver fibrosis is frequently associated with gut barrier dysfunction, and the lipopolysaccharides (LPS) -TLR4 pathway is common to the development of both. Intestinal alkaline phosphatase (IAP) has the ability to detoxify LPS, as well as maintain intestinal tight junction proteins and gut barrier integrity. Therefore, we hypothesized that IAP may function as a novel therapy to prevent liver fibrosis. Methods: Stool IAP activity from cirrhotic patients were determined. Common bile duct ligation (CBDL) and Carbon Tetrachloride-4 (CCl4)-induced liver fibrosis models were used in WT, IAP knockout (KO), and TLR4 KO mice supplemented with or without exogenous IAP in their drinking water. The gut barrier function and liver fibrosis markers were tested. Results: Human stool IAP activity was decreased in the setting of liver cirrhosis. In mice, IAP activity and genes expression decreased after CBDL and CCl4 exposure. Intestinal tight junction related genes and gut barrier function were impaired in both models of liver fibrosis. Oral IAP supplementation attenuated the decrease in small intestine tight junction protein gene expression and gut barrier function. Liver fibrosis markers were significantly higher in IAP KO compared to WT mice in both models, while oral IAP rescued liver fibrosis in both WT and IAP KO mice. In contrast, IAP supplementation did not attenuate fibrosis in TLR4 KO mice in either model. Conclusions: Endogenous IAP is decreased during liver fibrosis, perhaps contributing to the gut barrier dysfunction and worsening fibrosis. Oral IAP protects the gut barrier and further prevents the development of liver fibrosis via a TLR4-mediated mechanism.
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Affiliation(s)
- Yang Liu
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Paul M. Cavallaro
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Byeong-Moo Kim
- Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Tao Liu
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
- Department of Gastroenterological Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hongyan Wang
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
- Department of Gastroenterological Surgery, People's Hospital of Liaoning Province, Shenyang, China
| | - Florian Kühn
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Fatemeh Adiliaghdam
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Enyu Liu
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
- Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jian, China
| | - Robin Vasan
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
- Department of Surgery, University-Pittsburgh Medical Center, Pittsburgh, PA, US
| | - Ehsan Samarbafzadeh
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Matthew Z. Farber
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Junhui Li
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Meng Xu
- Department of General Surgery, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an, China
| | - Vidisha Mohad
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Michael Choi
- Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
| | - Richard A. Hodin
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
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17
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Yan C, Koda S, Wu J, Zhang BB, Yu Q, Netea MG, Tang RX, Zheng KY. Roles of Trained Immunity in the Pathogenesis of Cholangiopathies: A Therapeutic Target. Hepatology 2020; 72:1838-1850. [PMID: 32463941 DOI: 10.1002/hep.31395] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/21/2020] [Accepted: 04/28/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Chao Yan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Stephane Koda
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Jing Wu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Bei-Bei Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Qian Yu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.,Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Ren-Xian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Kui-Yang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, People's Republic of China.,National Experimental Demonstration Center for Basic Medicine Education, Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, People's Republic of China
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18
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Liu SP, Bian ZH, Zhao ZB, Wang J, Zhang W, Leung PSC, Li L, Lian ZX. Animal Models of Autoimmune Liver Diseases: a Comprehensive Review. Clin Rev Allergy Immunol 2020; 58:252-271. [PMID: 32076943 DOI: 10.1007/s12016-020-08778-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Autoimmune liver diseases (AILDs) are potentially life-threatening chronic liver diseases which include autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and recently characterized IgG4-related sclerosing cholangitis. They are caused by immune attack on hepatocytes or bile ducts, with different mechanisms and clinical manifestations. The etiologies of AILDs include a susceptible genetic background, environment insults, infections, and changes of commensal microbiota, but remain complicated. Understanding of the underlying mechanisms of AILDs is mandatory for early diagnosis and intervention, which is of great importance for better prognosis. Thus, animal models are developed to mimic the pathogenesis, find biomarkers for early diagnosis, and for therapeutic attempts of AILDs. However, no animal models can fully recapitulate features of certain AILD, especially the late stages of diseases. Certain limitations include different living condition, cell composition, and time frame of disease development and resolution. Moreover, there is no IgG4 in rodents which exists in human. Nevertheless, the understanding and therapy of AILDs have been greatly advanced by the development and mechanistic investigation of animal models. This review will provide a comprehensive overview of traditional and new animal models that recapitulate different features and etiologies of distinct AILDs.
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Affiliation(s)
- Shou-Pei Liu
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Zhen-Hua Bian
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.,School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Zhi-Bin Zhao
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Jinjun Wang
- College of Environmental Science and Engineering, Yangzhou University, Yangzhou, 225127, Jiangsu, China
| | - Weici Zhang
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Patrick S C Leung
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Liang Li
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China. .,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.
| | - Zhe-Xiong Lian
- Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China. .,Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China.
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19
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Hayashi M, Abe K, Fujita M, Takahashi A, Sekine H, Ohira H. Association between serum ficolin-1 level and disease progression in primary biliary cholangitis. PLoS One 2020; 15:e0238300. [PMID: 32915797 PMCID: PMC7485786 DOI: 10.1371/journal.pone.0238300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 08/13/2020] [Indexed: 12/12/2022] Open
Abstract
Pattern recognition molecules (PRMs) in the complement system contribute to homeostasis as mediators of complement activation. The contribution of PRMs to primary biliary cholangitis (PBC) is unknown. In the current study, we aimed to assess the association between PRMs and the clinical findings of PBC. A total of 122 PBC patients and 20 healthy controls were enrolled. We measured four different PRMs (mannose-binding lectin [MBL], ficolin-1, ficolin-2 and ficolin-3) using stored sera, and retrospectively analyzed the associations between PRMs and laboratory findings, histological findings, and the development of cirrhosis-related conditions. Ficolin-1 levels were significantly higher in the PBC patients than in the healthy controls (152 ng/mL vs 102 ng/mL, P = 0.034), but no significant differences were observed regarding MBL, ficolin-2, and ficolin-3 levels. Ficolin-1 was significantly correlated with alkaline phosphatase (ALP). Low ficolin-1 levels were significantly associated with the development of cirrhosis-related conditions independent for histological stage and ALP levels (hazard ratio: 0.933; 95% confidence interval: 0.875-0.994; P = 0.032). Patients with low levels of ficolin-1 (< 77 ng/mL) had a significantly increased rate of developing cirrhosis-related conditions. Low ficolin-1 levels were associated with disease progression independent of histological stage and ALP levels in patients with PBC.
