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Salzmann RJ, Krötz C, Mocan T, Mocan LP, Grapa C, Rottmann S, Reichelt R, Keller CM, Langhans B, Schünemann F, Pohl A, Böhler T, Bersiner K, Krawczyk M, Milkiewicz P, Sparchez Z, Lammert F, Gehlert S, Gonzalez-Carmona MA, Willms A, Strassburg CP, Kornek MT, Dold L, Lukacs-Kornek V. Increased type-I interferon level is associated with liver damage and fibrosis in primary sclerosing cholangitis. Hepatol Commun 2024; 8:e0380. [PMID: 38358371 PMCID: PMC10871749 DOI: 10.1097/hc9.0000000000000380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/17/2023] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND The level of type-I interferons (IFNs) in primary sclerosing cholangitis (PSC) was investigated to evaluate its association with disease activity and progression. METHODS Bioactive type-I IFNs were evaluated in a murine model of PSC and human patients' sera using a cell-based reporter assay and ELISA techniques. In total, 57 healthy participants, 71 PSC, and 38 patients with primary biliary cholangitis were enrolled in this study. RESULTS Bioactive type-I IFNs were elevated in the liver and serum of multidrug resistance protein 2-deficient animals and showed a correlation with the presence of CD45+ immune cells and serum alanine transaminase levels. Concordantly, bioactive type-I IFNs were elevated in the sera of patients with PSC as compared to healthy controls (sensitivity of 84.51%, specificity of 63.16%, and AUROC value of 0.8267). Bioactive IFNs highly correlated with alkaline phosphatase (r=0.4179, p<0.001), alanine transaminase (r=0.4704, p<0.0001), and gamma-glutamyl transpeptidase activities (r=0.6629, p<0.0001) but not with serum bilirubin. In addition, patients with PSC with advanced fibrosis demonstrated significantly higher type-I IFN values. Among the type-I IFN subtypes IFNα, β and IFNω could be detected in patients with PSC with IFNω showing the highest concentration among the subtypes and being the most abundant among patients with PSC. CONCLUSIONS The selectively elevated bioactive type-I IFNs specifically the dominating IFNω could suggest a novel inflammatory pathway that might also have a hitherto unrecognized role in the pathomechanism of PSC.
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Affiliation(s)
- Rebekka J.S. Salzmann
- Department of Immunodynamic, Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Christina Krötz
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Tudor Mocan
- UBBMed Department, Babes-Bolyai University, Cluj-Napoca, Romania
- Department of Gastroenterology, Prof. Dr. Octavian Fodor Regional Institute of Gastroenterology and Hepatology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Lavinia P. Mocan
- Department of Histology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristiana Grapa
- Department of Physiology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Sophia Rottmann
- Department of Immunodynamic, Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Ramona Reichelt
- Department of Immunodynamic, Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Cindy M. Keller
- Department of Immunodynamic, Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Bettina Langhans
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Frederik Schünemann
- Department for Biosciences of Sports, Institute of Sport Science, University of Hildesheim, Hildesheim, Germany
| | - Alexander Pohl
- Department for Biosciences of Sports, Institute of Sport Science, University of Hildesheim, Hildesheim, Germany
| | - Thomas Böhler
- Department for Biosciences of Sports, Institute of Sport Science, University of Hildesheim, Hildesheim, Germany
| | - Käthe Bersiner
- Department for Biosciences of Sports, Institute of Sport Science, University of Hildesheim, Hildesheim, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Milkiewicz
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Zeno Sparchez
- 3rd Medical Department, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | | | - Sebastian Gehlert
- Department for Biosciences of Sports, Institute of Sport Science, University of Hildesheim, Hildesheim, Germany
| | - Maria A. Gonzalez-Carmona
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Arnulf Willms
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
- Department of General and Visceral Surgery, German Armed Forces Hospital, Hamburg, Germany
| | - Christian P. Strassburg
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Miroslaw T. Kornek
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
| | - Leona Dold
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Veronika Lukacs-Kornek
- Department of Immunodynamic, Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
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Abstract
Autoimmune liver diseases (AILD) are a group of immune-mediated liver inflammatory diseases with three major forms including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Interaction of both genetic and environmental factors leads to the breakdown of self-tolerance, hence resulting in hyper-responsive of autoantibodies and aggressive autoreactive immune cells. Genetic studies have identified dozens of risk loci associated with initiation and development of AILD. However, the role of exogenous factors remains unclear. Recently, both infectious and inflammatory diseases have been associated with microbiota, which colonizes multiple mucosal surfaces and participates in human physiological process and function in immune system, particularly influencing liver, and biliary system via gut-liver axis. Emerging evidence on the role of gut microbiota has expanded our knowledge of AILD in both pathogenesis and potential therapeutic targets, along with putative diagnosis biomarkers. Herein we review the relationship between host and gut microbiota, discuss their potential roles in disease onset and progression, and summarize the compositional and functional alterations of the microbiota in AILD. We also highlighted the microbiota-based therapeutics such as antibiotics and fecal microbiota transplantation (FMT).
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Affiliation(s)
- Qiwei Qian
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wei He
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ruqi Tang
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiong Ma
- School of Medicine, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China -
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3
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Sakai T, Kondo M, Kawana Y, Inoue R. [A case of neuromyelitis optica spectrum disorders associated with primary biliary cholangitis: a twelve year follow-up study]. Rinsho Shinkeigaku 2022; 62:190-197. [PMID: 35228461 DOI: 10.5692/clinicalneurol.cn-001668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
We report the case of a 51-year-old woman who developed neuromyelitis optica spectrum disorders (NMOSD) associated with primary biliary cholangitis (PBC). When she was 38 years old, she subacutely developed headache and urinary retention. A diffusion weighted image (DWI) on brain MRI showed high signal intensity in the left temporal white matter, and T2 weighted image (T2WI) on spine MRI showed high signal intensities in the spinal cord. After the initial event, follow-ups at 2, 6 and 9 months revealed that she developed neurological symptoms, and T2WI on spine MRI showed high signal intensities in the cervical and thoracic regions of the spinal cord. On each episode, she was treated a course of intravenous methylprednisolone which resulted in improvement of her symptoms. At the age of 39 years, the serum levels of biliary enzymes began to elevate, and the serum levels were markedly elevated after the age of 40 years. When she was 40 years old, she developed optic neuritis of the right eye. At the age of 41 years, spine MRI again showed the cervical and thoracic spinal cord lesions. At the age of 51 years, she subacutely developed dizziness and urinary retention. DWI on brain MRI showed high signal intensities in the pons and medulla oblongata, and T2WI on spine MRI showed longitudinally extensive high signal intensities in the spinal cord, specifically between the C3 and C5 vertebral levels. The serological tests for autoantibodies revealed positive anti-aquaporine 4 antibody (AQP4-Ab), positive anti-mitochondrial antibody subtype M2 (AM2-Ab) and positive anti-nuclear antibody, and the interleukin-6 (IL-6) level was elevated in the cerebrospinal fluid. Simultaneous occurrence of AQP4-Ab-positive NMOSD and AM2-Ab-positive PBC is extremely rare, and has never been reported in Japan. The present case is the first case with simultaneous occurrence of AQP4-Ab-positive NMOSD and AM2-Ab-positive PBC in Japan. We suspect that IL-6, plasmablast and cytotoxic T lymphocyte were involved with the occurrence of NMOSD with PBC in the present case.
