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Fiorucci S, Urbani G, Di Giorgio C, Biagioli M, Distrutti E. Current Landscape and Evolving Therapies for Primary Biliary Cholangitis. Cells 2024; 13:1580. [PMID: 39329760 PMCID: PMC11429758 DOI: 10.3390/cells13181580] [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: 08/29/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024] Open
Abstract
Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Cristina Di Giorgio
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06123 Perugia, Italy;
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2
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Tang X, Ren X, Huang T, Miao Y, Ha W, Li Z, Yang L, Mi D. Prognostic and Immunological Significance of the Molecular Subtypes and Risk Signatures Based on Cuproptosis in Hepatocellular Carcinoma. Mediators Inflamm 2023; 2023:3951940. [PMID: 37124062 PMCID: PMC10139815 DOI: 10.1155/2023/3951940] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/26/2022] [Accepted: 03/27/2023] [Indexed: 05/02/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) remains a challenging medical problem. Cuproptosis is a novel form of cell death that plays a crucial role in tumorigenesis, angiogenesis, and metastasis. However, it remains unclear whether cuproptosis-related genes (CRGs) influence the outcomes and immune microenvironment of HCC patients. METHOD From The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, we obtained the mRNA expression file and related clinical information of HCC patients. We selected 19 CRGs as candidate genes for this study according to previous literature. We performed a differential expression analysis of the 19 CRGs between malignant and precancerous tissue. Based on the 19 CRGs, we enrolled cluster analysis to identify cuproptosis-related subtypes of HCC patients. A prognostic risk signature was created utilizing univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. We employed independent and stratification survival analyses to investigate the predictive value of this model. The functional enrichment features, mutation signatures, immune profile, and response to immunotherapy of HCC patients were also investigated according to the two molecular subtypes and the prognostic signature. RESULTS We found that 17 CRGs significantly differed in HCC versus normal samples. Cluster analysis showed two distinct molecular subtypes of cuproptosis. Cluster 1 is preferentially related to poor prognosis, high activity of immune response signaling, high mutant frequency of TP53, and distinct immune cell infiltration versus cluster 2. Through univariate and LASSO Cox regression analyses, we created a cuproptosis-related prognostic risk signature containing LIPT1, DLAT, MTF1, GLS, and CDKN2A. High-risk HCC patients were shown to have a worse prognosis. The risk signature was proved to be an independent predictor of prognosis in both the TCGA and ICGC datasets, according to multivariate analysis. The signature also performed well in different stratification of clinical features. The immune cells, which included regulatory T cells (Treg), B cells, macrophages, mast cells, NK cells, and aDCs, as well as immune functions containing cytolytic activity, MHC class I, and type II IFN response, were remarkably distinct between the high-risk and low-risk groups. The tumor immune dysfunction and exclusion (TIDE) score suggested that high-risk patients had a higher response rate to immune checkpoint inhibitors than low-risk patients. CONCLUSION This research discovered the potential prognostic and immunological significance of cuproptosis in HCC, improved the understanding of cuproptosis, and may deliver new directions for developing more efficacious therapeutic techniques for HCC patients.
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Affiliation(s)
- Xiaolong Tang
- The First Clinical Medical College, Lanzhou University, Lanzhou City, Gansu Province, China
- The Second Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, China
| | - Xiangqing Ren
- The First Clinical Medical College, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Tian Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Yandong Miao
- The Second Department of Medical Oncology, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai City, Shandong Province, China
| | - Wuhua Ha
- The First Clinical Medical College, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Zheng Li
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou City, Gansu Province, China
| | - Lixia Yang
- Gansu Academy of Traditional Chinese Medicine, Lanzhou City, Gansu Province, China
| | - Denghai Mi
- The First Clinical Medical College, Lanzhou University, Lanzhou City, Gansu Province, China
- Gansu Academy of Traditional Chinese Medicine, Lanzhou City, Gansu Province, China
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3
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McCommis KS, Finck BN. The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease. Biomolecules 2023; 13:261. [PMID: 36830630 PMCID: PMC9953669 DOI: 10.3390/biom13020261] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/26/2023] [Accepted: 01/28/2023] [Indexed: 02/03/2023] Open
Abstract
Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways in the liver in regulating hepatic and systemic energy metabolism and summarize the current state of targeting this pathway to treat diseases of the liver. Available evidence suggests that inhibiting the MPC in hepatocytes and other cells of the liver produces a variety of beneficial effects for treating type 2 diabetes and nonalcoholic steatohepatitis. We also highlight areas where our understanding is incomplete regarding the pleiotropic effects of MPC inhibition.
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Affiliation(s)
- Kyle S. McCommis
- Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA
| | - Brian N. Finck
- Center for Human Nutrition, Washington University School of Medicine, Saint Louis, MO 63110, USA
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Freitag M, Schwertz H. A New Role of NAP1L1 in Megakaryocytes and Human Platelets. Int J Mol Sci 2022; 23:ijms232314694. [PMID: 36499021 PMCID: PMC9737020 DOI: 10.3390/ijms232314694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/26/2022] Open
Abstract
Platelets (PLTs) are anucleate and considered incapable of nuclear functions. Contrastingly, nuclear proteins were detected in human PLTs. For most of these proteins, it is unclear if nuclear or alternatively assigned functions are performed, a question we wanted to address for nuclear assembly protein 1like 1 (NAP1L1). Using a wide array of molecular methods, including RNAseq, co-IP, overexpression and functional assays, we explored expression pattern and functionality of NAP1L1 in PLTs, and CD34+-derived megakaryocytes (MKs). NAP1L1 is expressed in PLTs and MKs. Co-IP experiments revealed that dihydrolipolylysine-residue acetyltransferase (DLAT encoded protein PDC-E2, ODP2) dynamically interacts with NAP1L1. PDC-E2 is part of the mitochondrial pyruvate-dehydrogenase (PDH) multi-enzyme complex, playing a crucial role in maintaining cellular respiration, and promoting ATP-synthesis via the respiratory chain. Since altered mitochondrial function is a hallmark of infectious syndromes, we analyzed PDH activity in PLTs from septic patients demonstrating increased activity, paralleling NAP1L1 expression levels. MKs PDH activity decreased following an LPS-challenge. Furthermore, overexpression of NAP1L1 significantly altered the ability of MKs to form proplatelet extensions, diminishing thrombopoiesis. These results indicate that NAP1L1 performs in other than nucleosome-assembly functions in PTLs and MKs, binding a key mitochondrial protein as a potential chaperone, and gatekeeper, influencing PDH activity and thrombopoiesis.
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Affiliation(s)
- Martin Freitag
- Department of Cardiac Surgery, Heart Center Leipzig-University Hospital, 04289 Leipzig, Germany
| | - Hansjörg Schwertz
- Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA
- Division of Occupational Medicine, University of Utah, Salt Lake City, UT 84112, USA
- Occupational Medicine at Billings Clinic Bozeman, Bozeman, MT 59715, USA
- Correspondence: or
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5
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Chen R, Tang R, Ma X, Gershwin ME. Immunologic Responses and the Pathophysiology of Primary Biliary Cholangitis. Clin Liver Dis 2022; 26:583-611. [PMID: 36270718 DOI: 10.1016/j.cld.2022.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis. A recent X-wide association study reveals a novel risk locus on the X chromosome, which reiterates the importance of Treg cells.