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Affiliation(s)
- Manabu Hayashi
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
- Department of Immunology, Fukushima Medical University, Fukushima, Japan
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Masashi Fujita
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Hideharu Sekine
- Department of Immunology, Fukushima Medical University, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
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20
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Ronca V, Mancuso C, Milani C, Carbone M, Oo YH, Invernizzi P. Immune system and cholangiocytes: A puzzling affair in primary biliary cholangitis. J Leukoc Biol 2020; 108:659-671. [PMID: 32349179 DOI: 10.1002/jlb.5mr0320-200r] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 03/09/2020] [Accepted: 03/19/2020] [Indexed: 12/13/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by the destruction of the small and medium bile ducts. Its pathogenesis is still unknown. Despite the genome wide association study findings, the therapies targeting the cytokines pathway, tested so far, have failed. The concept of the biliary epithelium as a key player of the PBC pathogenesis has emerged over the last few years. It is now well accepted that the biliary epithelial cells (BECs) actively participate to the genesis of the damage. The chronic stimulation of BECs via microbes and bile changes the cell phenotype toward an active state, which, across the production of proinflammatory mediators, can recruit, retain, and activate immune cells. The consequent immune system activation can in turn damage BECs. Thus, the crosstalk between both innate and adaptive immune cells and the biliary epithelium creates a paracrine loop responsible for the disease progression. In this review, we summarize the evidence provided in literature about the role of BECs and the immune system in the pathogenesis of PBC. We also dissect the relationship between the immune system and the BECs, focusing on the unanswered questions and the future potential directions of the translational research and the cellular therapy in this area.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- National Institute of Health Research Liver Biomedical Research Centre Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Clara Mancuso
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Chiara Milani
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Ye Htun Oo
- National Institute of Health Research Liver Biomedical Research Centre Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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21
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Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with non-suppurative destruction of the intrahepatic bile ducts. The interplay of genetics and environmental triggers contributes to the onset of the disease and subsequently results in cholestasis and progressive fibrosis. Recently, genome-wide association studies (GWAS) have identified multiple genes influencing the susceptibility to PBC in HLA and non-HLA loci. However, it is estimated that the known risk variants merely account for no more than 20% of the heritability of PBC and causes of the remaining heritability remain uncertain. Increasing evidence suggests that the presence of epigenetic abnormalities may explain the "missing heritability" that cannot be captured by GWAS. Among these epigenetic mechanisms, DNA methylation, histone modification, and noncoding RNAs (i.e. miRNA and lncRNA) are involved in the pathogenesis of PBC. Additionally, telomere dysregulation in biliary epithelial cells (BECs) may play a role in disease onset, whereas a deficiency in sex chromosome and skewed gene expression in the X chromosome may to some extent explain the female dominance in PBC.
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22
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D, Vierling JM, Adams D, Alpini G, Banales JM, Beuers U, Björnsson E, Bowlus C, Carbone M, Chazouillères O, Dalekos G, De Gottardi A, Harada K, Hirschfield G, Invernizzi P, Jones D, Krawitt E, Lanzavecchia A, Lian ZX, Ma X, Manns M, Mavilio D, Quigley EM, Sallusto F, Shimoda S, Strazzabosco M, Swain M, Tanaka A, Trauner M, Tsuneyama K, Zigmond E, Gershwin ME. The challenges of primary biliary cholangitis: What is new and what needs to be done. J Autoimmun 2019; 105:102328. [PMID: 31548157 DOI: 10.1016/j.jaut.2019.102328] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 08/18/2019] [Accepted: 08/20/2019] [Indexed: 02/06/2023]
Abstract
Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino, Lugano, Switzerland; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; European Reference Network ERN RARE-LIVER.
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK
| | - John M Vierling
- Division of Abdominal Transplantation and Section of Gastroenterology and Hepatology, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - David Adams
- Birmingham NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesMedical School, University of Birmingham, Birmingham, UK
| | - Gianfranco Alpini
- Indiana Center for Liver Research, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN, USA
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastián, Spain
| | - Ulrich Beuers
- European Reference Network ERN RARE-LIVER; Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Einar Björnsson
- Division of Gastroenterology and Hepatology, Landspitali the National University Hospital of Iceland, Reykjavík, Iceland
| | - Christopher Bowlus
- Division of Gastroenterology and Hepatology, University of California at Davis School of Medicine, Davis, CA, USA
| | - Marco Carbone
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan-Bicocca School of Medicine, Monza, Italy
| | - Olivier Chazouillères
- European Reference Network ERN RARE-LIVER; Service d'Hépatologie, Hôpital Saint-Antoine, Paris, France
| | - George Dalekos
- Institute of Internal Medicine and Hepatology, Department of Medicine and Research, Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece
| | - Andrea De Gottardi
- European Reference Network ERN RARE-LIVER; Epatocentro Ticino & Division of Gastroenterology and Hepatology Ente Ospedaliero Cantonale and Università della Svizzera Italiana, Lugano, Switzerland
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Gideon Hirschfield
- Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada
| | - Pietro Invernizzi
- European Reference Network ERN RARE-LIVER; Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan-Bicocca School of Medicine, Monza, Italy
| | - David Jones
- Institute of Cellular Medicine and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK
| | - Edward Krawitt
- Department of Medicine, University of Vermont, Burlington, VT, USA
| | | | - Zhe-Xiong Lian
- Institutes for Life Sciences, South China University of Technology, Higher Education Mega Center, Guangzhou, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - Michael Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Italy
| | - Eamon Mm Quigley
- Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA
| | - Federica Sallusto
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
| | - Shinji Shimoda
- Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Mario Strazzabosco
- Liver Center, Department of Medicine, Yale University, New Haven, CT, USA
| | - Mark Swain
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Ehud Zigmond
- Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, California, USA.
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23
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Ma WT, Gao F, Gu K, Chen DK. The Role of Monocytes and Macrophages in Autoimmune Diseases: A Comprehensive Review. Front Immunol 2019; 10:1140. [PMID: 31178867 PMCID: PMC6543461 DOI: 10.3389/fimmu.2019.01140] [Citation(s) in RCA: 220] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/07/2019] [Indexed: 12/19/2022] Open
Abstract
Monocytes (Mo) and macrophages (Mϕ) are key components of the innate immune system and are involved in regulation of the initiation, development, and resolution of many inflammatory disorders. In addition, these cells also play important immunoregulatory and tissue-repairing roles to decrease immune reactions and promote tissue regeneration. Several lines of evidence have suggested a causal link between the presence or activation of these cells and the development of autoimmune diseases. In addition, Mo or Mϕ infiltration in diseased tissues is a hallmark of several autoimmune diseases. However, the detailed contributions of these cells, whether they actually initiate disease or perpetuate disease progression, and whether their phenotype and functional alteration are merely epiphenomena are still unclear in many autoimmune diseases. Additionally, little is known about their heterogeneous populations in different autoimmune diseases. Elucidating the relevance of Mo and Mϕ in autoimmune diseases and the associated mechanisms could lead to the identification of more effective therapeutic strategies in the future.
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Affiliation(s)
- Wen-Tao Ma
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China.,School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Fei Gao
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Kui Gu
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - De-Kun Chen
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China
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24
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Immunological abnormalities in patients with primary biliary cholangitis. Clin Sci (Lond) 2019; 133:741-760. [DOI: 10.1042/cs20181123] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 02/28/2019] [Accepted: 03/05/2019] [Indexed: 12/13/2022]
Abstract
Abstract
Primary biliary cholangitis (PBC), an autoimmune liver disease occurring predominantly in women, is characterized by high titers of serum anti-mitochondrial antibodies (AMAs) and progressive intrahepatic cholestasis. The immune system plays a critical role in PBC pathogenesis and a variety of immune cell subsets have been shown to infiltrate the portal tract areas of patients with PBC. Amongst the participating immune cells, CD4 T cells are important cytokine-producing cells that foster an inflammatory microenvironment. Specifically, these cells orchestrate activation of other immune cells, including autoreactive effector CD8 T cells that cause biliary epithelial cell (BEC) injury and B cells that produce large quantities of AMAs. Meanwhile, other immune cells, including dendritic cells (DCs), natural killer (NK) cells, NKT cells, monocytes, and macrophages are also important in PBC pathogenesis. Activation of these cells initiates and perpetuates bile duct damage in PBC patients, leading to intrahepatic cholestasis, hepatic damage, liver fibrosis, and eventually cirrhosis or even liver failure. Taken together, the body of accumulated clinical and experimental evidence has enhanced our understanding of the immunopathogenesis of PBC and suggests that immunotherapy may be a promising treatment option. Herein, we summarize current knowledge regarding immunological abnormalities of PBC patients, with emphasis on underlying pathogenic mechanisms. The differential immune response which occurs over decades of disease activity suggests that different therapies may be needed at different stages of disease.