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Affiliation(s)
- Toshiyuki Sakai
- Department of Neurology, Saiseikai Matsusaka General Hospital
| | - Masahide Kondo
- Department of Neurology, Saiseikai Matsusaka General Hospital
| | - Yosuke Kawana
- Department of Neurology, Saiseikai Matsusaka General Hospital
| | - Ryuichi Inoue
- Department of Neurology, Saiseikai Matsusaka General Hospital
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4
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Determination of T Cell Responses in Thai Systemic Sclerosis Patients. J Immunol Res 2022; 2022:5072154. [PMID: 35310606 PMCID: PMC8924789 DOI: 10.1155/2022/5072154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/12/2022] [Accepted: 02/21/2022] [Indexed: 11/17/2022] Open
Abstract
Objectives This study is aimed at determining the role of T cells by assessing the numbers of IFN-γ- and IL-2-secreting T cells following stimulation with peptides derived from DNA topoisomerase-I protein in Thai SSc patients. Methods Fifty Thai SSc patients and 50 healthy controls (HC) joined this study. IFN-γ and IL-2 levels upon stimulation of T cells with 6 peptides derived from DNA topoisomerase-I protein were determined. Anti-nuclear antibodies (ANA) and anti-Scl-70 antibodies were determined by using the ELISA method. Results In SSc patients, we detected a significantly higher number of IFN-γ- and IL-2-secreting CD8+ T cells than IFN-γ- and IL-2-secreting CD4+ T cells after stimulation with pooled peptides derived from DNA topoisomerase-I protein. A similar percentage of CD4+IL-2+, CD4+IFN-γ+, and CD8+IL-2+ were detected following stimulation with DNA topoisomerase-I protein -in SSc patients with anti-Scl-70 antibody (SSc/anti-Scl-70+) and those without. In contrast, the amount of CD8+IFN-γ+ cells was significantly higher in SSc/anti-Scl-70+ than those without. Stimulation with individual peptides showed that CSLRVEHINLHPELD (sPep3; 15 amino acids; position 505-519 of DNA topoisomerase-I protein) was the optimal epitope that induced T cells secreting the highest levels of IFN-γ and IL-2. A higher percentage of IFN-γ+CD4+ T cells was detected in SSc/anti-Scl-70+ than those without the following stimulation with peptides 2 (amino acid position 475-486 [RAVALYFIDKLA] of protein DNA topoisomerase). Conclusion The results from this study emphasize the critical role of DNA topoisomerase-I peptides on the activation of T cells in SSc patients. The findings provide a better understanding of SSc's immunopathogenesis and may lead to the development of diagnostic tools and specific treatments for SSc in the future.
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5
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Mitochondrial Proteins as Source of Cancer Neoantigens. Int J Mol Sci 2022; 23:ijms23052627. [PMID: 35269772 PMCID: PMC8909979 DOI: 10.3390/ijms23052627] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 01/27/2023] Open
Abstract
In the past decade, anti-tumour immune responses have been successfully exploited to improve the outcome of patients with different cancers. Significant progress has been made in taking advantage of different types of T cell functions for therapeutic purposes. Despite these achievements, only a subset of patients respond favorably to immunotherapy. Therefore, there is a need of novel approaches to improve the effector functions of immune cells and to recognize the major targets of anti-tumour immunity. A major hallmark of cancer is metabolic rewiring associated with switch of mitochondrial functions. These changes are a consequence of high energy demand and increased macromolecular synthesis in cancer cells. Such adaptations in tumour cells might generate novel targets of tumour therapy, including the generation of neoantigens. Here, we review the most recent advances in research on the immune response to mitochondrial proteins in different cellular conditions.
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6
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Carambia A, Gottwick C, Schwinge D, Stein S, Digigow R, Şeleci M, Mungalpara D, Heine M, Schuran FA, Corban C, Lohse AW, Schramm C, Heeren J, Herkel J. Nanoparticle-mediated targeting of autoantigen peptide to cross-presenting liver sinusoidal endothelial cells protects from CD8 T-cell-driven autoimmune cholangitis. Immunology 2021; 162:452-463. [PMID: 33346377 PMCID: PMC7968394 DOI: 10.1111/imm.13298] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 11/20/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022] Open
Abstract
Autoimmune diseases are caused by adaptive immune responses to self‐antigens. The development of antigen‐specific therapies that suppress disease‐related, but not unrelated immune responses in general, is an important goal of biomedical research. We have previously shown that delivery of myelin peptides to liver sinusoidal endothelial cells (LSECs) using LSEC‐targeting nanoparticles provides effective protection from CD4 T‐cell‐driven autoimmune encephalomyelitis. Here, we investigated whether this methodology might also serve antigen‐specific treatment of a CD8 T‐cell‐driven autoimmune disease. As a model for CD8 T‐cell‐mediated autoimmunity, we used OT‐1 T‐cell‐driven cholangitis in K14‐OVAp mice expressing the cognate MHC I‐restricted SIINFEKL peptide in cholangiocytes. To study whether peptide delivery to LSECs could modulate cholangitis, SIINFEKL peptide‐conjugated nanoparticles were administered intravenously one day before transfer of OT‐1 T cells; five days after cell transfer, liver pathology and hepatic infiltrates were analysed. SIINFEKL peptide‐conjugated nanoparticles were rapidly taken up by LSECs in vivo, which effectively cross‐presented the delivered peptide on MHC I molecules. Intriguingly, K14‐OVAp mice receiving SIINFEKL‐loaded nanoparticles manifested significantly reduced liver damage compared with vehicle‐treated K14‐OVAp mice. Mechanistically, treatment with LSEC‐targeting SIINFEKL‐loaded nanoparticles significantly reduced the number of liver‐infiltrating OT‐1 T cells, which up‐regulated expression of the co‐inhibitory receptor PD‐1 and down‐regulated cytotoxic effector function and inflammatory cytokine production. These findings show that tolerogenic LSECs can effectively internalize circulating nanoparticles and cross‐present nanoparticle‐bound peptides on MHC I molecules. Therefore, nanoparticle‐mediated autoantigen peptide delivery to LSECs might serve the antigen‐specific treatment of CD8 T‐cell‐driven autoimmune disease.