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Affiliation(s)
- Ruiling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
| | - M Eric Gershwin
- Division of Rheumatology-Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
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6
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Kilanczyk E, Banales JM, Jurewicz E, Milkiewicz P, Milkiewicz M. p-STAT3 is a PDC-E2 interacting partner in human cholangiocytes and hepatocytes with potential pathobiological implications. Sci Rep 2021; 11:21649. [PMID: 34737337 PMCID: PMC8569217 DOI: 10.1038/s41598-021-01060-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 10/22/2021] [Indexed: 01/13/2023] Open
Abstract
The E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC) is the key autoantigen in primary biliary cholangitis (PBC) and STAT3 is an inflammatory modulator that participates in the pathogenesis of many liver diseases. This study investigated whether PDC-E2 interacts with STAT3 in human cholangiocytes (NHC) and hepatocytes (Hep-G2) under cholestatic conditions induced by glyco-chenodeoxycholic acid (GCDC). GCDC induced PDC-E2 expression in the cytoplasmic and nuclear fraction of NHC, whereas in Hep-G2 cells PDC-E2 expression was induced only in the cytoplasmic fraction. GCDC-treatment stimulated phosphorylation of STAT3 in the cytoplasmic fraction of NHC. siRNA-mediated gene silencing of PDC-E2 reduced the expression of pY-STAT3 in NHC but not in HepG2 cells. Immunoprecipitation and a proximity ligation assay clearly demonstrated that GCDC enhanced pY-STAT3 binding to PDC-E2 in the nuclear and cytoplasmic fraction of NHC cells. Staining with Mitotracker revealed mitochondrial co-localization of PDC-E2/pS-STAT3 complexes in NHC and Hep-G2 cells. In cirrhotic PBC livers the higher expression of both PDC-E2 and pY-STAT3 was observed. The immunoblot analysis demonstrated the occurrence of double bands of PDC-E2 protein in control livers, which was associated with a lower expression of pY-STAT3. Our data indicate the interaction between PDC-E2 and phosphorylated STAT3 under cholestatic conditions, which may play a role in the development of PBC.
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Affiliation(s)
- Ewa Kilanczyk
- Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland.
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital - Ikerbasque, CIBERehd, San Sebastian, Spain
| | | | - Piotr Milkiewicz
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland.,Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
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7
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Vojdani A, Vojdani E, Kharrazian D. Reaction of Human Monoclonal Antibodies to SARS-CoV-2 Proteins With Tissue Antigens: Implications for Autoimmune Diseases. Front Immunol 2021; 11:617089. [PMID: 33584709 PMCID: PMC7873987 DOI: 10.3389/fimmu.2020.617089] [Citation(s) in RCA: 224] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/14/2020] [Indexed: 12/14/2022] Open
Abstract
We sought to determine whether immune reactivity occurs between anti-SARS-CoV-2 protein antibodies and human tissue antigens, and whether molecular mimicry between COVID-19 viral proteins and human tissues could be the cause. We applied both human monoclonal anti-SARS-Cov-2 antibodies (spike protein, nucleoprotein) and rabbit polyclonal anti-SARS-Cov-2 antibodies (envelope protein, membrane protein) to 55 different tissue antigens. We found that SARS-CoV-2 antibodies had reactions with 28 out of 55 tissue antigens, representing a diversity of tissue groups that included barrier proteins, gastrointestinal, thyroid and neural tissues, and more. We also did selective epitope mapping using BLAST and showed similarities and homology between spike, nucleoprotein, and many other SARS-CoV-2 proteins with the human tissue antigens mitochondria M2, F-actin and TPO. This extensive immune cross-reactivity between SARS-CoV-2 antibodies and different antigen groups may play a role in the multi-system disease process of COVID-19, influence the severity of the disease, precipitate the onset of autoimmunity in susceptible subgroups, and potentially exacerbate autoimmunity in subjects that have pre-existing autoimmune diseases. Very recently, human monoclonal antibodies were approved for use on patients with COVID-19. The human monoclonal antibodies used in this study are almost identical with these approved antibodies. Thus, our results can establish the potential risk for autoimmunity and multi-system disorders with COVID-19 that may come from cross-reactivity between our own human tissues and this dreaded virus, and thus ensure that the badly-needed vaccines and treatments being developed for it are truly safe to use against this disease.
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Affiliation(s)
- Aristo Vojdani
- Department of Immunology, Immunosciences Laboratory, Inc., Los Angeles, CA, United States.,Department of Preventive Medicine, Loma Linda University School of Medicine, Loma Linda, CA, United States
| | | | - Datis Kharrazian
- Department of Preventive Medicine, Loma Linda University School of Medicine, Loma Linda, CA, United States.,Department of Neurology, Harvard Medical School, Boston, MA, United States.,Department of Neurology, Massachusetts General Hospital, Charlestown, MA, United States
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8
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Vojdani A, Vojdani E, Kharrazian D. Reaction of Human Monoclonal Antibodies to SARS-CoV-2 Proteins With Tissue Antigens: Implications for Autoimmune Diseases. Front Immunol 2020; 11:617089. [PMID: 33584709 DOI: 10.3389/fimmu.2020.617089/full] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/14/2020] [Indexed: 05/20/2023] Open
Abstract
We sought to determine whether immune reactivity occurs between anti-SARS-CoV-2 protein antibodies and human tissue antigens, and whether molecular mimicry between COVID-19 viral proteins and human tissues could be the cause. We applied both human monoclonal anti-SARS-Cov-2 antibodies (spike protein, nucleoprotein) and rabbit polyclonal anti-SARS-Cov-2 antibodies (envelope protein, membrane protein) to 55 different tissue antigens. We found that SARS-CoV-2 antibodies had reactions with 28 out of 55 tissue antigens, representing a diversity of tissue groups that included barrier proteins, gastrointestinal, thyroid and neural tissues, and more. We also did selective epitope mapping using BLAST and showed similarities and homology between spike, nucleoprotein, and many other SARS-CoV-2 proteins with the human tissue antigens mitochondria M2, F-actin and TPO. This extensive immune cross-reactivity between SARS-CoV-2 antibodies and different antigen groups may play a role in the multi-system disease process of COVID-19, influence the severity of the disease, precipitate the onset of autoimmunity in susceptible subgroups, and potentially exacerbate autoimmunity in subjects that have pre-existing autoimmune diseases. Very recently, human monoclonal antibodies were approved for use on patients with COVID-19. The human monoclonal antibodies used in this study are almost identical with these approved antibodies. Thus, our results can establish the potential risk for autoimmunity and multi-system disorders with COVID-19 that may come from cross-reactivity between our own human tissues and this dreaded virus, and thus ensure that the badly-needed vaccines and treatments being developed for it are truly safe to use against this disease.