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25
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Thuy LTT, Hai H, Hieu VN, Dat NQ, Hoang DV, Kawada N. Antifibrotic Therapy for Liver Cirrhosis. THE EVOLVING LANDSCAPE OF LIVER CIRRHOSIS MANAGEMENT 2019:167-189. [DOI: 10.1007/978-981-13-7979-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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26
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Rodrigues PM, Perugorria MJ, Santos-Laso A, Bujanda L, Beuers U, Banales JM. Primary biliary cholangitis: A tale of epigenetically-induced secretory failure? J Hepatol 2018; 69:1371-1383. [PMID: 30193962 DOI: 10.1016/j.jhep.2018.08.020] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/14/2018] [Accepted: 08/24/2018] [Indexed: 12/16/2022]
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune-related destruction of small to medium size intrahepatic bile ducts. The aetiology of PBC is unknown and its pathogenesis remains obscure. Both genetic variants and environmental factors have been linked to increased PBC susceptibility, with other alterations known to cooperate in disease pathobiology. Increasing evidence indicates the presence of epigenetic abnormalities in PBC, particularly alterations of cholangiocellular microRNAs (miRNAs or miRs). This review highlights and discusses the most relevant epigenetic alterations found in patients with PBC, focusing on the role of miR-506 in the promotion of cholestasis and immune activation.
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Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Alvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
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27
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Ma HD, Zhao ZB, Ma WT, Liu QZ, Gao CY, Li L, Wang J, Tsuneyama K, Liu B, Zhang W, Zhou Y, Gershwin ME, Lian ZX. Gut microbiota translocation promotes autoimmune cholangitis. J Autoimmun 2018; 95:47-57. [PMID: 30340822 PMCID: PMC6290354 DOI: 10.1016/j.jaut.2018.09.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 09/17/2018] [Accepted: 09/23/2018] [Indexed: 02/07/2023]
Abstract
Gut microbiota and bacterial translocation have been implicated as significant contributors to mucosal immune responses and tolerance; alteration of microbial molecules, termed pathogen-associated molecular patterns (PAMP) and bacterial translocation are associated with immune pathology. However, the mechanisms by which dysregulated gut microbiota promotes autoimmunity is unclear. We have taken advantage of a well-characterized murine model of primary biliary cholangitis, dnTGFβRII mice, and an additional unique construct, toll-like receptor 2 (TLR2)-deficient dnTGFβRII mice coined dnTGFβRIITLR2-/- mice to investigate the influences of gut microbiota on autoimmune cholangitis. Firstly, we report that dnTGFβRII mice manifest altered composition of gut microbiota and that alteration of this gut microbiota by administration of antibiotics significantly alleviates T-cell-mediated infiltration and bile duct damage. Second, toll-like receptor 2 (TLR2)-deficient dnTGFβRII mice demonstrate significant exacerbation of autoimmune cholangitis when their epithelial barrier integrity was disrupted. Further, TLR2-deficiency mediates downregulated expression of tight junction-associated protein ZO-1 leading to increased gut permeability and bacterial translocation from gut to liver; use of antibiotics reduces microbiota translocation to liver and also decreases biliary pathology. In conclusion, our data demonstrates the important role of gut microbiota and bacterial translocation in the pathogenesis of murine autoimmune cholangitis.
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MESH Headings
- Ampicillin/pharmacology
- Animals
- Anti-Bacterial Agents/pharmacology
- Autoimmune Diseases/drug therapy
- Autoimmune Diseases/microbiology
- Autoimmune Diseases/pathology
- Bacterial Translocation/drug effects
- Bacterial Translocation/immunology
- Bile Ducts/drug effects
- Bile Ducts/immunology
- Bile Ducts/microbiology
- Bile Ducts/pathology
- Colon/drug effects
- Colon/immunology
- Colon/microbiology
- Colon/pathology
- Feces/microbiology
- Female
- Gastrointestinal Microbiome/drug effects
- Gastrointestinal Microbiome/immunology
- Gene Expression Regulation
- Immunity, Mucosal/drug effects
- Liver/drug effects
- Liver/immunology
- Liver/microbiology
- Liver/pathology
- Liver Cirrhosis, Biliary/drug therapy
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/microbiology
- Liver Cirrhosis, Biliary/pathology
- Metronidazole/pharmacology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neomycin/pharmacology
- Receptor, Transforming Growth Factor-beta Type II/deficiency
- Receptor, Transforming Growth Factor-beta Type II/genetics
- Receptor, Transforming Growth Factor-beta Type II/immunology
- Signal Transduction
- Toll-Like Receptor 2/deficiency
- Toll-Like Receptor 2/genetics
- Toll-Like Receptor 2/immunology
- Zonula Occludens-1 Protein/genetics
- Zonula Occludens-1 Protein/immunology
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Affiliation(s)
- Hong-Di Ma
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, China; Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China; Liver Immunology Laboratory, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhi-Bin Zhao
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, China; Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China; Liver Immunology Laboratory, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Wen-Tao Ma
- Liver Immunology Laboratory, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Qing-Zhi Liu
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, China; Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China; Liver Immunology Laboratory, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Cai-Yue Gao
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, China; Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China; Liver Immunology Laboratory, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Liang Li
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, China; Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China; Liver Immunology Laboratory, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
| | - Jinjun Wang
- College of Environmental Science and Engineering, Yangzhou University, Yangzhou, 225127, Jiangsu Province, China
| | - Koichi Tsuneyama
- Department of Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Bin Liu
- Department of Rheumatology and Immunology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
| | - Yongjian Zhou
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, China.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
| | - Zhe-Xiong Lian
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, China; Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China; Liver Immunology Laboratory, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
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28
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Schwinge D, Schramm C. Sex-related factors in autoimmune liver diseases. Semin Immunopathol 2018; 41:165-175. [DOI: 10.1007/s00281-018-0715-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 09/18/2018] [Indexed: 12/13/2022]
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29
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Reuveni D, Gore Y, Leung PSC, Lichter Y, Moshkovits I, Kaminitz A, Brazowski E, Lefebvre E, Vig P, Varol C, Halpern Z, Shibolet O, Gershwin ME, Zigmond E. The Critical Role of Chemokine (C-C Motif) Receptor 2-Positive Monocytes in Autoimmune Cholangitis. Front Immunol 2018; 9:1852. [PMID: 30158929 PMCID: PMC6104446 DOI: 10.3389/fimmu.2018.01852] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 07/26/2018] [Indexed: 12/12/2022] Open
Abstract
The therapy of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases despite significant improvements in our understanding of both immunological and molecular events that lead to loss of tolerance to the E2 component of pyruvate dehydrogenase, the immunodominant autoepitope of PBC. It is well known that Ly6Chi monocytes are innate immune cells infiltrating inflammatory sites that are dependent on the expression of C–C motif chemokine receptor 2 (CCR2) for emigration from bone marrow. Importantly, humans with PBC have a circulating monocyte pro-inflammatory phenotype with macrophage accumulation in portal tracts. We have taken advantage of an inducible chemical xenobiotic model of PBC and recapitulated the massive infiltration of monocytes to portal areas. To determine the clinical significance, we immunized both CCR2-deficient mice and controls with 2OA-BSA and noted that CCR2 deficiency is protective for the development of autoimmune cholangitis. Importantly, because of the therapeutic potential, we focused on inhibiting monocyte infiltration through the use of cenicriviroc (CVC), a dual chemokine receptor CCR2/CCR5 antagonist shown to be safe in human trials. Importantly, treatment with CVC resulted in amelioration of all aspects of disease severity including serum total bile acids, histological severity score, and fibrosis stage. In conclusion, our results indicate a major role for Ly6Chi monocytes and for CCR2 in PBC pathogenesis and suggest that inhibition of this axis by CVC should be explored in humans through the use of clinical trials.