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Affiliation(s)
- Antonella Carambia
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Cornelia Gottwick
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Dorothee Schwinge
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Stephanie Stein
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | - Markus Heine
- Department of Biochemistry, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Fenja A Schuran
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Carlotta Corban
- Department of Biochemistry, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Joerg Heeren
- Department of Biochemistry, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Herkel
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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7
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Zhao SX, Li WC, Fu N, Zhou GD, Liu SH, Jiang LN, Zhang YG, Wang RQ, Nan YM, Zhao JM. Emperipolesis mediated by CD8 + T cells correlates with biliary epithelia cell injury in primary biliary cholangitis. J Cell Mol Med 2019; 24:1268-1275. [PMID: 31851780 PMCID: PMC6991671 DOI: 10.1111/jcmm.14752] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/20/2019] [Accepted: 09/25/2019] [Indexed: 12/14/2022] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease characterized by chronic destruction of the bile ducts. A major unanswered question regarding the pathogenesis of PBC is the precise mechanisms of small bile duct injury. Emperipolesis is one of cell-in-cell structures that is a potential histological hallmark associated with chronic hepatitis B. This study aimed to clarify the pathogenesis and characteristics of emperipolesis in PBC liver injury. Sixty-six PBC patients, diagnosed by liver biopsy combined with laboratory test, were divided into early-stage PBC (stages I and II, n = 39) and late-stage PBC (stages III and IV, n = 27). Emperipolesis was measured in liver sections stained with haematoxylin-eosin. The expressions of CK19, CD3, CD4, CD8, CD20, Ki67 and apoptosis of BECs were evaluated by immunohistochemistry or immunofluorescence double labelling. Emperipolesis was observed in 62.1% of patients with PBC, and BECs were predominantly host cells. The number of infiltrating CD3+ and CD8+ T cells correlated with the advancement of emperipolesis (R2 = 0.318, P < .001; R2 = 0.060, P < .05). The cell numbers of TUNEL-positive BECs and double staining for CK19 and Ki67 showed a significant positive correlation with emperipolesis degree (R2 = 0.236, P < .001; R2 = 0.267, P < .001). We conclude that emperipolesis mediated by CD8+ T cells appears to be relevant to apoptosis of BEC and thus may aggravate the further injury of interlobular bile ducts.
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Affiliation(s)
- Su-Xian Zhao
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Wen-Cong Li
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Na Fu
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Guang-de Zhou
- Department of Pathology and Hepatology Institution, The Fifth Medical Center, General Hospital of PLA, Beijing, P.R. China
| | - Shu-Hong Liu
- Department of Pathology and Hepatology Institution, The Fifth Medical Center, General Hospital of PLA, Beijing, P.R. China
| | - Li-Na Jiang
- Department of Pathology and Hepatology Institution, The Fifth Medical Center, General Hospital of PLA, Beijing, P.R. China
| | - Yu-Guo Zhang
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Rong-Qi Wang
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Yue-Min Nan
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Jing-Min Zhao
- Department of Pathology and Hepatology Institution, The Fifth Medical Center, General Hospital of PLA, Beijing, P.R. China
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8
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Mani J, Wang L, Hückelhoven AG, Schmitt A, Gedvilaite A, Jin N, Kleist C, Ho AD, Schmitt M. Definition and characterization of novel HLA-*A02-restricted CD8+ T cell epitopes derived from JCV polyomavirus with clinical relevance. Oncotarget 2018; 8:2485-2500. [PMID: 27705933 PMCID: PMC5356818 DOI: 10.18632/oncotarget.12387] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 09/19/2016] [Indexed: 11/25/2022] Open
Abstract
Human JC and BK polyomaviruses (JCV/BKV) can establish a latent infection without any clinical symptoms in healthy individuals. In immunocompromised hosts infection or reactivation of JCV and BKV can cause lethal progressive multifocal leukoencephalopathy (PML) and hemorrhagic cystitis, respectively. Vaccination with JCV/BKV derived antigen epitope peptides or adoptive transfer of virus-specific T cells would constitute an elegant approach to clear virus-infected cells. Furthermore, donor leukocyte infusion (DLI) is another therapeutic approach which could be helpful for patients with JCV/BKV infections.So far, only few immunodominant T cell epitopes of JCV and BKV have been described and therefore is a fervent need for the definition of novel epitopes. In this study, we identified novel T cell epitopes by screening libraries of overlapping peptides derived from the major capsid protein VP1 of JCV. Virus like particles (VLPs) were used to confirm naturally processing. Two human leucocyte antigen (HLA)-A*02-restricted epitopes were characterized by fine mapping with overlapping peptides and nonamer peptide sequences were identified. Cytokine release profile of the epitope-specific T cells was analyzed by enzyme-linked immunospot (ELISPOT) assays and by flow cytometry. We demonstrated that T cell responses were of polyfunctional nature with the potential of epitope-specific killing and cross-reactivity between JCV and BKV. These novel epitopes might constitute a new potential tool to design effective diagnostic and therapeutic approaches against both polyomaviruses.
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Affiliation(s)
- Jiju Mani
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Lei Wang
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Angela G Hückelhoven
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Anita Schmitt
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Alma Gedvilaite
- Department of Eukaryote Genetic Engineering, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania
| | - Nan Jin
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.,Department of Hematology, ZhongDa Hospital, Southeast University, Nanjing, P. R. China
| | - Christian Kleist
- Department of Transplantation Immunology, Heidelberg University Hospital, Heidelberg, Germany.,Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Anthony D Ho
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - Michael Schmitt
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
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9
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Abstract
The three common themes that underlie the induction and perpetuation of autoimmunity are genetic predisposition, environmental factors, and immune regulation. Environmental factors have gained much attention for their role in triggering autoimmunity, with increasing evidence of their influence as demonstrated by epidemiological studies, laboratory research, and animal studies. Environmental factors known to trigger and perpetuate autoimmunity include infections, gut microbiota, as well as physical and environmental agents. To address these issues, we will review major potential mechanisms that underlie autoimmunity including molecular mimicry, epitope spreading, bystander activation, polyclonal activation of B and T cells, infections, and autoinflammatory activation of innate immunity. The association of the gut microbiota on autoimmunity will be particularly highlighted by their interaction with pharmaceutical agents that may lead to organ-specific autoimmunity. Nonetheless, and we will emphasize this point, the precise mechanism of environmental influence on disease pathogenesis remains elusive.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy.
| | - Patrick S C Leung
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA, USA
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10
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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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11
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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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Reshetnyak VI. Primary biliary cirrhosis: Clinical and laboratory criteria for its diagnosis. World J Gastroenterol 2015; 21:7683-7708. [PMID: 26167070 PMCID: PMC4491957 DOI: 10.3748/wjg.v21.i25.7683] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 04/07/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic granulomatous, and destructive inflammatory lesion of small intralobular and septal bile ducts, which is likely to be caused by an autoimmune mechanism with a the presence of serum antimitochondrial antibodies and a potential tendency to progress to cirrhosis. Despite the fact that the etiology of this disease has been unknown so far, there has been a considerable body of scientific evidence that can reveal the clinical and laboratory signs of PBC and the individual components of its pathogenesis and elaborate diagnostic criteria for the disease and its symptomatic therapy. Deficiencies in autoimmune tolerance are critical factors for the initiation and perpetuation of the disease. The purpose of this review is to summarize the data available in the literature and the author's findings on clinical and laboratory criteria for the diagnosis of PBC. This review describes the major clinical manifestations of the disease and the mechanisms of its development. It presents the immunological, biochemical, and morphological signs of PBC and their significance for its diagnosis. A great deal of novel scientific evidence for the problem of PBC has been accumulated. However, the inadequate efficiency of therapy for the disease lends impetus to the quest for its etiological factors and to further investigations of its pathogenetic mechanisms and, on this basis, to searches for new methods for its early diagnosis.