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Affiliation(s)
- Aristo Vojdani
- Department of Immunology, Immunosciences Laboratory, Inc., Los Angeles, CA, United States
- Department of Preventive Medicine, Loma Linda University School of Medicine, Loma Linda, CA, United States
| | | | - Datis Kharrazian
- Department of Preventive Medicine, Loma Linda University School of Medicine, Loma Linda, CA, United States
- Department of Neurology, Harvard Medical School, Boston, MA, United States
- Department of Neurology, Massachusetts General Hospital, Charlestown, MA, United States
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9
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Cao H, Zhu B, Qu Y, Zhang W. Abnormal Expression of ERα in Cholangiocytes of Patients With Primary Biliary Cholangitis Mediated Intrahepatic Bile Duct Inflammation. Front Immunol 2019; 10:2815. [PMID: 31867004 PMCID: PMC6907097 DOI: 10.3389/fimmu.2019.02815] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Accepted: 11/15/2019] [Indexed: 01/09/2023] Open
Abstract
ERα, one of the classical receptors of estrogen, has been found to be abnormally up-regulated in patients with primary biliary cholangitis (PBC), which is an important factor leading to ductopenia. ERα-mediated signaling pathways are involved in proliferation of human intrahepatic biliary epithelial cells (HiBECs) and portal inflammation. Our previous studies have shown that the expression levels of ERα in the liver tissues of PBC patients are positively correlated with the levels of serum pro-inflammatory cytokines. The present study was designed to assess the relationship between abnormal ERα expression in small bile ducts and the progression of PBC. We examined the levels of multiple cytokines and analyzed their relationship with clinical parameters of livers functions in a cohort of 43 PBC patients and 45 healthy controls (HC). The levels of ERα expression and the relation with the levels of cytokines were further assessed. The localization of cytokines and ERα-mediated signaling pathways in liver were examined using immunohistochemistry. The possible underlying mechanisms of these alterations in PBC were explored in vitro. Our results demonstrated that the levels of IL-6, IL-8, and TNF-α were increased in PBC patients, and positively correlated with the serum AKP levels and ERα expression levels. Moreover, the expression of these cytokines were up-regulated in HiBECs that were stimulated with 17β-estradiol and PPT (an ERα agonist) and they also were positive in intrahepatic bile duct of PBC patients. The ERα-mediated expression of pro-inflammatory cytokines was induced by JNK, P38, and STAT3 phosphorylation in HiBECs. In addition, the CD54 expression was increased in HiBECs after ERα activation, which induced peripheral blood monouclear cells (PBMCs) recruitment. In conclusion, the present study highlighted a key role of abnormal ERα expression in inducing an inflammatory phenotype of HiBECs, which was critical in the development of inflammation and damage in small bile duct.
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Affiliation(s)
| | | | | | - Wei Zhang
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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10
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Gulamhusein AF, Hirschfield GM. Pathophysiology of primary biliary cholangitis. Best Pract Res Clin Gastroenterol 2018; 34-35:17-25. [PMID: 30343706 DOI: 10.1016/j.bpg.2018.05.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/22/2018] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis is a prototypical autoimmune disease characterized by an overwhelming female predominance, a distinct clinical phenotype, and disease specific anti-mitochondrial antibodies targeted against a well-defined auto-antigen. In a genetically susceptible host, multi-lineage loss of tolerance to the E2 component of the 2-oxo-dehydrogenase pathway and dysregulated immune pathways directed at biliary epithelial cells leads to cholestasis, progressive biliary fibrosis, and cirrhosis in a subset of patients. Several key insights have shed light on the complex pathogenesis of disease. First, characteristic anti-mitochondrial antibodies (AMAs) target lipoic acid containing immunodominant epitopes, particularly pyruvate dehydrogenase complex (PDC-E2), on the inner mitochondrial membrane of BECs. Next, breakdown of the protective apical bicarbonate rich umbrella may sensitize BECs to aberrant apoptotic pathways leaving the antigenic PDC-E2 epitope immunologically tact within an apoptotic bleb. A multi-lineage immune response ensues characterized by an imbalance between effector and regulatory activity resulting in progressive and self-perpetuating biliary injury. Genome wide studies shed light on important pathways involved in disease, key among them being IL-12. Epigenetic mechanisms and microRNAs may play help shed light on the missing heritability and female preponderance of disease. Taken together, these findings have dramatically advanced our understanding of disease and may lead to important therapeutic advances.
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Affiliation(s)
- Aliya F Gulamhusein
- Toronto Centre for Liver Disease, 200 Elizabeth Street, Toronto, ON, Canada.
| | - Gideon M Hirschfield
- Centre for Liver Research and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK.
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11
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Wang J, Yang G, Dubrovsky AM, Choi J, Leung PSC. Xenobiotics and loss of tolerance in primary biliary cholangitis. World J Gastroenterol 2016; 22:338-348. [PMID: 26755880 PMCID: PMC4698496 DOI: 10.3748/wjg.v22.i1.338] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 08/15/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Data from genome wide association studies and geoepidemiological studies established that a combination of genetic predisposition and environmental stimulation is required for the loss of tolerance in primary biliary cholangitis (PBC). The serologic hallmark of PBC are the presence of high titer anti-mitochondrial autoantibodies (AMA) that recognize the lipoyl domain of the mitochondrial pyruvate dehydrogenase E2 (PDC-E2) subunit. Extensive efforts have been directed to investigate the molecular basis of AMA. Recently, experimental data has pointed to the thesis that the breaking of tolerance to PDC-E2 is a pivotal event in the initial etiology of PBC, including environmental xenobiotics including those commonly found in cosmetics and food additives, suggesting that chemical modification of the PDC-E2 epitope may render its vulnerable to become a neo-antigen and trigger an immune response in genetically susceptible hosts. Here, we will discuss the natural history, genetics and immunobiology of PBC and structural constraints of PDC-E2 in AMA recognition which makes it vulnerable to chemical modification.
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12
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Yamagiwa S, Kamimura H, Takamura M, Aoyagi Y. Autoantibodies in primary biliary cirrhosis: recent progress in research on the pathogenetic and clinical significance. World J Gastroenterol 2014; 20:2606-2612. [PMID: 24627596 PMCID: PMC3949269 DOI: 10.3748/wjg.v20.i10.2606] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 11/22/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease characterized by immune-mediated destruction of the small- and medium-sized intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMA) in the serum. AMA are detected in over 90% of patients with PBC, whereas their prevalence in the general population is extremely low, varying from 0.16% to 1%. Previous studies have shown that the unique characteristics of biliary epithelial cells undergoing apoptosis may result in a highly direct and very specific immune response to mitochondrial autoantigens. Moreover, recent studies have demonstrated that serum from AMA-positive PBC patients is reactive with a number of xenobiotic modified E2 subunits of the pyruvate dehydrogenase complex, which is not observed in the serum of normal individuals. These findings indicate that chemicals originating from the environment may be associated with a breakdown in the tolerance to mitochondrial autoantigens. While it is currently generally accepted that AMA are the most specific serological markers of PBC, more than 60 autoantibodies have been investigated in patients with PBC, and some have previously been considered specific to other autoimmune diseases. This review covers the recent progress in research on the pathogenetic and clinical significance of important autoantibodies in PBC. Determining the pathogenic role of those autoantibodies in PBC remains a priority of basic and clinical research.