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Affiliation(s)
- Debby Reuveni
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Gore
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Yael Lichter
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Itay Moshkovits
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ayelet Kaminitz
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eli Brazowski
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Eric Lefebvre
- Allergan Plc, South San Francisco, CA, United States
| | - Pamela Vig
- Allergan Plc, South San Francisco, CA, United States
| | - Chen Varol
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Zamir Halpern
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Oren Shibolet
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Ehud Zigmond
- The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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30
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Liaskou E, Patel SR, Webb G, Bagkou Dimakou D, Akiror S, Krishna M, Mells G, Jones DE, Bowman SJ, Barone F, Fisher BA, Hirschfield GM. Increased sensitivity of Treg cells from patients with PBC to low dose IL-12 drives their differentiation into IFN-γ secreting cells. J Autoimmun 2018; 94:143-155. [PMID: 30119881 DOI: 10.1016/j.jaut.2018.07.020] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/30/2018] [Accepted: 07/31/2018] [Indexed: 02/06/2023]
Abstract
IL-12 is a pro-inflammatory cytokine that induces the production of interferon-γ (IFNγ) and favours the differentiation of T helper 1 (Th1) cells. In the presence of IL-12 human Treg cells acquire a Th1-like phenotype with reduced suppressive activity in vitro. Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterised by high Th1 and Th17 infiltrating cells, reduced frequencies of Treg cells, and a genetic association with IL-12 signalling. Herein, we sought to evaluate the IL-12 signalling pathway in PBC pathology, by studying human samples from patients with PBC, alongside those with primary Sjögren's syndrome (pSS)(autoimmune disease with IL-12 signalling gene association), primary sclerosing cholangitis (PSC) (cholestatic liver disease without IL-12 gene association) and healthy individuals. Our data revealed that TLR stimulation of PBC (n = 17) and pSS monocytes (n = 6) resulted in significant induction of IL12A mRNA (p < 0.05, p < 0.01, respectively) compared to PSC monocytes (n = 13) and at similar levels to HC monocytes (n = 8). PSC monocytes expressed significantly less IL-12p70 (108 pg/ml, mean) and IL-23 (358 pg/ml) compared to HC (458 pg/ml and 951 pg/ml, respectively) (p < 0.01, p < 0.05). Treg cells from patients with PBC (n = 16) and pSS (n = 3) but not PSC (n = 10) and HC (n = 8) responded to low dose (10 ng/ml) IL-12 stimulation by significant upregulation of IFNγ (mean 277 and 254 pg/ml, respectively) compared to PSC and HC Treg cells (mean 22 and 77 pg/ml, respectively)(p < 0.05). This effect was mediated by the rapid and strong phosphorylation of STAT4 on Treg cells from patients with PBC and pSS (p < 0.05) but not PSC and HC. In the liver of patients with PBC (n = 7) a significantly higher proportion of IL-12Rβ2+Tregs (16% on average) was detected (p < 0.05) compared to other liver disease controls (5%)(n = 18) which also showed ex vivo high IFNG and TBET expression. CONCLUSION: Our data show an increased sensitivity of PBC and pSS Treg cells to low dose IL-12 stimulation, providing ongoing support for the importance of the IL12-IL-12Rβ2-STAT4 pathway on Treg cells in disease pathogenesis and potentially treatment.
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Affiliation(s)
- Evaggelia Liaskou
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Samita R Patel
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Gwilym Webb
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Danai Bagkou Dimakou
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Sarah Akiror
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Mahesh Krishna
- Weiss School of Natural Sciences, Rice University, Houston, TX, USA
| | - George Mells
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Dave E Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK; NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle-upon-Tyne, UK
| | - Simon J Bowman
- Institute of Inflammation and Ageing and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Francesca Barone
- Institute of Inflammation and Ageing and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Benjamin A Fisher
- Institute of Inflammation and Ageing and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Gideon M Hirschfield
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; University Hospitals Birmingham, Birmingham, UK; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada.
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31
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Cheung AC, Lorenzo Pisarello MJ, LaRusso NF. Pathobiology of biliary epithelia. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1220-1231. [PMID: 28716705 PMCID: PMC5777905 DOI: 10.1016/j.bbadis.2017.06.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 06/22/2017] [Accepted: 06/26/2017] [Indexed: 12/12/2022]
Abstract
Cholangiocytes are epithelial cells that line the intra- and extrahepatic biliary tree. They serve predominantly to mediate the content of luminal biliary fluid, which is controlled via numerous signaling pathways influenced by endogenous (e.g., bile acids, nucleotides, hormones, neurotransmitters) and exogenous (e.g., microbes/microbial products, drugs etc.) molecules. When injured, cholangiocytes undergo apoptosis/lysis, repair and proliferation. They also become senescent, a form of cell cycle arrest, which may prevent propagation of injury and/or malignant transformation. Senescent cholangiocytes can undergo further transformation to a senescence-associated secretory phenotype (SASP), where they begin secreting pro-inflammatory and pro-fibrotic signals that may contribute to disease initiation and progression. These and other concepts related to cholangiocyte pathobiology will be reviewed herein. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Angela C Cheung
- Division of Gastroenterology and Hepatology, Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, United States
| | - Maria J Lorenzo Pisarello
- Division of Gastroenterology and Hepatology, Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, United States
| | - Nicholas F LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, United States.
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32
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Lleo A, Marzorati S, Anaya JM, Gershwin ME. Primary biliary cholangitis: a comprehensive overview. Hepatol Int 2017; 11:485-499. [PMID: 29164395 DOI: 10.1007/s12072-017-9830-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 10/05/2017] [Indexed: 12/15/2022]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by biliary destruction, progressive cholestasis, and potentially liver cirrhosis. Patients develop a well-orchestrated immune reaction, both innate and adaptive, against mitochondrial antigens that specifically targets intrahepatic biliary cells. A puzzling feature of PBC is that the immune attack is predominantly organ specific, although the mitochondrial autoantigens are found in all nucleated cells. The disease results from a combination of genetic and environmental risk factors; however, the exact pathogenesis remains unclear. Serologically, PBC is characterized by presence of antimitochondrial antibodies, which are present in 90-95 % of patients and are often detectable years before clinical signs appear. Like other complex disorders, PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. A significant number of patients develop end-stage liver disease and eventually require liver transplantation. Recent studies from large international cohorts have better identified prognostic factors, suggesting a change in patient management based on risk stratification. Therapeutic options are changing. In this review we discuss data on the autoimmune responses and treatment of the disease.
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Affiliation(s)
- Ana Lleo
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, MI, Italy
- Department of Biomedical Sciences, Humanitas University, Rozzano, MI, Italy
| | - Simona Marzorati
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, MI, Italy
| | - Juan-Manuel Anaya
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA.
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33
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Jose SS, Bendickova K, Kepak T, Krenova Z, Fric J. Chronic Inflammation in Immune Aging: Role of Pattern Recognition Receptor Crosstalk with the Telomere Complex? Front Immunol 2017; 8:1078. [PMID: 28928745 PMCID: PMC5591428 DOI: 10.3389/fimmu.2017.01078] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 08/18/2017] [Indexed: 12/22/2022] Open
Abstract
Age-related decline in immunity is characterized by stem cell exhaustion, telomere shortening, and disruption of cell-to-cell communication, leading to increased patient risk of disease. Recent data have demonstrated that chronic inflammation exerts a strong influence on immune aging and is closely correlated with telomere length in a range of major pathologies. The current review discusses the impact of inflammation on immune aging, the likely molecular mediators of this process, and the various disease states that have been linked with immunosenescence. Emerging findings implicate NF-κB, the major driver of inflammatory signaling, in several processes that regulate telomere maintenance and/or telomerase activity. While prolonged triggering of pattern recognition receptors is now known to promote immunosenescence, it remains unclear how this process is linked with the telomere complex or telomerase activity. Indeed, enzymatic control of telomere length has been studied for many decades, but alternative roles of telomerase and potential influences on inflammatory responses are only now beginning to emerge. Crosstalk between these pathways may prove to be a key molecular mechanism of immunosenescence. Understanding how components of immune aging interact and modify host protection against pathogens and tumors will be essential for the design of new vaccines and therapies for a wide range of clinical scenarios.