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13
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Soluble HLA technology as a strategy to evaluate the impact of HLA mismatches. J Immunol Res 2014; 2014:246171. [PMID: 25254222 PMCID: PMC4165401 DOI: 10.1155/2014/246171] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 07/15/2014] [Accepted: 08/05/2014] [Indexed: 11/17/2022] Open
Abstract
HLA class I incompatibilities still remain one of the main barriers for unrelated bone marrow transplantation (BMT); hence the molecular understanding of how to mismatch patients and donors and still have successful clinical outcomes will guide towards the future of unrelated BMT. One way to estimate the magnitude of polymorphisms within the PBR is to determine which peptides can be selected by individual HLA alleles and subsequently presented for recognition by T cells. The features (structure, length, and sequence) of different peptides each confer an individual pHLA landscape and thus directly shape the individual immune response. The elution and sequencing of peptides by mass spectrometric analysis enable determining the bona fide repertoire of presented peptides for a given allele. This is an effective and simple way to compare the functions of allelic variants and make a first assessment of their degree of permissivity. We describe the methodology used for peptide sequencing and the limitations of peptide prediction tools compared to experimental methods. We highlight the altered peptide features that are observed between allelic variants and the need to discover the altered peptide repertoire in situations of "artificial" graft versus host disease (GvHD) that occur in HLA-specific hypersensitive immune responses to drugs.
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Wang JJ, Yang GX, Zhang WC, Lu L, Tsuneyama K, Kronenberg M, Véla JL, Lopez-Hoyos M, He XS, Ridgway WM, Leung PSC, Gershwin ME. Escherichia coli infection induces autoimmune cholangitis and anti-mitochondrial antibodies in non-obese diabetic (NOD).B6 (Idd10/Idd18) mice. Clin Exp Immunol 2014; 175:192-201. [PMID: 24128311 DOI: 10.1111/cei.12224] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2013] [Indexed: 01/14/2023] Open
Abstract
Several epidemiological studies have demonstrated that patients with primary biliary cirrhosis (PBC) have a higher incidence of urinary tract infections (UTI) and there is significant homology of the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2), between mammals and bacteria. Previous work has demonstrated that non-obese diabetic (NOD).B6 Idd10/Idd18 infected with Novosphingobium aromaticivorans developed liver lesions similar to human PBC. It was postulated that the biliary disease was dependent upon the presence of the unique N. aro glycosphingolipids in activating natural killer T (NK T) cells. To address this issue, we infected NOD.B6 Idd10/Idd18 mice with either Escherichia coli, N. aro or use of a phosphate-buffered saline (PBS) vehicle control and serially followed animals for the appearance of liver pathology and anti-mitochondrial autoantibodies (AMA). Of striking importance, the biliary disease of E. coli-infected mice was more severe than N. Aro-infected mice and the titre of AMA was higher in E. coli-infected mice. Furthermore, the immunopathology did not correlate with the ability of bacterial extracts to produce antigen-dependent activation of NK T cells. Our data suggest that the unique glycosphingolipids of N. aro are not required for the development of autoimmune cholangitis. Importantly, the data highlight the clinical significance of E. coli infection in a genetically susceptible host, and we suggest that the appearance of autoimmune cholangitis is dependent upon molecular mimicry. These data highlight that breach of tolerance to PDC-E2 is probably the first event in the natural history of PBC in genetically susceptible hosts.
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Affiliation(s)
- J J Wang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA
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Guidelines for the management of primary biliary cirrhosis: The Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan. Hepatol Res 2014; 44 Suppl S1:71-90. [PMID: 24397841 DOI: 10.1111/hepr.12270] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Kopycinska J, Kempińska-Podhorodecka A, Haas T, Elias E, DePinho RA, Paik J, Milkiewicz P, Milkiewicz M. Activation of FoxO3a/Bim axis in patients with Primary Biliary Cirrhosis. Liver Int 2013; 33:231-8. [PMID: 23295054 DOI: 10.1111/liv.12030] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2012] [Accepted: 10/16/2012] [Indexed: 12/30/2022]
Abstract
BACKGROUND/AIMS Impaired regulation of apoptosis has been suggested to play a role in the pathogenesis of Primary Biliary Cirrhosis (PBC). In this study, we analysed a signalling pathway that comprises the transcription factor FoxO3a and its downstream target Bim, a Bcl-2 interacting mediator of apoptosis. MATERIALS & METHODS The tissues examined included livers explanted from patients with cirrhotic PBC, primary sclerosing cholangitis (PSC), alcoholic liver disease (ALD) and liver biopsies from patients with non-cirrhotic PBC. Large margin resections of hepatocellular carcinoma were used as controls. RESULTS Expression of FoxO3a and Bim mRNA was significantly enhanced in both non-cirrhotic and end-stage PBC (2.2-fold and 4.3-fold increases, respectively), but not in the other disorders. Similarly, FOXO3a protein level was increased in end-stage PBC (P < 0.05 vs. control). A significant increase in Bim mRNA in non-cirrhotic and cirrhotic PBC was observed (2.2-fold and 8.2-fold respectively). In addition, the most pro-apoptotic isoform of Bim dominated in livers of PBC patients (2.5- fold increase vs. control; P < 0.05). Enhanced FoxO3a and Bim expression was associated with a substantial activation of caspase-3 in PBC (2-fold increase vs. controls; P < 0.0001), whereas it was decreased in both ALD and PSC (46% and 67% reductions respectively). The relationship between FoxO3a and Bim was further investigated in the livers of FoxO-deficient mice. The somatic deletion of FoxO3a caused a significant decrease in Bim, but not caspase-3 protein expression confirming the crucial role of FoxO3a in induction of Bim gene transcription. CONCLUSIONS Our results imply that the FoxO3/Bim signalling pathway can be of importance in the livers of patients with PBC.