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Abstract
Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis.
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14
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Molecular mechanisms of hepatic apoptosis. Cell Death Dis 2014; 5:e996. [PMID: 24434519 PMCID: PMC4040708 DOI: 10.1038/cddis.2013.499] [Citation(s) in RCA: 244] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 11/07/2013] [Accepted: 11/07/2013] [Indexed: 02/07/2023]
Abstract
Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis.
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Wang J, Budamagunta MS, Voss JC, Kurth MJ, Lam KS, Lu L, Kenny TP, Bowlus C, Kikuchi K, Coppel RL, Ansari AA, Gershwin ME, Leung PSC. Antimitochondrial antibody recognition and structural integrity of the inner lipoyl domain of the E2 subunit of pyruvate dehydrogenase complex. THE JOURNAL OF IMMUNOLOGY 2013; 191:2126-33. [PMID: 23894195 DOI: 10.4049/jimmunol.1301092] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Antimitochondrial autoantibodies (AMAs), the serological hallmark of primary biliary cirrhosis, are directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2). However, comprehensive analysis of the amino acid residues of PDC-E2 lipoyl β-sheet with AMA specificity is lacking. In this study, we postulated that specific residues within the lipoyl domain are critical to AMA recognition by maintaining conformational integrity. We systematically replaced each of 19 residue peptides of the inner lipoyl domain with alanine and analyzed these mutants for reactivities against 60 primary biliary cirrhosis and 103 control sera. Based on these data, we then constructed mutants with two, three, or four replacements and, in addition, probed the structure of the substituted domains using thiol-specific spin labeling and electron paramagnetic resonance (EPR) of a (5)Ile→Ala and (12)Ile→Ala double mutant. Single alanine replacement at (5)Ile, (12)Ile, and (15)Glu significantly reduced AMA recognition. In addition, mutants with two, three, or four replacements at (5)Ile, (12)Ile, and (15)Glu reduced AMA reactivity even further. Indeed, EPR reveals a highly flexible structure within the (5)Ile and (12)Ile double-alanine mutant. Autoreactivity is largely focused on specific residues in the PDC-E2 lipoyl domain critical in maintaining the lipoyl loop conformation necessary for AMA recognition. Collectively, the AMA binding studies and EPR analysis demonstrate the necessity of the lipoyl β-sheet structural conformation in anti-PDC-E2 recognition.
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Affiliation(s)
- Jinjun Wang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, Davis, CA 95616, USA
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The immunophysiology and apoptosis of biliary epithelial cells: primary biliary cirrhosis and primary sclerosing cholangitis. Clin Rev Allergy Immunol 2013; 43:230-41. [PMID: 22689287 DOI: 10.1007/s12016-012-8324-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Biliary epithelial cells (BECs) provide the first line of defense against lumenal microbes in the biliary system. BECs express a variety of pathogen recognition receptors and can activate several intracellular signaling cascades to initiate antimicrobial defenses, including production of several anti-microbial peptides, cytokines, chemokines, and adhesion molecules. BECs also secrete immunoglobulin A and interact with other cells through expression and release of adhesion molecules and immune mediators. Recently, several reports suggest a correlation between apoptosis and autoimmunity through ineffective clearance of self-antigens. Primary biliary cirrhosis (PBC) is a slowly progressive, autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated destruction of BECs. We have demonstrated that the AMA self-antigen, namely the E2 subunit of the pyruvate dehydrogenase complex, is detectable in its antigenically reactive form within apoptotic blebs from human intrahepatic biliary epithelial cells and activates innate immune responses. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and the presence of concentric fibrosis of intrahepatic and/or extrahepatic bile ducts, eventually leading to cirrhosis. However, apoptosis does not appear to play a central role in PSC. Despite both diseases involving immune-mediated injury to bile ducts, apoptosis occurs more commonly overall in PBC where it likely plays a unique role.
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Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2013; 8:303-30. [PMID: 23347352 DOI: 10.1146/annurev-pathol-020712-164014] [Citation(s) in RCA: 225] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony-stimulating factor-stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention.
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Affiliation(s)
- Gideon M Hirschfield
- Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom
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18
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Chen RC, Naiyanetr P, Shu SA, Wang J, Yang GX, Thomas PK, Guggenheim KC, Butler JD, Bowlus C, Tao MH, Kurth MJ, Ansari AA, Kaplan M, Coppel RL, Lleo A, Gershwin ME, Leung PS. Antimitochondrial antibody heterogeneity and the xenobiotic etiology of primary biliary cirrhosis. Hepatology 2013; 57:1498-1508. [PMID: 23184636 PMCID: PMC3601563 DOI: 10.1002/hep.26157] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Accepted: 10/18/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED Antimitochondrial antibodies (AMAs) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with primary biliary cirrhosis (PBC) and are present before the onset of clinical disease. The recent demonstration that AMAs recognize xenobiotic modified PDC-E2 with higher titers than native PDC-E2 raises the possibility that the earliest events involved in loss of tolerance are related to xenobiotic modification. We hypothesized that reactivity to such xenobiotics would be predominantly immunoglobulin M (IgM) and using sera from a large cohort of PBC patients and controls (n = 516), we examined in detail sera reactivity against either 6,8-bis(acetylthio) octanoic acid (SAc)-conjugated bovine serum albumin (BSA), recombinant PDC-E2 (rPDC-E2) or BSA alone. Further, we also defined the relative specificity to the SAc moiety using inhibition enzyme-linked immunosorbent assay (ELISA); SAc conjugate and rPDC-E2-specific affinity-purified antibodies were also examined for antigen specificity, isotype, and crossreactivity. Reactivity to SAc conjugates is predominantly IgM; such reactivity reflects a footprint of previous xenobiotic exposure. Indeed, this observation is supported by both direct binding, crossreactivity, and inhibition studies. In both early and late-stage PBC, the predominant Ig isotype to SAc is IgM, with titers higher with advanced stage disease. We also note that there was a higher level of IgM reactivity to SAc than to rPDC-E2 in early-stage versus late-stage PBC. Interestingly, this finding is particularly significant in light of the structural similarity between SAc and the reduced form of lipoic acid, a step which is similar to the normal physiological oxidation of lipoic acid. CONCLUSION Specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e., by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host.