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Affiliation(s)
- Shyam Sushama Jose
- Cellular and Molecular Immunoregulation Group (CMI), Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne’s University Hospital Brno, Brno, Czechia
- Department of Biology, Faculty of Medicine, Masaryk University, Czechia
| | - Kamila Bendickova
- Cellular and Molecular Immunoregulation Group (CMI), Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne’s University Hospital Brno, Brno, Czechia
| | - Tomas Kepak
- Pediatric Oncology Translational Research (POTR), International Clinical Research Center (ICRC), St. Anne’s University Hospital Brno, Brno, Czechia
- Pediatric Hematology and Oncology, University Hospital Brno, Brno, Czechia
| | - Zdenka Krenova
- Pediatric Oncology Translational Research (POTR), International Clinical Research Center (ICRC), St. Anne’s University Hospital Brno, Brno, Czechia
- Pediatric Hematology and Oncology, University Hospital Brno, Brno, Czechia
| | - Jan Fric
- Cellular and Molecular Immunoregulation Group (CMI), Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne’s University Hospital Brno, Brno, Czechia
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34
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Umemura T, Sekiguchi T, Joshita S, Yamazaki T, Fujimori N, Shibata S, Ichikawa Y, Komatsu M, Matsumoto A, Shums Z, Norman GL, Tanaka E, Ota M. Association between serum soluble CD14 and IL-8 levels and clinical outcome in primary biliary cholangitis. Liver Int 2017; 37:897-905. [PMID: 27860118 DOI: 10.1111/liv.13316] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 11/09/2016] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts that often leads to liver decompensation and liver failure. Although the biochemical response to ursodeoxycholic acid (UDCA) can predict disease outcome in PBC, few biomarkers have been identified as prognostic tools applicable prior to UDCA treatment. We therefore sought to identify such indicators of long-term outcome in PBC in the Japanese population. METHODS The prebiopsy serum samples and subsequent clinical data of 136 patients with PBC treated with UDCA were analysed over a median follow-up period of 8.8 years. Serum levels of biomarkers related to microbial translocation (sCD14, EndoCAb and I-FABP) were measured along with those of 33 cytokines and chemokines and additional auto-antibodies. Associations between the tested parameters and the clinical outcomes of liver decompensation and liver-related death/liver transplantation were evaluated using the Cox proportional hazards model with stepwise methods and Kaplan-Meier analysis. RESULTS Elevated levels of serum IL-8, and sCD14 before UDCA therapy were significantly associated with both liver decompensation and liver-related death/liver transplantation. In multivariate analyses, IL-8≥46.5 pg/mL or sCD14≥2.0 μg/mL at enrolment demonstrated the same results. Kaplan-Meier analysis also revealed IL-8 and sCD14 to be significantly associated with a poor outcome. sCD14 was significantly correlated with IL-8. EndoCAb and I-FABP were not related to disease outcome. CONCLUSIONS Serum IL-8 and sCD14 levels before UDCA therapy represent noninvasive surrogate markers of prognosis in patients with PBC.
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Affiliation(s)
- Takeji Umemura
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomohiro Sekiguchi
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoo Yamazaki
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoyuki Fujimori
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Soichiro Shibata
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuki Ichikawa
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Michiharu Komatsu
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | | | | | - Eiji Tanaka
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masao Ota
- Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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35
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Tian J, Yang G, Chen HY, Hsu DK, Tomilov A, Olson KA, Dehnad A, Fish SR, Cortopassi G, Zhao B, Liu FT, Gershwin ME, Török NJ, Jiang JX. Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J 2016; 30:4202-4213. [PMID: 27630169 PMCID: PMC5102125 DOI: 10.1096/fj.201600392rr] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 09/01/2016] [Indexed: 12/19/2022]
Abstract
Macrophage activation is an important feature of primary biliary cholangitis (PBC) pathogenesis and other cholestatic liver diseases. Galectin-3 (Gal3), a pleiotropic lectin, is produced by monocytic cells and macrophages. However, its role in PBC has not been addressed. We hypothesized that Gal3 is a key to induce NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in macrophages and in turn to propagate proinflammatory IL-17 signaling. In liver tissues from patients with PBC and dnTGF-βRII mice, a model of autoimmune cholangitis, the expression of Gal3, NLRP3, and the adaptor protein adaptor apoptosis-associated speck-like protein was induced, with the downstream activation of caspase-1 and IL-1β. In wild-type hepatic macrophages, deoxycholic acid induced the association of Gal3 and NLRP3 with direct activation of the inflammasome, resulting in an increase in IL-1β. Downstream retinoid-related orphan receptor C mRNA, IL-17A, and IL-17F were induced. In Gal3-/- macrophages, no inflammasome activation was detected. To confirm the key role of Gal3 in the pathogenesis of cholestatic liver injury, we generated dnTGF-βRII/galectin-3-/- (dn/Gal3-/-) mice, which showed impaired inflammasome activation along with significantly improved inflammation and fibrosis. Taken together, our data point to a novel role of Gal3 as an initiator of inflammatory signaling in autoimmune cholangitis, mediating the activation of NLRP3 inflammasome and inducing IL-17 proinflammatory cascades. These studies provide a rationale to target Gal3 in autoimmune cholangitis and potentially other cholestatic diseases.-Tian, J., Yang, G., Chen, H.-Y., Hsu, D. K., Tomilov, A., Olson, K. A., Dehnad, A., Fish, S. R., Cortopassi, G., Zhao, B., Liu, F.-T., Gershwin, M. E., Török, N. J., Jiang, J. X. Galectin-3 regulates inflammasome activation in cholestatic liver injury.
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Affiliation(s)
- Jijing Tian
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
| | - Guoxiang Yang
- Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis Medical Center, Sacramento, California, USA
| | - Huan-Yuan Chen
- Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA
- Institute of Biomedical Sciences, Academia Sinica, Taipei City, Taiwan
| | - Daniel K Hsu
- Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA
| | - Alexey Tomilov
- Department of Molecular Biosciences, University of California Davis, Sacramento, California, USA
| | - Kristin A Olson
- Department of Pathology, University of California Davis Medical Center, Sacramento, California, USA; and
| | - Ali Dehnad
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA
| | - Sarah R Fish
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA
| | - Gino Cortopassi
- Department of Molecular Biosciences, University of California Davis, Sacramento, California, USA
| | - Bin Zhao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
| | - Fu-Tong Liu
- Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA
- Institute of Biomedical Sciences, Academia Sinica, Taipei City, Taiwan
| | - M Eric Gershwin
- Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis Medical Center, Sacramento, California, USA
| | - Natalie J Török
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA
- Veterans Administration Northern California Medical Center, Mather, California, USA
| | - Joy X Jiang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA;
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Kiziltas S. Toll-like receptors in pathophysiology of liver diseases. World J Hepatol 2016; 8:1354-1369. [PMID: 27917262 PMCID: PMC5114472 DOI: 10.4254/wjh.v8.i32.1354] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 08/17/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated molecular patterns. Given constant exposure to pathogens from gut, strict control of TLR-associated signaling pathways is essential in the liver, which otherwise may lead to inappropriate production of pro-inflammatory cytokines and interferons and may generate a predisposition to several autoimmune and chronic inflammatory diseases. The liver is considered to be a site of tolerance induction rather than immunity induction, with specificity in hepatic cell functions and distribution of TLR. Recent data emphasize significant contribution of TLR signaling in chronic liver diseases via complex immune responses mediating hepatocyte (i.e., hepatocellular injury and regeneration) or hepatic stellate cell (i.e., fibrosis and cirrhosis) inflammatory or immune pathologies. Herein, we review the available data on TLR signaling, hepatic expression of TLRs and associated ligands, as well as the contribution of TLRs to the pathophysiology of hepatic diseases.