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Affiliation(s)
- Justyna Kopycinska
- Medical Biology Laboratory, Pomeranian Medical University, Szczecin, Poland
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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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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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Ishibashi H, Nakanuma Y, Ueno Y, Egawa H, Koike K, Komori A, Sakisaka S, Shimoda S, Shirabe K, Zeniya M, Soejima Y, Takeyama Y, Tanaka A, Nakamuta M, Nakamura M, Harada K, Fukushima N, Maehara Y, Morizane T, Tsubouchi H. Clinical Guideline of Primary Biliary Cirrhosis 2012 The Intractable Hepato-Biliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan. ACTA ACUST UNITED AC 2012. [DOI: 10.2957/kanzo.53.633] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Hiromi Ishibashi
- International University of Health and Welfare/Fukuoka Sanno Hospital, Fukuoka, Japan
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
- Chairman of the Working Group
| | - Yasuni Nakanuma
- Department of Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
- Chairman of the Subcommittee Meeting of PBC
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hiroto Egawa
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazuhiko Koike
- Gastroenterology, Jikei University Graduate School of Medicine, Tokyo, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
| | - Shotaro Sakisaka
- Department of Medicine and Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Shinji Shimoda
- Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Ken Shirabe
- Department of Surgery and Science, Kyushu University, Fukuoka, Japan
| | - Mikio Zeniya
- Gastroenterology, Jikei University Graduate School of Medicine, Tokyo, Japan
| | - Yuji Soejima
- Department of Surgery and Science, Kyushu University, Fukuoka, Japan
| | - Yasuaki Takeyama
- Department of Medicine and Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kenichi Harada
- Department of Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Nobuyoshi Fukushima
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Kyushu University, Fukuoka, Japan
| | | | - Hirohito Tsubouchi
- Digestive Disease and Life-style Related Disease, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Chairman of the Intractable Hepato-Biliary Disease Study Group
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Medina JF. Role of the anion exchanger 2 in the pathogenesis and treatment of primary biliary cirrhosis. Dig Dis 2011; 29:103-12. [PMID: 21691115 DOI: 10.1159/000324144] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The essential anion exchanger (AE) involved in biliary bicarbonate secretion is AE2/SLC4A2, a membrane protein which has also been recognized to be relevant for the regulation of the intracellular pH (pH(i)) in several cell types. Previously, we reported that the expression of AE2 mRNA is diminished in liver biopsies and peripheral blood mononuclear cells from patients with primary biliary cirrhosis (PBC). Immunohistochemical studies indicated that the expression of the AE2 protein is decreased in the bile ducts and hepatocytes in PBC livers. Moreover, we found that bile duct cells isolated from PBC patients and cultured for a few passages exhibit defective Na(+)-independent Cl(-)/HCO(3)(-) exchange. Interestingly, positron emission tomography studies have shown that PBC patients, even at early stages of the disease, fail to secrete bicarbonate to bile in response to secretin, a defect that can be partially reversed after several months of treatment with ursodeoxycholic acid. Altogether, these findings sustain our hypothesis that dysfunctions related to AE2 might have a role in the pathogenesis of PBC. Inadequate AE2 function in lymphocytes may disturb pH(i) regulation in these cells and alter immune homeostasis leading to autoimmunity. On the other hand, reduced AE2 in cholangiocytes could cause cholestasis and oxidative stress of bile duct cells. Cholangiocyte changes, together with altered immune homeostasis, could favor the development of antimitochondrial antibodies and the autoimmune attack on biliary ducts. Our recent findings that Ae2(a,b)-deficient mice indeed display most of these features strongly support the notion that AE2 abnormalities may be involved in the pathogenesis of PBC.
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Affiliation(s)
- Juan F Medina
- Division of Gene Therapy and Hepatology - Liver Unit, School of Medicine, Clinic and CIMA University of Navarra, and Ciberehd, Pamplona, Spain.
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Schütz C, Oelke M, Schneck JP, Mackensen A, Fleck M. Killer artificial antigen-presenting cells: the synthetic embodiment of a 'guided missile'. Immunotherapy 2010; 2:539-50. [PMID: 20636007 DOI: 10.2217/imt.10.26] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
At present, the treatment of T-cell-dependent autoimmune diseases relies exclusively on strategies leading to nonspecific suppression of the immune systems causing a substantial reduced ability to control concomitant infections or malignancies. Furthermore, long-term treatment with most drugs is accompanied by several serious adverse effects and does not consequently result in cure of the primary immunological malfunction. By contrast, antigen-specific immunotherapy offers the potential to achieve the highest therapeutic efficiency in accordance with minimal adverse effects. Therefore, several studies have been performed utilizing antigen-presenting cells specifically engineered to deplete allo- or antigen-specific T cells ('guided missiles'). Many of these strategies take advantage of the Fas/Fas ligand signaling pathway to efficiently induce antigen-presenting cell-mediated apoptosis in targeted T cells. In this article, we discuss the advantages and shortcomings of a novel non-cell-based 'killer artificial antigen-presenting cell' strategy, developed to overcome obstacles related to current cell-based approaches for the treatment of T-cell-mediated autoimmunity.
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Affiliation(s)
- Christian Schütz
- Department of Internal Medicine I, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.
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Bade-Döding C, Theodossis A, Gras S, Kjer-Nielsen L, Eiz-Vesper B, Seltsam A, Huyton T, Rossjohn J, McCluskey J, Blasczyk R. The impact of human leukocyte antigen (HLA) micropolymorphism on ligand specificity within the HLA-B*41 allotypic family. Haematologica 2010; 96:110-8. [PMID: 20934997 DOI: 10.3324/haematol.2010.030924] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Polymorphic differences between human leukocyte antigen (HLA) molecules affect the specificity and conformation of their bound peptides and lead to differential selection of the T-cell repertoire. Mismatching during allogeneic transplantation can, therefore, lead to immunological reactions. DESIGN AND METHODS We investigated the structure-function relationships of six members of the HLA-B*41 allelic group that differ by six polymorphic amino acids, including positions 80, 95, 97 and 114 within the antigen-binding cleft. Peptide-binding motifs for B*41:01, *41:02, *41:03, *41:04, *41:05 and *41:06 were determined by sequencing self-peptides from recombinant B*41 molecules by electrospray ionization tandem mass spectrometry. The crystal structures of HLA-B*41:03 bound to a natural 16-mer self-ligand (AEMYGSVTEHPSPSPL) and HLA-B*41:04 bound to a natural 11-mer self-ligand (HEEAVSVDRVL) were solved. RESULTS Peptide analysis revealed that all B*41 alleles have an identical anchor motif at peptide position 2 (glutamic acid), but differ in their choice of C-terminal pΩ anchor (proline, valine, leucine). Additionally, B*41:04 displayed a greater preference for long peptides (>10 residues) when compared to the other B*41 allomorphs, while the longest peptide to be eluted from the allelic group (a 16mer) was obtained from B*41:03. The crystal structures of HLA-B*41:03 and HLA-B*41:04 revealed that both alleles interact in a highly conserved manner with the terminal regions of their respective ligands, while micropolymorphism-induced changes in the steric and electrostatic properties of the antigen-binding cleft account for differences in peptide repertoire and auxiliary anchoring. CONCLUSIONS Differences in peptide repertoire, and peptide length specificity reflect the significant functional evolution of these closely related allotypes and signal their importance in allogeneic transplantation, especially B*41:03 and B*41:04, which accommodate longer peptides, creating structurally distinct peptide-HLA complexes.
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Abstract
The systemic autoimmune diseases are a complex group of disorders characterized by elaboration of high titer autoantibodies and immune-mediated damage of tissues. Two striking features of autoimmune rheumatic diseases are their self-sustaining nature and capacity for autoamplification, exemplified by disease flares. These features suggest the presence of a feed-forward cycle in disease propagation, in which immune effector pathways drive the generation/release of autoantigens, which in turn fuel the immune response. There is a growing awareness that structural modification during cytotoxic granule-induced cell death is a frequent and striking feature of autoantigens, and may be an important principle driving disease. This review focuses on granzyme B (GrB)-mediated cleavage of autoantigens including (i) features of GrB cleavage sites within autoantigens, (ii) co-location of cleavage sites with autoimmune epitopes, and (iii) GrB sensitivity of autoantigens in disease-relevant target tissue. The mechanisms whereby GrB-induced changes in autoantigen structure may contribute to the initiation and propagation of autoimmunity are reviewed and reveal that GrB has the potential to create or destroy autoimmune epitopes. As there remains no direct evidence showing a causal function for GrB cleavage of antigens in the generation of autoimmunity, this review highlights important outstanding questions about the function of GrB in autoantigen selection.