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Affiliation(s)
- Richy C.Y. Chen
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA 95616
| | - Phornnop Naiyanetr
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA 95616
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Shang-An Shu
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA 95616
| | - Jinjun Wang
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA 95616
| | - Guo-Xiang Yang
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA 95616
| | - P. Kenny Thomas
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA 95616
| | | | | | | | - Mi-Hua Tao
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Mark J. Kurth
- Department of Chemistry, University of California, Davis, CA 95616
| | - Aftab A. Ansari
- Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Marshall Kaplan
- Department of Medicine, Division of Gastroenterology, New England Medical Center, Tufts University School of Medicine, Boston, MA 02111
| | - Ross L. Coppel
- Department of Medical Microbiology, Monash University, Melbourne, Australia
| | - Ana Lleo
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano (Milan), Italy
| | - M. Eric Gershwin
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA 95616
| | - Patrick S.C. Leung
- Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA 95616
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19
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Tsuda M, Zhang W, Yang GX, Tsuneyama K, Ando Y, Kawata K, Park O, Leung PS, Coppel RL, Ansari AA, Ridgway WM, Gao B, Lian ZX, Flavell R, He XS, Gershwin ME. Deletion of interleukin (IL)-12p35 induces liver fibrosis in dominant-negative TGFβ receptor type II mice. Hepatology 2013; 57:806-16. [PMID: 22576253 PMCID: PMC3424295 DOI: 10.1002/hep.25829] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Accepted: 05/01/2012] [Indexed: 12/20/2022]
Abstract
Mice with a dominant-negative transforming growth factor β receptor restricted to T cells (dnTGFβRII mice) develop an inflammatory biliary ductular disease that strongly resembles human primary biliary cirrhosis (PBC). Furthermore, deletion of the gene encoding interleukin (IL)-12p40 resulted in a strain (IL-12p40(-/-) dnTGFβRII) with dramatically reduced autoimmune cholangitis. To further investigate the role of the IL-12 cytokine family in dnTGFβRII autoimmune biliary disease, we deleted the gene encoding the IL-12p35 subunit from dnTGFβRII mice, resulting in an IL-12p35(-/-) dnTGFβRII strain which is deficient in two members of the IL-12 family, IL-12 and IL-35. In contrast to IL-12p40(-/-) mice, the IL-12p35(-/-) mice developed liver inflammation and bile duct damage with similar severity but delayed onset as the parental dnTGFβRII mice. The p35(-/-) mice also demonstrated a distinct cytokine profile characterized by a shift from a T-helper 1 (Th1) to a Th17 response. Strikingly, liver fibrosis was frequently observed in IL-12p35(-/-) mice. In conclusion, IL-12p35(-/-) dnTGFβRII mice, histologically and immunologically, reflect key features of PBC, providing a useful generic model to understand the immunopathology of human PBC.
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Affiliation(s)
- Masanobu Tsuda
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616,Department of Emergency and Critical Care Medicine, Kansai Medical University, Osaka 570-8506, Japan
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Guo-Xiang Yang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Koichi Tsuneyama
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616,Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan
| | - Yugo Ando
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Kazuhito Kawata
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Ogyi Park
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892
| | - Patrick S.C. Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Ross L. Coppel
- Department of Microbiology, Monash University, Victoria, 3168, Australia
| | - Aftab A. Ansari
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322
| | - William M. Ridgway
- Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892
| | - Zhe-Xiong Lian
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616,Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Richard Flavell
- Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520
| | - Xiao-Song He
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
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20
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Environment and primary biliary cirrhosis: electrophilic drugs and the induction of AMA. J Autoimmun 2013; 41:79-86. [PMID: 23352659 DOI: 10.1016/j.jaut.2012.12.007] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Revised: 12/17/2012] [Accepted: 12/20/2012] [Indexed: 12/12/2022]
Abstract
Environmental stimulation is a major factor in the initiation and perpetuation of autoimmune diseases. We have addressed this issue and focused on primary biliary cirrhosis (PBC), an autoimmune disease of the liver. Immunologically, PBC is distinguished by immune mediated destruction of the intra hepatic bile ducts and the presence of high titer antimitochondrial autoantibodies (AMA) directed against a highly specific epitope within the lipoic acid binding domain of the pyruvate dehydrogenase E2 subunit (PDC-E2). We submit that the uniqueness of AMA epitope specificity and the conformational changes of the PDC-E2 lipoyl domain during physiological acyl transfer could be the lynchpin to the etiology of PBC and postulate that chemical xenobiotics modification of the lipoyl domain of PDC-E2 is sufficient to break self-tolerance, with subsequent production of AMA in patients with PBC. Indeed, using quantitative structure activity relationship (QSAR) analysis on a peptide-xenobiotic conjugate microarray platform, we have demonstrated that when the lipoyl domain of PDC-E2 was modified with specific synthetic small molecule lipoyl mimics, the ensuing structures displayed highly specific reactivity to PBC sera, at levels often higher than the native PDC-E2 molecule. Hereby, we discuss our recent QSAR analysis data on specific AMA reactivity against a focused panel of lipoic acid mimic in which the lipoyl di-sulfide bond are modified. Furthermore, data on the immunological characterization of antigen and Ig isotype specificities against one such lipoic acid mimic; 6,8-bis(acetylthio)octanoic acid (SAc), when compared with rPDC-E2, strongly support a xenobiotic etiology in PBC. This observation is of particular significance in that approximately one third of patients who have taken excessive acetaminophen (APAP) developed AMA with same specificity as patients with PBC, suggesting that the lipoic domain are a target of APAP electrophilic metabolites such as NAPQI. We submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate loss of tolerance and lead to the development of PBC.
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21
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Leung PSC, Lam K, Kurth MJ, Coppel RL, Gershwin ME. Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis? Trends Mol Med 2012; 18:577-82. [PMID: 22920894 DOI: 10.1016/j.molmed.2012.07.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 07/08/2012] [Accepted: 07/11/2012] [Indexed: 01/09/2023]
Abstract
The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of antimitochondrial autoantibodies (AMAs) directed against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). The PBC-related autoepitope of PDC-E2 contains lipoic acid, and previous work has demonstrated that mimics of lipoic acid following immunization of mice lead to a PBC-like disease. Furthermore, approximately one-third of patients who have ingested excessive amounts of acetaminophen (paracetamol) develop AMA of the same specificity as patients with PBC. Quantitative structure-activity relationship (QSAR) data indicates that acetaminophen metabolites are particularly immunoreactive with AMA, and we submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate a loss of tolerance and lead to the development of PBC.
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Affiliation(s)
- Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
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22
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Tsuda M, Ambrosini YM, Zhang W, Yang GX, Ando Y, Rong G, Tsuneyama K, Sumida K, Shimoda S, Bowlus CL, Leung PS, He XS, Coppel RL, Ansari AA, Lian ZX, Gershwin ME. Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis. Hepatology 2011; 54:1293-302. [PMID: 21735469 PMCID: PMC3184190 DOI: 10.1002/hep.24526] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED In primary biliary cirrhosis (PBC), patients develop a multilineage response to a highly restricted peptide of the E2 component of pyruvate dehydrogenase (PDC-E2) involving autoantibody and autoreactive cluster of differentiation (CD)4(+) and CD8(+) T-cell responses. Recent data from murine models have suggested that liver-infiltrating CD8(+) cells play a critical role in biliary destruction in PBC. We hypothesized that chronic antigen stimulation of CD8(+) T cells alters effector memory T cell (T(EM) ) frequency and function similar to that seen with chronic viral infections, including failure to terminally differentiate and relative resistance to apoptosis. We have rigorously phenotyped CD8(+) T-cell subpopulations from 132 subjects, including 76 patients with PBC and 56 controls, and report a higher frequency of T(EM) cells characterized as CD45RO(high) CD57(+) CD8(high), but expressing the gut homing integrin, α4β7, in peripheral blood mononuclear cells of PBC. These CD8(high) T(EM) cells have reduced expression of Annexin V after TCR stimulation. Consistent with a T(EM) phenotype, CD45RO(high) CD57(+) CD8(high) T cells express higher levels of granzyme A, granzyme B, perforin, CCR5 and α4β7, and lower levels of CCR7 and CD28 than other CD8(high) T cells. Furthermore, interleukin (IL)-5 produced by CD8(+) CD57(+) T lymphocytes upon in vitro T-cell receptor stimulation are increased in PBC. Histologically, CD8(+) CD57(+) T cells accumulate around the portal area in PBC. Moreover, CD8(+) CD57(+) T cells respond specifically to the major histocompatibility class I epitope of PDC-E2. CONCLUSION In conclusion, our data demonstrate that CD45RO(high) CD57(+) CD8(high) T cells are a subset of terminally differentiated cytotoxic T(EM) cells, which could play a critical role in the progressive destruction of biliary epithelial cells.