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Affiliation(s)
- Safak Kiziltas
- Safak Kiziltas, Department of Gastroenterology, Baskent University Istanbul Hospital, 34662 Istanbul, Turkey
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Czaja AJ. Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis. World J Gastroenterol 2016; 22:9257-9278. [PMID: 27895415 PMCID: PMC5107691 DOI: 10.3748/wjg.v22.i42.9257] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 10/07/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023] Open
Abstract
The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora (dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens (molecular mimicry). Activated gut-derived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.
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Qin B, Wei T, Wang L, Ma N, Tang Q, Liang Y, Yang Z, Zhou L, Zhong R. Decreased expression of TIPE2 contributes to the hyperreactivity of monocyte to Toll-like receptor ligands in primary biliary cirrhosis. J Gastroenterol Hepatol 2016; 31:1177-83. [PMID: 26644386 DOI: 10.1111/jgh.13251] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 11/03/2015] [Accepted: 11/29/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Previous studies have shown differential TIPE2 expression in several autoimmune diseases. However, the expression levels of TIPE2 in primary biliary cirrhosis (PBC) remained unclear. The purposes of this study were to evaluate TIPE2 expression levels in patients with PBC and further investigate its role in PBC pathogenesis. METHODS A total of 40 PBC patients and 44 healthy controls were included in the present study. Quantitative reverse-transcription polymerase chain reaction and western blotting were used to determine the differences in mRNA and protein expression levels of TIPE2. The correlations of TIPE2 expression levels and clinical characteristics, inflammatory cytokines, and ursodeoxycholic acid treatment were also assessed. Besides, the influence of TIPE2 on the reactivity of monocyte to Toll-like receptor ligands was further analyzed. RESULTS The expression levels of TIPE2 were significantly decreased in PBC patients compared with normal controls (P < 0.01). The expression levels of TIPE2 were negatively correlated with alanine aminotransferase (r = -0.40, P = 0.01), alkaline phosphatase (r = -0.36, P = 0.02), gamma glutamyl transpeptidase (r = -0.53, P < 0.01), tumor necrosis factor (TNF)-α (r = -0.332, P = 0.03), interleukin (IL)-1β (r = -0.386, P = 0.01), and IL-8 (r = -0.366, P = 0.02) levels in sera from PBC patients. TIPE2 expression level could be significantly increased after ursodeoxycholic acid treatment (P < 0.01). The production of TNF-α, IL-1β, and IL-8 by monocytes from PBC patients after stimulation with lipopolysaccharide and lipoteichoic acid was significantly increased when TIPE2 was knocked down. Furthermore, TIPE2 knockdown could promote activation of nuclear factor-κB pathways through increasing phosphorylation and degradation of IκB in peripheral blood monocytes from PBC patients. CONCLUSION The present study reported that insufficient expression of TIPE2 might be involved in the hyperreactivity of monocyte to Toll-like receptor ligands in PBC.
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Affiliation(s)
- Baodong Qin
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Tingting Wei
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Lili Wang
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ning Ma
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qingqin Tang
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yan Liang
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zaixing Yang
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Lin Zhou
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Renqian Zhong
- Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
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Wang J, Qin Y, Mi X. The protective effects of bone marrow-derived mesenchymal stem cell (BMSC) on LPS-induced acute lung injury via TLR3-mediated IFNs, MAPK and NF-κB signaling pathways. Biomed Pharmacother 2016; 79:176-87. [PMID: 27044826 DOI: 10.1016/j.biopha.2016.02.037] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 02/16/2016] [Accepted: 02/16/2016] [Indexed: 12/29/2022] Open
Abstract
The study attempted to clarify the protective role of bone marrow-derived mesenchymal stem cell (BMSC) transplantation on LPS-induced acute lung injury (ALI) of rats. BMSC were obtained from bone marrow of rat, cultured and proliferated in vitro. Rats of ALI were established through lipopolysaccharide (LPS) administration. Male rats were allocated to control group, ALI group and BMSC, transplantation group. Rats were sacrificed after BMSC injection after 12h, 24h and 48h. Here we investigated the role of BMSC in LPS-induced alveolar macrophages to further demonstrate the mechanism of BMSC to lung injury. TLR3, a member of Toll-like receptor family, has been found in macrophages and the cell surface. In our study, first BMSC successfully reversed LPS-induced lung injury by hematoxylin-eosin (H&E) staining, ameliorated apoptosis via TUNEL and flow cytometer analysis, as well as improved cell structure. And then, western blot, quantitative real-time PCR, immunohistochemistry and immunofluorescence analysis were used to confirm that TLR3 was significantly down-regulated for BMSC treatment. Subsequently, TRIF and RIP1, down-streaming signals of TLR3, were inhibited greatly, leading to TRAF3, MAPK as well as NF-κB inactivity. Our results indicated that BMSC transplantation group displayed inhibitory effects on interferon (IFNs) levels via TLR3 in LPS-induced ALI and preventive effects on inflammation response via TLR3-regualted MAPK and NF-κB signaling pathway in LPS-induced lung injury. The present study indicated that BMSC could display protective effects on LPS-induced ALI and provide an experimental basis for clinical therapy.
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Affiliation(s)
- Jingcai Wang
- Department of Pediatrics, People's Hospital of Liaocheng, Shandong 252000, China
| | - Ying Qin
- General Hospital of Jinan Iron and Steel Group Co., Ltd., Shandong 252000, China.
| | - Xiuju Mi
- Department of Pediatrics, People's Hospital of Liaocheng, Shandong 252000, China
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Shimoda S, Tanaka A. It is time to change primary biliary cirrhosis (PBC): New nomenclature from "cirrhosis" to "cholangitis", and upcoming treatment based on unveiling pathology. Hepatol Res 2016; 46:407-15. [PMID: 26518139 DOI: 10.1111/hepr.12615] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 10/22/2015] [Accepted: 10/26/2015] [Indexed: 12/15/2022]
Abstract
Primary biliary cirrhosis (PBC) is a chronic, organ-specific, autoimmune liver disease characterized by progressive cholestasis, eventually leading to cirrhosis. Several lines of evidence have revealed a crucial role of adaptive as well as innate immune responses in the etiopathogenesis of PBC, and more recently, the biology of bile duct cells and genome-wide association studies (GWAS) demonstrated several key molecules and pathways in this enigmatic disease. Although ursodeoxycholic acid (UDCA) has been the only approved drug for PBC with clinical evidences for improvement of long-term outcomes, a substantial population have suboptimal responses to UDCA, resulting in unfavorable outcomes. In this regard, second-line treatment for patients refractory to UDCA is strongly awaited. In Japan, bezafibrate (BF) has been frequently used for this purpose, yet recent clinical trials failed to clearly demonstrate clinical efficacy of BF. Novel pharmacotherapies targeted to key molecules and pathways in PBC are upcoming. Finally, we sincerely call on all members of the Japan Society of Hepatology to use from this moment on the name "primary biliary cholangitis" for the disease known by its abbreviation PBC, in keeping with a very recent global agreement.