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Skowera A, Ellis RJ, Varela-Calviño R, Arif S, Huang GC, Van-Krinks C, Zaremba A, Rackham C, Allen JS, Tree TIM, Zhao M, Dayan CM, Sewell AK, Unger WW, Unger W, Drijfhout JW, Ossendorp F, Roep BO, Peakman M. CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope. J Clin Invest 2008; 118:3390-402. [PMID: 18802479 DOI: 10.1172/jci35449] [Citation(s) in RCA: 211] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2008] [Accepted: 07/21/2008] [Indexed: 12/15/2022] Open
Abstract
The final pathway of beta cell destruction leading to insulin deficiency, hyperglycemia, and clinical type 1 diabetes is unknown. Here we show that circulating CTLs can kill beta cells via recognition of a glucose-regulated epitope. First, we identified 2 naturally processed epitopes from the human preproinsulin signal peptide by elution from HLA-A2 (specifically, the protein encoded by the A*0201 allele) molecules. Processing of these was unconventional, requiring neither the proteasome nor transporter associated with processing (TAP). However, both epitopes were major targets for circulating effector CD8+ T cells from HLA-A2+ patients with type 1 diabetes. Moreover, cloned preproinsulin signal peptide-specific CD8+ T cells killed human beta cells in vitro. Critically, at high glucose concentration, beta cell presentation of preproinsulin signal epitope increased, as did CTL killing. This study provides direct evidence that autoreactive CTLs are present in the circulation of patients with type 1 diabetes and that they can kill human beta cells. These results also identify a mechanism of self-antigen presentation that is under pathophysiological regulation and could expose insulin-producing beta cells to increasing cytotoxicity at the later stages of the development of clinical diabetes. Our findings suggest that autoreactive CTLs are important targets for immune-based interventions in type 1 diabetes and argue for early, aggressive insulin therapy to preserve remaining beta cells.
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Affiliation(s)
- Ania Skowera
- Department of Immunobiology, King's College London, London, United Kingdom
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Sakaki M, Hiroishi K, Baba T, Ito T, Hirayama Y, Saito K, Tonoike T, Kushima M, Imawari M. Intrahepatic status of regulatory T cells in autoimmune liver diseases and chronic viral hepatitis. Hepatol Res 2008; 38:354-61. [PMID: 18021223 DOI: 10.1111/j.1872-034x.2007.00284.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
AIM Regulatory T cells (Tregs) maintain immunological tolerance and suppress autoreactive immune responses. We evaluated the intrahepatic status of Tregs in patients with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), chronic hepatitis C (CH-C), or chronic hepatitis B (CH-B). METHODS We analyzed 85 patients (20 AIH, 22 PBC, 27 CH-C, and 16 CH-B) and 14 controls. Using liver tissue samples obtained by needle biopsy or from marginal parts of resected metastatic liver tumors in the controls, immunohistochemical analyses of forkhead box P3(+), which is a specific marker for Tregs, CD4(+), and CD8(+) cells were performed. RESULTS Intrahepatic Tregs were significantly more infiltrated in patients with liver diseases than in the controls. There were significantly fewer intrahepatic Tregs in the AIH patients than in the PBC patients (P = 0.037). Patients with alow frequency of intrahepatic Tregs were detected significantly more in the AIH and CH-B groups than in the PBC and CH-C groups (P < 0.05). In addition, the frequency of Tregs decreased in the liver of PBC patients as the pathological stage of the disease advanced. We found significantly less infiltration of CD4(+) T cells in AIH than in other diseases (P < 0.05). Liver-infiltrating CD8(+) T cells were detected more frequently in the CH-B group than in other groups (P < 0.003). CONCLUSION Intrahepatic Tregs were increased in both patients with autoimmune liver diseases and those with viral hepatitis. In autoimmune liver diseases, intrahepatic Tregs were fewer in the AIH patients than in the PBC patients.
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Affiliation(s)
- Masashi Sakaki
- Second Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan
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26
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Longhi MS, Hussain MJ, Bogdanos DP, Quaglia A, Mieli-Vergani G, Ma Y, Vergani D. Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2. Hepatology 2007; 46:472-84. [PMID: 17559153 DOI: 10.1002/hep.21658] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Autoimmune hepatitis type 2 (AIH-2) is a severe organ-specific disorder characterized by liver kidney microsomal antibody type 1 targeting cytochrome P4502D6 (CYP2D6). Growing evidence implicates the involvement of CD8 T cell immune responses in its pathogenesis. We investigated CYP2D6-specific CD8 T cell human leukocyte antigen (HLA)-A2 restricted responses in AIH-2 (20 patients, 11 HLA-A2+). Binding affinity of CYP2D6 peptides to HLA-A2 was predicted by the algorithm SYFPEITHI and assessed in vivo by T2 cell assays. CD8 T cell interferon (IFN)-gamma production was assessed via intracellular cytokine staining, cytotoxicity via chromium release assay, and frequency of circulating and intrahepatic CYP2D6-specific CD8 T cells via tetramer staining. CYP2D6-specific CD8 T cell reactivity was tested at diagnosis and during treatment and correlated with indices of disease activity. Seven CYP2D6 peptides with high HLA-A2 binding affinity colocalizing with known B cell or CD4 T cell epitopes were selected. Five sequences inducing high levels of IFN-gamma were used for HLA-A2 tetramer construction. Frequency, IFN-gamma production, and cytotoxicity of CYP2D6-specific CD8 T cells were higher at diagnosis than during treatment. Intensity of CYP2D6-specific CD8 T cell responses correlated with disease activity. Immune responses to CYP2D6(245-254) were the strongest both at diagnosis and during treatment. CONCLUSION HLA-A2-restricted, CYP2D6-specific CD8 T cell immune responses vary according to disease stage and correlate with hepatocyte damage. CD8 T cell targets on CYP2D6-in particular CYP2D6(245-254)-may be the focus of novel immune intervention in AIH-2. (HEPATOLOGY 2007.).
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Affiliation(s)
- Maria Serena Longhi
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, UK
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Voo KS, Zeng G, Mu JB, Zhou J, Su XZ, Wang RF. CD4+ T-cell response to mitochondrial cytochrome B in human melanoma. Cancer Res 2006; 66:5919-26. [PMID: 16740732 DOI: 10.1158/0008-5472.can-05-4574] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Mitochondrial DNA (mtDNA) is highly susceptible to mutations due to the low level of DNA repair and the presence of a high level of reactive oxygen species in the organelle. Although mtDNA mutations have been implicated in degenerating diseases, aging, and cancer, very little is known about the role of T cells in immunosurveillance for mtDNA aberrations. Here, we describe T-cell recognition of a peptide translated from an alternative open reading frame of the mitochondrial cytochrome b (cyt b) gene in melanoma cells established from a patient. To understand how the cyt b gene is transcribed and translated in tumor cells, we found that cyt b-specific CD4(+) T cells only recognized protein fractions derived from cytoplasm and not from mitochondria. However, T-cell recognition of tumor cells could be inhibited by treatment of tumor cells with rhodamine 6G inhibitor, which depletes mitochondria. These findings suggest that cyt b mRNA is leaked out of the mitochondria and then translated in the cytoplasm for presentation to CD4(+) T cells. The cyt b cDNAs from this patient contain highly heteroplasmic transition mutations compared with control cell lines, suggesting a compromise of mitochondrial integrity that may have contributed to melanoma induction or progression. These findings provide the first example of a mitochondrial immune target for CD4(+) T cells and therefore have implications for the immunosurveillance of mitochondrial aberrations in cancer patients.