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Affiliation(s)
- Masanobu Tsuda
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616,Department of Emergency and Critical Care Medicine, Kansai Medical University, Osaka 570-8507, Japan
| | - Yoko M. Ambrosini
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Guo-Xiang Yang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Yugo Ando
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Guanghua Rong
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Koichi Tsuneyama
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616,Department of Pathology (I), Toyama Medical and Pharmaceutical University, Toyama, Japan
| | - Kosuke Sumida
- Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Shinji Shimoda
- Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Christopher L. Bowlus
- Division of Gastroenterology and Hepatology, University of California at Davis, Sacramento, CA 95817
| | - Patrick S.C. Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Xiao-Song He
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
| | - Ross L. Coppel
- Department of Microbiology, Monash University, Clayton 3800, Australia
| | - Aftab A. Ansari
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322
| | - Zhe-Xiong Lian
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616,Institute of Immunology and School of Life Sciences, University of Science and Technology of China, 443 Huangshan Road, Hefei, 230027, China
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616
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23
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Naiyanetr P, Butler JD, Meng L, Pfeiff J, Kenny TP, Guggenheim KG, Reiger R, Lam K, Kurth MJ, Ansari AA, Coppel RL, López-Hoyos M, Gershwin ME, Leung PSC. Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity. J Autoimmun 2011; 37:209-16. [PMID: 21763105 DOI: 10.1016/j.jaut.2011.06.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 05/24/2011] [Accepted: 06/01/2011] [Indexed: 12/27/2022]
Abstract
Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.
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Affiliation(s)
- Phornnop Naiyanetr
- Division of Rheumatology, Allergy, and Clinical Immunology, Department of Internal Medicine, University of California, Davis, CA 95616, USA
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24
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Chueh FY, Leong KF, Cronk RJ, Venkitachalam S, Pabich S, Yu CL. Nuclear localization of pyruvate dehydrogenase complex-E2 (PDC-E2), a mitochondrial enzyme, and its role in signal transducer and activator of transcription 5 (STAT5)-dependent gene transcription. Cell Signal 2011; 23:1170-8. [PMID: 21397011 DOI: 10.1016/j.cellsig.2011.03.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2010] [Revised: 02/28/2011] [Accepted: 03/03/2011] [Indexed: 10/18/2022]
Abstract
STAT (signal transducer and activator of transcription) proteins play a critical role in cellular response to a wide variety of cytokines and growth factors by regulating specific nuclear genes. STAT-dependent gene transcription can be finely tuned through the association with co-factors in the nucleus. We showed previously that STAT5 (including 5a and 5b) specifically interacts with a mitochondrial enzyme PDC-E2 (E2 subunit of pyruvate dehydrogenase complex) in both leukemic T cells and cytokine-stimulated cells. However, the functional significance of this novel association remains largely unknown. Here we report that PDC-E2 may function as a co-activator in STAT5-dependent nuclear gene expression. Subcellular fractionation analysis revealed that a substantial amount of PDC-E2 was constitutively present in the nucleus of BaF3, an interleukin-3 (IL-3)-dependent cell line. IL-3-induced tyrosine-phosphorylated STAT5 associated with nuclear PDC-E2 in co-immunoprecipitation analysis. These findings were confirmed by confocal immunofluorescence microscopy showing constant nuclear localization of PDC-E2 and its co-localization with STAT5 after IL-3 stimulation. Similar to mitochondrial PDC-E2, nuclear PDC-E2 was lipoylated and associated with PDC-E1. Overexpression of PDC-E2 in BaF3 cells augmented IL-3-induced STAT5 activity as measured by reporter assay with consensus STAT5-binding sites. Consistent with the reporter data, PDC-E2 overexpression in BaF3 cells led to elevated mRNA levels of endogenous SOCS3 (suppressor of cytokine signaling 3) gene, a known STAT5 target. We further identified two functional STAT5-binding sites in the SOCS3 gene promoter important for its IL-3-inducibility. The observation that both cis-acting elements were essential to detect the stimulatory effect by PDC-E2 strongly supports the role of PDC-E2 in up-regulating the transactivating ability of STAT5. All together, our results reveal a novel function of PDC-E2 in the nucleus. It also raises the possibility of nuclear-mitochondrial crosstalk through the interaction between STAT5 and PDC-E2.
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Affiliation(s)
- Fu-Yu Chueh
- Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA
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Douguchi J, Hashiguchi A, Sakamoto M. Construction of human monoclonal single-chain Fv antibodies against small-cell lung cancer by phage display libraries derived from cell-immunized SCID mice engrafted with human peripheral blood lymphocytes. Proteomics Clin Appl 2010; 3:1265-72. [PMID: 21136949 DOI: 10.1002/prca.200900060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
In this study, we describe a phage display strategy to obtain human monoclonal single-chain Fv (scFv) antibodies binding target cancer cell surface proteins. By developing a cancer cell immunization protocol for SCID mice engrafted with human peripheral blood lymphocytes in combination with an antibody phage display method, we have isolated phage antibodies binding small-cell lung cancer cell line H889 by subtractive selection. One of the isolated scFv antibodies, 12EAb, recognized the E2 component of pyruvate dehydrogenase complex (PDC-E2) by immunoprecipitation according to MALDI-TOF MS analysis. Furthermore, we have confirmed the plasma membrane localization of PDC-E2 in small-cell lung cancer cells by immunocytochemistry and cell surface protein biotinylation, although PDC-E2 is usually located in the mitochondrial matrix. These results, including unique localization of identified antigens, were obtained by proteomic approaches. The present methods can be applied to generate human monoclonal scFv antibodies against tumor cells and to identify new molecular targets for immunotherapy and markers for diagnosis.