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Affiliation(s)
- Shinji Shimoda
- Department of Medicine and Biosystemic Science, Faculty of Medicine, Kyushu University, Fukuoka, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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Sun Y, Haapanen K, Li B, Zhang W, Van de Water J, Gershwin ME. Women and primary biliary cirrhosis. Clin Rev Allergy Immunol 2016; 48:285-300. [PMID: 25241227 DOI: 10.1007/s12016-014-8449-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Primary biliary cirrhosis occurs more frequently in women, and previous studies indicated that the average age of primary biliary cirrhosis (PBC) onset makes pregnancy in PBC patients uncommon. However, more recently, improved diagnostic testing has enabled detection of PBC in younger women, including those of childbearing age. This has led investigators to become increasingly interested in the relationship between the ontogeny of PBC and pregnancy. Published cases indicate that the typical age for pregnant women to be diagnosed with PBC is in the early 30s, and that during gestation, pruritus and jaundice are the most common symptoms. During gestation, susceptible women may experience onset of PBC resulting from the drastic changes in female hormones; this would include not only the mitochondrial damage due to accumulation of bile acids but also changes in the immune response during the different stages of pregnancy that might play an important role in the breakdown of self-tolerance. The mechanisms underlying the potential relationship between PBC and pregnancy warrant further investigation. For women first diagnosed with PBC during gestation, or those for whom first appearance of a flare up occurs during and postpartum, investigation of the immune response throughout gestation could provide new avenues for immunologic therapeutic intervention and the discovery of new treatment strategies for PBC.
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Affiliation(s)
- Ying Sun
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
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Shimoda S, Hisamoto S, Harada K, Iwasaka S, Chong Y, Nakamura M, Bekki Y, Yoshizumi T, Shirabe K, Ikegami T, Maehara Y, He XS, Gershwin ME, Akashi K. Natural killer cells regulate T cell immune responses in primary biliary cirrhosis. Hepatology 2015; 62:1817-27. [PMID: 26264889 PMCID: PMC4681684 DOI: 10.1002/hep.28122] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 08/05/2015] [Indexed: 12/16/2022]
Abstract
UNLABELLED The hallmark of primary biliary cirrhosis (PBC) is the presence of autoreactive T- and B-cell responses that target biliary epithelial cells (BECs). Biliary cell cytotoxicity is dependent upon initiation of innate immune responses followed by chronic adaptive, as well as bystander, mechanisms. Critical to these mechanisms are interactions between natural killer (NK) cells and BECs. We have taken advantage of the ability to isolate relatively pure viable preparations of liver-derived NK cells, BECs, and endothelial cells, and studied interactions between NK cells and BECs and focused on the mechanisms that activate autoreactive T cells, their dependence on interferon (IFN)-γ, and expression of BEC major histocompatibility complex (MHC) class I and II molecules. Here we show that at a high NK/BEC ratio, NK cells are cytotoxic for autologous BECs, but are not dependent on autoantigen, yet still activate autoreactive CD4(+) T cells in the presence of antigen presenting cells. In contrast, at a low NK/BEC ratio, BECs are not lysed, but IFN-γ production is induced, which facilitates expression of MHC class I and II molecules on BEC and protects them from lysis upon subsequent exposure to autoreactive NK cells. Furthermore, IFN-γ secreted from NK cells after exposure to autologous BECs is essential for this protective function and enables autoreactive CD4(+) T cells to become cytopathic. CONCLUSIONS NK cell-mediated innate immune responses are likely critical at the initial stage of PBC, but also facilitate and maintain the chronic cytopathic effect of autoantigen-specific T cells, essential for progression of disease.
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Affiliation(s)
- Shinji Shimoda
- Department of Medicine and Biosystemic Science Graduate School of Medical Sciences Kyushu University Fukuoka, Japan
| | - Satomi Hisamoto
- Department of Medicine and Biosystemic Science Graduate School of Medical Sciences Kyushu University Fukuoka, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Sho Iwasaka
- Department of Medicine and Biosystemic Science Graduate School of Medical Sciences Kyushu University Fukuoka, Japan
| | - Yong Chong
- Department of Medicine and Biosystemic Science Graduate School of Medical Sciences Kyushu University Fukuoka, Japan
| | - Minoru Nakamura
- Clinical Research Center in National Hospital Organization (NHO) Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
| | - Yuki Bekki
- Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka, Japan
| | - Ken Shirabe
- Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka, Japan
| | - Toru Ikegami
- Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka, Japan
| | - Xiao-Song He
- Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California at Davis, Davis, CA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California at Davis, Davis, CA
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science Graduate School of Medical Sciences Kyushu University Fukuoka, Japan
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Nieto JC, Sánchez E, Romero C, Román E, Poca M, Guarner C, Juárez C, Soriano G, Vidal S. Impaired innate immune response of leukocytes from ascitic fluid of patients with spontaneous bacterial peritonitis. J Leukoc Biol 2015; 98:819-825. [PMID: 26254307 DOI: 10.1189/jlb.3ab0315-106r] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Accepted: 06/23/2015] [Indexed: 12/24/2022] Open
Abstract
An ascitic microenvironment can condition the immune response of cells from cirrhotic patients with spontaneous bacterial peritonitis. To characterize this response, we determined the cytokine concentrations in ascitic fluid and analyzed the phenotype and function of ascitic leukocytes at diagnosis and after antibiotic-induced resolution in sterile ascites and ascitic fluid of 2 spontaneous bacterial peritonitis variants: positive and negative bacteriological culture. At diagnosis, a high concentration was found of IL-6 and IL-10 in the ascitic fluid from negative and positive bacteriological culture. The IL-6 concentration correlated with the percentage of neutrophils (R = 0.686, P < 0.001). In this context, positive and negative culture neutrophils had an impaired oxidative burst, and, after the antibiotic, the negative culture spontaneous bacterial peritonitis burst was fully recovered. Higher concentrations of IL-6 and IL-10 correlated with the presence of low granular CD 14(low) macrophages (R = -0.436, P = 0.005 and R = 0.414, P = 0.007, respectively). Positive culture spontaneous bacterial peritonitis macrophages expressed the lowest levels of CD16, CD86, CD11b and CD206, and HLA-DR, suggesting an impaired global function. Treatment increased all markers on the positive culture macrophages and CD11b and CD86 on negative culture macrophages. In negative culture spontaneous bacterial peritonitis, this increase was accompanied by phagocytic function recovery. The antibiotics then reverted the marker levels on positive and negative culture macrophages to the levels on sterile ascitis macrophages and restored ascitic negative culture cell function.
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Affiliation(s)
- Juan Camilo Nieto
- *Department of Immunology and Liver Section, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca IIB-Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain; and Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Elisabet Sánchez
- *Department of Immunology and Liver Section, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca IIB-Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain; and Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Cristina Romero
- *Department of Immunology and Liver Section, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca IIB-Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain; and Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Eva Román
- *Department of Immunology and Liver Section, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca IIB-Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain; and Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Maria Poca
- *Department of Immunology and Liver Section, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca IIB-Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain; and Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Carlos Guarner
- *Department of Immunology and Liver Section, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca IIB-Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain; and Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Cándido Juárez
- *Department of Immunology and Liver Section, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca IIB-Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain; and Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Germán Soriano
- *Department of Immunology and Liver Section, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca IIB-Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain; and Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Silvia Vidal
- *Department of Immunology and Liver Section, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca IIB-Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain; and Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Boghal RH, Stephenson B, Afford SC. Immune cell communication in liver disease and liver regeneration. SIGNALING PATHWAYS IN LIVER DISEASES 2015:110-129. [DOI: 10.1002/9781118663387.ch8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Clinical and pathophysiological consequences of alterations in the microbiome in cirrhosis. Am J Gastroenterol 2015; 110:1399-410; quiz 1411. [PMID: 26416191 DOI: 10.1038/ajg.2015.313] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 08/04/2015] [Indexed: 02/06/2023]
Abstract
Cirrhosis is a major cause of mortality worldwide. Exponential rises in prevalence have been observed secondary to increases in obesity and alcohol consumption. Multiple lines of evidence implicate gut-derived bacteria and bacterial ligands as a central driver of pathogenesis. Recent developments in culture-independent techniques have facilitated a more accurate description of microbiome composition in cirrhosis and led to the description of measures of dysbiosis shown to be associated with disease. More importantly, metagenomic studies are adding to an understanding of the functional contribution of the microbiota and may prove to be a more clinically relevant biomarker than phylogenetic studies. Much like other dysbiotic states such as inflammatory bowel disease, the microbiota in cirrhosis is characterized by a low microbial and genetic diversity. Therapeutic strategies to diminish this process are currently limited to selective intestinal decontamination with antibiotics. This review summarizes the available data and develops a framework for the use of current and future treatment strategies to diminish the consequences of dysbiosis in cirrhosis. Interventional strategies to bind bacterial products in the gut lumen and blood, and modulate the magnitude of host sensing mechanisms remain an unmet clinical need. A greater understanding of the host-microbiota interaction in cirrhosis is of key importance to inform future interventional strategies to diminish the currently escalating burden of the disease.