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Affiliation(s)
- Kui Shin Voo
- The Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, Houston, Texas, USA
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Abstract
Primary biliary cirrhosis (PBC) is a disease of unknown etiology leading to progressive destruction of small intrahepatic bile ducts and eventually to liver cirrhosis and failure. It is characterised by female predominance and serum auto-antibodies to mitochondrial antigens targeting the E2 components of the 2-oxoacid dehydrogenase complex. Although they are associated with disease pathogenesis, no concrete evidence has been presented so far. Epidemiological data indicate that a geographical clustering of cases and possible environmental factors are implicated in pathogenesis. A number of genetic factors play a role in determining disease susceptibility or progression, although no definitive conclusion has been reached so far. A key factor to immune pathogenesis is considered to be the breakdown of immune tolerance, either through molecular mimicry or through the so called determinant density model. In this review, the available data regarding the pathogenesis of primary biliary cirrhosis are described and discussed. A new unifying hypothesis based on early endothelin overproduction in primary biliary cirrhosis (PBC) is presented and discussed.
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Ichiki Y, Selmi C, Shimoda S, Ishibashi H, Gordon SC, Gershwin ME. Mitochondrial antigens as targets of cellular and humoral auto-immunity in primary biliary cirrhosis. Clin Rev Allergy Immunol 2006; 28:83-91. [PMID: 15879615 DOI: 10.1385/criai:28:2:083] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Several factors point toward an auto-immune pathogenesis for primary biliary cirrhosis(PBC), mostly based on the presence of serum auto-antibodies to mitochondrial antigens(AMAs) and autoreactive T cells (both helper and cytotoxic). Interestingly, epitopes recognized by AMA and T-cell clones are located within overlapping areas of the antigens. Moreover,a role for an imbalance in cytokine pattern and for natural-killer lymphocytes has also been proposed. Despite several experimental reports, no clear evidence is available regarding the interaction of these factors leading to bile duct destruction. This article reviews the current reports regarding the auto-immune reaction against mitochondrial auto-antigens in PBC.
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Affiliation(s)
- Yasunori Ichiki
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, TB192, Davis, CA, USA
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Selmi C, Ichiki Y, Invernizzi P, Podda M, Gershwin ME. The enigma of primary biliary cirrhosis. Clin Rev Allergy Immunol 2006; 28:73-81. [PMID: 15879614 DOI: 10.1385/criai:28:2:073] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic disease characterized by a striking predominance in female patients (with most cases diagnosed between ages 40 and 60 yr) as well as serum auto-antibodies to mitochondrial antigens, elevated serum immunoglobulin M,progressive destruction of intrahepatic bile ducts, and, ultimately, liver cirrhosis and failure(1). The precise mechanisms leading to selective destruction of biliary epithelial cells lining intrahepatic bile ducts are still unknown, although numerous immunomediated pathways have been proposed. Genetic background appears to be important in determining susceptibility to the disease (2), but no clear association with alleles in the major histocompatibility complex has been identified. Molecular mimicry either by infections (3) or xenobiotics (4) has been proposed to be capable of breaking tolerance in genetically predisposed individuals, thus leading to onset of PBC. This article describes and discusses the available data regarding the immunomediated pathogenesis of PBC (with particular attention to auto-antibodies and autoreactive T-cells) and presents the recent evidence indicating a role for either xenobiotic chemicals or novel infectious agents in the induction of the disease.
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Affiliation(s)
- Carlo Selmi
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
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31
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Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, Chuang YH, Nakamura T, Saito S, Shimoda S, Tanaka A, Bowlus CL, Takano Y, Ansari AA, Coppel RL, Gershwin ME. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 2006; 43:729-37. [PMID: 16557534 DOI: 10.1002/hep.21123] [Citation(s) in RCA: 231] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
CD4+CD25high regulatory T cells (Tregs) play a critical role in self-tolerance, as seen in murine autoimmunity. Studies on Tregs in human autoimmunity have focused primarily on peripheral blood samples. A study targeting diseased tissue should identify direct relationships between Tregs and autoimmunity. Peripheral blood samples were collected from 91 patients with primary biliary cirrhosis (PBC), 28 immediate relatives, and 41 healthy controls, and Treg frequencies were determined as a percentage of CD4+CD25high T cells in CD4+TCR-alphabeta+ T cells. A tissue-targeted determination of frequency and distribution of FoxP3+ Tregs was also performed on 90 different liver tissue specimens exhibiting PBC (n = 52), chronic hepatitis C (CHC) (n = 30), and autoimmune hepatitis (AIH) (n = 8). Treg suppression studies were performed on 50 PBC patients and 27 controls. Patients with PBC demonstrated a relative reduction of Tregs compared with controls (P < .0002). Interestingly, a deficiency in CD4+CD25+ Tregs was also found in the daughters and sisters of PBC patients compared with controls (P < .0007). However, functional studies did not reveal a global PBC Treg defect. The level of FoxP3-expressing Tregs was markedly lower in affected PBC portal tracts compared with CHC and AIH (P < .001). In addition, the CD8+T cell/FoxP3+ Treg ratio was significantly higher in livers of late-stage PBC compared with those of CHC (P < .001) and early-stage AIH (P < .001). In conclusion, these data provide support for a genetic modulation of Treg frequency and illustrate the role Tregs play in the loss of tolerance in PBC.
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MESH Headings
- Autoimmunity
- CD4 Lymphocyte Count
- CD4-Positive T-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/pathology
- Case-Control Studies
- Forkhead Transcription Factors/metabolism
- Glucocorticoid-Induced TNFR-Related Protein
- Hepatitis C, Chronic/blood
- Hepatitis C, Chronic/immunology
- Hepatitis, Autoimmune/blood
- Hepatitis, Autoimmune/immunology
- Humans
- Liver/immunology
- Liver Cirrhosis, Biliary/blood
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/pathology
- Liver Cirrhosis, Biliary/physiopathology
- Receptors, Interleukin-2/metabolism
- Receptors, Nerve Growth Factor/metabolism
- Receptors, Tumor Necrosis Factor/metabolism
- Severity of Illness Index
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/pathology
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Affiliation(s)
- Ruth Y Lan
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California--Davis, Davis, CA 95616, USA
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Isse K, Harada K, Sato Y, Nakanuma Y. Characterization of biliary intra-epithelial lymphocytes at different anatomical levels of intrahepatic bile ducts under normal and pathological conditions: numbers of CD4+CD28- intra-epithelial lymphocytes are increased in primary biliary cirrhosis. Pathol Int 2006; 56:17-24. [PMID: 16398675 DOI: 10.1111/j.1440-1827.2006.01913.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Distribution of intra-epithelial lymphocytes along intrahepatic biliary tree (bIEL), and their density and phenotype were examined in normal and diseased livers, particularly in primary biliary cirrhosis (PBC). Immunohistochemically, bIEL were examined in 28 normal livers, 13 cases of chronic viral hepatitis (CVH), 13 cases of PBC, five cases of primary sclerosing cholangitis (PSC), seven cases of extrahepatic biliary obstruction (EBO), and 16 hepatolithiatic livers. In normal livers, bIEL were relatively dense at large and septal bile ducts compared to interlobular ducts. Most of them were positive for CD3 and CD8, while a few were positive for CD4, CD20 and CD57. In CVH, PSC and EBO, neither distribution, phenotype nor density of bIEL differed from normal liver. In hepatolithiasis, numbers of CD8(+)bIEL were increased in stone-containing ducts. In PBC, numbers of CD4(+)CD28(-)bIEL, which are reportedly responsible for target tissue destruction in autoimmune diseases, were markedly increased in damaged interlobular ducts. In conclusion, CD3(+)CD8(+)bIEL may be involved in immune homeostasis of intrahepatic bile ducts in normal livers and in CVH, PSC and EBO. Altered distribution and phenotypes of bIEL in PBC and hepatolithiasis may reflect their participation in biliary lesions. Increased CD4(+)CD28(-)bIEL in damaged bile ducts of PBC may be related to immune-mediated biliary damage.