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Affiliation(s)
- Junya Douguchi
- Department of Pathology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
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Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease in which an immune-mediated injury targets the small intrahepatic bile ducts. PBC is further characterized by highly specific serum antimitochondrial autoantibodies (AMA) and autoreactive T cells, a striking female predominance, a strong genetic susceptibility, and a plethora of candidate environmental factors to trigger the disease onset. For these reasons PBC appears ideal to represent the developments of the clonal selection theory over the past decades. First, a sufficiently potent autoimmunogenic stimulus in PBC would require the coexistence of numerous pre-existing conditions (mostly genetic, as recently illustrated by genome-wide association studies and animal models) to perpetuate the destruction of the biliary epithelium by the immune system via the persistence of forbidden clones. Second, the proposed modifications of mitochondrial autoantigens caused by infectious agents and/or xenobiotics well illustrate the possibility that peculiar changes in the antigen structure and flexibility may contribute to tolerance breakdown. Third, the unique apoptotic features demonstrated for cholangiocytes are the ideal setting for the development of mitochondrial autoantigen presentation to the immune system through macrophages and AMA thus turning the non traditional mitochondrial antigen into a traditional one. This article will review the current knowledge on PBC etiology and pathogenesis in light of the clonal selection theory developments.
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Lohse AW, Weiler-Normann C, Tiegs G. Immune-mediated liver injury. J Hepatol 2010; 52:136-44. [PMID: 19913936 DOI: 10.1016/j.jhep.2009.10.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2009] [Revised: 09/14/2009] [Accepted: 09/16/2009] [Indexed: 02/06/2023]
Affiliation(s)
- Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
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29
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Abstract
Primary biliary cirrhosis (PBC) is characterized by unknown etiologies, anti-mitochondrial antibodies, injury of the biliary duct and the lack of a definite remedy. The etiologies of PBC have been well-discussed, including microorganisms and xenobiotics as the triggers for initiating the disease, and an abnormality of immune-tolerance. Recently, several animal models of PBC have been developed that may lead to the development of new therapies. Here, we reviewed the articles that address the etiology of PBC and the therapy for this disease for the confirmation of our current positions and future directions.
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Affiliation(s)
- Koji Fukushima
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Seiryo, Aobaku, Sendai, Japan
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30
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Leung PS, Rossaro L, Davis PA, Park O, Tanaka A, Kikuchi K, Miyakawa H, Norman GL, Lee W, Gershwin ME. Antimitochondrial antibodies in acute liver failure: implications for primary biliary cirrhosis. Hepatology 2007; 46:1436-42. [PMID: 17657817 PMCID: PMC3731127 DOI: 10.1002/hep.21828] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
UNLABELLED In our previous work, including analysis of more than 10,000 sera from control patients and patients with a variety of liver diseases, we have demonstrated that with the use of recombinant autoantigens, antimitochondrial autoantibodies (AMAs) are only found in primary biliary cirrhosis (PBC) and that a positive AMA is virtually pathognomonic of either PBC or future development of PBC. Although the mechanisms leading to the generation of AMA are enigmatic, we have postulated that xenobiotic-induced and/or oxidative modification of mitochondrial autoantigens is a critical step leading to loss of tolerance. This thesis suggests that a severe liver oxidant injury would lead to AMA production. We analyzed 217 serum samples from 69 patients with acute liver failure (ALF) collected up to 24 months post-ALF, compared with controls, for titer and reactivity with the E2 subunits of pyruvate dehydrogenase, branched chain 2-oxo-acid dehydrogenase, and 2-oxo-glutarate dehydrogenase. AMAs were detected in 28/69 (40.6%) ALF patients with reactivity found against all of the major mitochondrial autoantigens. In addition, and as further controls, sera were analyzed for autoantibodies to gp210, Sp100, centromere, chromatin, soluble liver antigen, tissue transglutaminase, and deaminated gliadin peptides; the most frequently detected nonmitochondrial autoantibody was against tissue transglutaminase (57.1% of ALF patients). CONCLUSION The strikingly high frequency of AMAs in ALF supports the thesis that oxidative stress-induced liver damage may lead to AMA induction. The rapid disappearance of AMAs in these patients provides further support for the contention that PBC pathogenesis requires additional factors, including genetic susceptibility.
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Affiliation(s)
- Patrick S.C. Leung
- Division of Rheumatology/Allergy, University of California, Davis, CA 95616
| | - Lorenzo Rossaro
- Division of Gastroenterology and Hepatology, University of California, Davis Medical Center, Sacramento, CA 95817
| | - Paul A. Davis
- Division of Rheumatology/Allergy, University of California, Davis, CA 95616
| | - Ogyi Park
- Division of Rheumatology/Allergy, University of California, Davis, CA 95616
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University, School of Medicine, Tokyo, 173-8605, Japan
| | - Kentaro Kikuchi
- Fourth Department of Internal Medicine, Teikyo University School of Medicine, Kanagawa, 213-8507, Japan
| | - Hiroshi Miyakawa
- Fourth Department of Internal Medicine, Teikyo University School of Medicine, Kanagawa, 213-8507, Japan
| | | | - William Lee
- Clinical Center for Liver Disease, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - M. Eric Gershwin
- Division of Rheumatology/Allergy, University of California, Davis, CA 95616
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Basu A, Saito K, Meyer K, Ray RB, Friedman SL, Chang YH, Ray R. Stellate cell apoptosis by a soluble mediator from immortalized human hepatocytes. Apoptosis 2007; 11:1391-400. [PMID: 16830231 DOI: 10.1007/s10495-006-8312-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Activated hepatic stellate cells (HSCs) are the major source of extracellular matrix in fibrosis and cirrhosis. In this study, we have investigated the role of hepatitis C virus (HCV) core protein induced immortalized human hepatocytes (IHH) on HSC growth. Preferential growth of IHH and apoptosis of activated human hepatic stellate cells (LX2) were observed upon coculture of these two cell types in a dual chamber or in the presence of conditioned medium (CM) from IHH. CM did not display a growth inhibitory role on other hepatic (Huh-7, HepG2, Hep3B and THLE) and non-hepatic (HeLa, MCF-7, and BHK) epithelial cells, indicating that the soluble mediator from IHH does not have a generalized effect on cell lines examined in our study. Further studies suggested that CM from IHH increased the expression of TRAIL receptors on LX2 cell surface, and induced apoptosis by a caspase dependent mechanism. Peptide mass fingerprinting of the purified soluble mediator from CM suggested that gelsolin fragments may play a role in apoptosis of LX2 cells. Taken together, our results suggested that a soluble mediator secreted from immortalized human hepatocytes plays an important role in hepatic stellate cell growth regulation.
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Affiliation(s)
- Arnab Basu
- Department of Internal Medicine, Saint Louis University, St. Louis, MO 63110, USA
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Reshetnyak VI. Concept on the pathogenesis and treatment of primary biliary cirrhosis. World J Gastroenterol 2006; 12:7250-7262. [PMID: 17143938 PMCID: PMC4087480 DOI: 10.3748/wjg.v12.i45.7250] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2006] [Revised: 07/28/2006] [Accepted: 09/04/2006] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterized by chronic, progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis, leading to liver failure in the absence of treatment. Little is known about the etiology of PBC. PBC is characterized by anti-mitochondrial antibodies and destruction of intra-hepatic bile ducts. The serologic hallmark of PBC is the presence of auto-antibodies to mitochondria, especially to the E2 component of the pyruvate dehydrogenase complex (PDC). Current theories on the pathogenesis of PBC favor the hypothesis that the disease develops as a result of an inappropriate immune response following stimulation by an environmental or infectious agent. Some reports suggest that xenobiotics and viral infections may induce PBC. The pathogenetic mechanism is believed to be caused by a defect in immunologic tolerance, resulting in the activation and expansion of self-antigen specific T and B lymphocyte clones and the production of circulating autoantibodies in addition to a myriad of cytokines and other inflammatory mediators. This leads to ductulopenia and persistent cholestasis, by developing end-stage hepatic-cell failure. In this review are given our own and literary data about mechanisms of development of intrahepatic cholestasis and possible ways of its correction.