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Kouroumalis E, Notas G. Primary biliary cirrhosis: From bench to bedside. World J Gastrointest Pharmacol Ther 2015; 6:32-58. [PMID: 26261733 PMCID: PMC4526840 DOI: 10.4292/wjgpt.v6.i3.32] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 11/19/2014] [Accepted: 05/18/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic non-suppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient’s genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated. A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed.
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Chávez-Tapia NC, González-Rodríguez L, Jeong M, López-Ramírez Y, Barbero-Becerra V, Juárez-Hernández E, Romero-Flores JL, Arrese M, Méndez-Sánchez N, Uribe M. Current evidence on the use of probiotics in liver diseases. J Funct Foods 2015; 17:137-151. [DOI: 10.1016/j.jff.2015.05.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Vu T, Rahimian A, Stybayeva G, Gao Y, Kwa T, Van de Water J, Revzin A. Reconfigurable microfluidic device with integrated antibody arrays for capture, multiplexed stimulation, and cytokine profiling of human monocytes. BIOMICROFLUIDICS 2015; 9:044115. [PMID: 26339315 PMCID: PMC4529433 DOI: 10.1063/1.4928128] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 07/27/2015] [Indexed: 06/05/2023]
Abstract
Monocytes represent a class of immune cells that play a key role in the innate and adaptive immune response against infections. One mechanism employed by monocytes for sensing foreign antigens is via toll-like receptors (TLRs)-transmembrane proteins that distinguish classes of foreign pathogens, for example, bacteria (TLR4, 5, and 9) vs. fungi (TLR2) vs. viruses (TLR3, 7, and 8). Binding of antigens activates a signaling cascade through TLR receptors that culminate in secretion of inflammatory cytokines. Detection of these cytokines can provide valuable clinical data for drug developers and disease investigations, but this usually requires a large sample volume and can be technically inefficient with traditional techniques such as flow cytometry, enzyme-linked immunosorbent assay, or luminex. This paper describes an approach whereby antibody arrays for capturing cells and secreted cytokines are encapsulated within a microfluidic device that can be reconfigured to operate in serial or parallel mode. In serial mode, the device represents one long channel that may be perfused with a small volume of minimally processed blood. Once monocytes are captured onto antibody spots imprinted into the floor of the device, the straight channel is reconfigured to form nine individually perfusable chambers. To prove this concept, the microfluidic platform was used to capture monocytes from minimally processed human blood in serial mode and then to stimulate monocytes with different TLR agonists in parallel mode. Three cytokines, tumor necrosis factor-α, interleukin (IL)-6, and IL-10, were detected using anti-cytokine antibody arrays integrated into each of the six chambers. We foresee further use of this device in applications such as pediatric immunology or drug/vaccine testing where it is important to balance small sample volume with the need for high information content.
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Affiliation(s)
- Tam Vu
- Department of Biomedical Engineering, University of California , 451 Health Sciences Drive, Suite 2619, Davis, California 95616, USA
| | - Ali Rahimian
- Department of Biomedical Engineering, University of California , 451 Health Sciences Drive, Suite 2619, Davis, California 95616, USA
| | - Gulnaz Stybayeva
- Department of Biomedical Engineering, University of California , 451 Health Sciences Drive, Suite 2619, Davis, California 95616, USA
| | - Yandong Gao
- Department of Biomedical Engineering, University of California , 451 Health Sciences Drive, Suite 2619, Davis, California 95616, USA
| | - Timothy Kwa
- Department of Biomedical Engineering, University of California , 451 Health Sciences Drive, Suite 2619, Davis, California 95616, USA
| | - Judy Van de Water
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine , 451 Health Sciences Drive, Suite 6510, Davis, California 95616, USA
| | - Alexander Revzin
- Department of Biomedical Engineering, University of California , 451 Health Sciences Drive, Suite 2619, Davis, California 95616, USA
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Zhang L, Ma D, Li X, Deng C, Shi Q, You X, Leng X, Li M, Tang F, Zhang F, Li Y. Gene expression profiles of peripheral blood mononuclear cells in primary biliary cirrhosis. Clin Exp Med 2015; 14:409-16. [PMID: 23958878 DOI: 10.1007/s10238-013-0253-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 07/25/2013] [Indexed: 01/28/2023]
Abstract
Previous studies on gene expression profiles in primary biliary cirrhosis (PBC) have exclusively focused on liver tissue or intrahepatic cells. Since the pathological process is systemic, other complementary studies in blood cells seemed to be reasonable. In this research, we try to explore differentially expressed genes in peripheral blood mononuclear cells (PBMCs) of PBC patients. Nine PBC patients and 9 healthy controls were recruited as Cohort 1 for a microarray study of screening. Total RNA of PBMCs from each individual was isolated and screened by oligonucleotide microarray (22 K). Then, differentially expressed genes were categorized into signaling pathways. Expression levels of three important genes, tyrosine kinase binding protein (TYROBP), C–C motif chemokine 5 (CCL5) and cathepsin L (CTSL) were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) in a second Cohort 2 (30 PBC patients and 20 healthy controls). Results show that sixty-five genes differentially expressed in PBC were identified, 20 of which were up-regulated and 45 of which were down-regulated. Twenty-seven signaling pathways were identified. TYROBP and CCL5 were proved to be down-regulated in PBC, and CTSL was proved to be up-regulated (p < 0.05) in PBC, which were all consistent with the screening study. In conclusions, the analysis of gene expression in PBMCs of PBC and the comparison of gene profiles between PBMCs and the liver may provide new clues to the pathogenesis of the disease.
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Ma D, Li X, Zhang L, Deng C, Zhang T, Wang L, Hu C, Li Y, Zhang F. S100A12 expression in patients with primary biliary cirrhosis. Immunol Invest 2014; 44:13-22. [PMID: 25313445 DOI: 10.3109/08820139.2014.914530] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES S100 calcium binding protein A12 (S100A12) has been supposed to be a pro-inflammatory factor associated with non-infectious inflammatory diseases. However, whether S100A12 is involved in the inflammatory process of primary biliary cirrhosis (PBC) has not been shown. METHODS The levels of S100A12 mRNA transcripts in peripheral mononuclear blood cells (PBMCs) of 66 Chinese patients with primary biliary cirrhosis (PBC), 62 healthy controls (HC) and 55 chronic hepatitis B (CHB) were measured by qRT-PCR. S100A12 serum concentrations in 34 PBC patients were measured by ELISA. RESULTS The levels of S100A12 mRNA transcripts in PBMCs of patients with PBC were significantly higher than healthy controls (p < 0.01) and that of patients with CHB (p < 0.01). Importantly, the levels of S100A12 mRNA in PBMCs and S100A12 protein levels in serum were positively correlated with biochemical indicators of bile duct and hepatocyte damage. CONCLUSION S100A12 might participate in the damage of biliary epithelial cells and hepatocytes in PBC, and analysis of S100A12 expression could be useful as a surrogate marker for the evaluation of PBC activity.
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Affiliation(s)
- Danxu Ma
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences , Beijing , China
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