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Rieger R, Leung PSC, Jeddeloh MR, Kurth MJ, Nantz MH, Lam KS, Barsky D, Ansari AA, Coppel RL, Mackay IR, Gershwin ME. Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. J Autoimmun 2006; 27:7-16. [PMID: 16876981 DOI: 10.1016/j.jaut.2006.06.002] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2006] [Revised: 06/20/2006] [Accepted: 06/23/2006] [Indexed: 01/03/2023]
Abstract
Antimitochondrial antibodies (AMA) are unique among autoimmune serologic reactants because of their extremely high association with the index disease primary biliary cirrhosis (PBC). This autoantibody response is specifically directed only to the lipoyl domain of the mitochondrial 2-oxo-acid dehydrogenase complexes, which prompted us to search for environmental mimotopes in the form of xenobiotics and led to our identification of 2-octynoic acid as a high-affinity reactant for AMA. To focus on the chemical characteristics requisite for binding of AMA to the xenobiotic-modified self-peptide, quantitative structure-activity relationship (QSAR) studies were performed using a panel of alkynoic compounds, including examination of the length of the carbon chain and the location of the triple bond in the identified mimotope. Analyses of octynamides that varied in the position of the triple bond demonstrated that only the 2-octynamide reacted strongly with PBC sera. Furthermore, among 2-alkynamides with varying carbon chain length, 2-octyn-, 2-nonyn- (particularly) and 2-decynamide exhibited the highest reactivity. Thus, an optimal chemical structure of the xenobiotically modified epitope recognized by AMA-positive PBC sera is provided by 2-nonynoic acid. The methyl ester of this compound is ranked 2,324th out of 12,945 compounds to which there is occupational exposure, with an 80% female prevalence due to its use in cosmetic products. Our findings illustrate an unusual polyreactivity of anti-PDC-E2 and support the idea of epitope mimicry in the genesis of this autoantibody and perhaps of PBC itself.
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Affiliation(s)
- Roman Rieger
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, GBSF 6510, 95616, USA
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Kim BJ, Hood BL, Aragon RA, Hardwick JP, Conrads TP, Veenstra TD, Song BJ. Increased oxidation and degradation of cytosolic proteins in alcohol-exposed mouse liver and hepatoma cells. Proteomics 2006; 6:1250-60. [PMID: 16408314 PMCID: PMC1368983 DOI: 10.1002/pmic.200500447] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
We recently developed a sensitive method using biotin-N-maleimide (biotin-NM) as a probe to positively identify oxidized mitochondrial proteins. In this study, biotin-NM was used to identify oxidized cytosolic proteins in alcohol-fed mouse livers. Alcohol treatment for 6 wk elevated the levels of CYP2E1 and nitrotyrosine, a marker of oxidative stress. Markedly increased levels of oxidized proteins were detected in alcohol-fed mouse livers compared to pair-fed controls. The biotin-NM-labeled oxidized proteins from alcohol-exposed mouse livers were subsequently purified with streptavidin-agarose and resolved on 2-DE. More than 90 silver-stained protein spots that displayed differential intensities on 2-D gels were identified by MS. Peptide sequence analysis revealed that many enzymes or proteins involved in stress response, chaperone activity, intermediary metabolism, and antioxidant defense systems such as peroxiredoxin were oxidized after alcohol treatment. Smaller fragments of many proteins were repeatedly detected only in alcohol-fed mice, indicating that many oxidized proteins after alcohol exposure were degraded. Immunoblot results showed that the level of oxidized peroxiredoxin (inactivated) was markedly increased in the alcohol-exposed mouse livers and ethanol-sensitive hepatoma cells compared to the corresponding controls. Our results may explain the underlying mechanism for cellular dysfunction and increased susceptibility to other toxic agents following alcohol-mediated oxidative stress.
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Affiliation(s)
- Bong-Jo Kim
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Brian L. Hood
- Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., Frederick, MD, USA and
| | - Richard A. Aragon
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - James P. Hardwick
- Department of Biochemistry, Northeastern Ohio University College of Medicine, Rootstown, OH, USA
| | - Thomas P. Conrads
- Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., Frederick, MD, USA and
| | - Timothy D. Veenstra
- Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, Inc., Frederick, MD, USA and
| | - Byoung J. Song
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
- To whom correspondence should be addressed: Dr. B. J. Song, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892-9410, USA. (e-mail); (Fax) 1-301-594-3113
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Ala A, Stanca CM, Bu-Ghanim M, Ahmado I, Branch AD, Schiano TD, Odin JA, Bach N. Increased prevalence of primary biliary cirrhosis near Superfund toxic waste sites. Hepatology 2006; 43:525-31. [PMID: 16496326 DOI: 10.1002/hep.21076] [Citation(s) in RCA: 154] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are uncommon liver diseases of unknown etiology. Reported clustering of PBC cases may be due to environmental factors. Individuals with PBC have a high prevalence of thyroid disease and thyroid disease is reportedly more prevalent near Superfund toxic waste sites (SFS). The objective of this study was to examine the prevalence and potential clustering of individuals with PBC and PSC near SFS. De-identified clinical and demographic data were used to determine the observed prevalence for each New York City zip code (n = 174) and borough (n = 5) of patients with PBC (PBC-OLT) or PSC (PSC-OLT) who were listed for liver transplantation. The expected prevalence was calculated using Organ Procurement and Transfer Network (OPTN) and U.S. Census data. Both PBC-OLT patients and patients not listed for liver transplantation (PBC-MSSM) were included in the cluster analysis. Prevalence ratios of PBC-OLT and PSC-OLT cases were compared for each zip code and for each borough with regard to the proximity or density of SFS, respectively. SaTScan software was used to identify clusters of PBC-OLT cases and PBC-MSSM cases. Prevalence ratio of PBC-OLT, not PSC-OLT, was significantly higher in zip codes containing or adjacent to SFS (1.225 vs. 0.670, respectively, P = .025). The borough of Staten Island had the highest prevalence ratio of PBC-OLT cases and density of SFS. Significant clusters of both PBC-OLT and PBC-MSSM were identified surrounding SFS. In conclusion, toxin exposure may be a risk factor influencing the clustering of PBC cases.
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Affiliation(s)
- Aftab Ala
- Mount Sinai School of Medicine, New York, NY 10029, USA
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Selmi C, Invernizzi P, Zuin M, Podda M, Seldin MF, Gershwin ME. Genes and (auto)immunity in primary biliary cirrhosis. Genes Immun 2005; 6:543-56. [PMID: 16034472 DOI: 10.1038/sj.gene.6364248] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strengthens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed.
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Affiliation(s)
- C Selmi
- Division of Internal Medicine, San Paolo School of Medicine, University of Milan, Milan, Italy
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