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Affiliation(s)
- Kumiko Isse
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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Longhi MS, Ma Y, Mitry RR, Bogdanos DP, Heneghan M, Cheeseman P, Mieli-Vergani G, Vergani D. Effect of CD4+ CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis. J Autoimmun 2005; 25:63-71. [PMID: 16005184 DOI: 10.1016/j.jaut.2005.05.001] [Citation(s) in RCA: 166] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2005] [Revised: 04/21/2005] [Accepted: 05/11/2005] [Indexed: 01/10/2023]
Abstract
BACKGROUND AND AIMS CD4 T lymphocytes constitutively expressing the IL-2-receptor alpha-chain (CD25) (T-regs) are central to self-tolerance maintenance, preventing the proliferation and effector function of autoreactive T-cells. In autoimmune hepatitis T-regs are defective in number but maintain the ability to suppress IFNgamma production by CD4+CD25- T-cells. We have studied the ability of CD4+CD25+ (T-regs) to regulate proliferation and cytokine production by CD8 T-cells in patients with autoimmune hepatitis at diagnosis and during remission. METHODS Twenty-five patients were studied. T-regs were purified from PBMCs by CD4 negative selection followed by CD25 positive selection, using immunomagnetic beads. The ability of T-regs to suppress CD8 T-cell proliferation was assessed by 3H-thymidine incorporation; their ability to regulate cytokine production by intracellular cytokine staining. RESULTS We found that T-regs are unable to regulate CD8 T-cell proliferation and cytokine production in patients studied at diagnosis, while they suppress CD8 T-cell proliferation and induce an elevation of IL-4 producing CD8 T-cells in patients during drug-induced remission. CONCLUSION Inability of T-regs to regulate CD8 T-cell function at diagnosis may contribute to the initiation of autoimmune liver damage. The ability of T-regs to regulate CD8 proliferation and IL-4 production during drug-induced remission suggests a role for immunosuppressive treatment at reconstituting T-regs function.
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Affiliation(s)
- Maria Serena Longhi
- Institute of Liver Studies, King's College London, King's College Hospital, Denmark Hill, London SE5 9RS, UK
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Affiliation(s)
- Marshall M Kaplan
- Division of Gastroenterology, Tufts-New England Medical Center, Boston, MA 02111, USA.
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Huang YH, Tao MH, Hu CP, Syu WJ, Wu JC. Identification of novel HLA-A*0201-restricted CD8+ T-cell epitopes on hepatitis delta virus. J Gen Virol 2004; 85:3089-3098. [PMID: 15448372 DOI: 10.1099/vir.0.80183-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hepatitis delta virus (HDV) superinfection causes a poor prognosis in hepatitis B virus-infected patients and effective therapy is lacking. Cytotoxic T-lymphocyte (CTL) responses play an important role in the pathogenesis of chronic viral hepatitis; however, the CD8+ T-cell epitopes of HDV have never been defined. Potential HLA-A*0201-restricted HDV peptides were selected from the SYFPEITHI database and screened by T2 cell-stabilization assay. HLA-A*0201 transgenic mice on a C57BL/6 background were injected intramuscularly with an HDV DNA vaccine. Splenocytes were stained directly ex vivo with HLA-A*0201-peptide tetramers after immunization. Epitope-specific CTL responses were confirmed by cytotoxic assays. HLA-A2, chronically infected HDV patients were also enrolled, to assess the existence of HDV-specific CD8+ T cells, based on findings in animals. Following HDV DNA vaccination, nearly 0.9 % of the total splenic CD8+ T cells were specific for peptides HDV 26-34 and HDV 43-51 in HLA-A*0201 transgenic mice, which was significantly higher than the number found in non-transgenic mice or in transgenic mice that had been immunized with control plasmid. HDV 26-34- and 43-51-specific CTL lines were able to produce CTL responses to each peptide. Interestingly, HDV 26-34- and HDV 43-51-specific CD8+ T cells were also detectable in two chronically infected HDV patients in the absence of active HDV replication. In conclusion, HDV 26-34 and 43-51 are novel HLA-A*0201-restricted CTL epitopes on genotype I HDV. HDV 26-34- and 43-51-specific CTLs have been detected in chronic hepatitis delta patients without active disease. Evoking CTL responses to HDV may be an alternative approach to controlling HDV viraemia in patients with chronic hepatitis delta.
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Affiliation(s)
- Yi-Hsiang Huang
- Institute of Clinical Medicine, National Yang-Ming University, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, 201 Shih-Pai Road, Sec. 2, Taipei 112, Taiwan, Republic of China
| | - Mi-Hua Tao
- Division of Cancer Research, Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan, Republic of China
| | - Cheng-Po Hu
- Department of Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
| | - Wan-Jr Syu
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, Republic of China
| | - Jaw-Ching Wu
- Institute of Clinical Medicine, National Yang-Ming University, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, 201 Shih-Pai Road, Sec. 2, Taipei 112, Taiwan, Republic of China
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Ichiki Y, Shimoda S, Ishibashi H, Gershwin ME. Is primary biliary cirrhosis a model autoimmune disease? Autoimmun Rev 2004; 3:331-6. [PMID: 15246030 DOI: 10.1016/j.autrev.2004.04.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2004] [Revised: 04/10/2004] [Accepted: 04/11/2004] [Indexed: 11/16/2022]
Abstract
Primary biliary cirrhosis (PBC) has been coined a model autoimmune disease. In fact, it does share many similarities with other autoimmune diseases, but there are striking differences that illustrate the uniqueness of the immunopathology. Firstly, similar to other autoimmune diseases, there is an intense humoral and cellular response to an intracytoplasmic antigen. There is also an overlap of the epitopes recognized by autoreactive CD4(+), CD8(+) T cells as well as B cells. Patients with PBC are also predominantly female, and there is a higher family history of other autoimmune diseases. In contrast, however, there are no specific HLA associations in PBC. Further, there are no spontaneous or induced animal models of PBC. In addition, early in the biliary lesions of PBC, there is an eosinophilic infiltration and, often, there are granulomas. Finally, unlike several other human autoimmune diseases, patients with PBC have recognition of but one major epitope, and there is no evidence for determinant spreading. Hence, although the immune response of PBC has been vigorously defined, there remain major gaps in understanding the most difficult issue of all, namely etiology.
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Affiliation(s)
- Yasunori Ichiki
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, TB192, One Shields Avenue, Davis, CA 95616, USA
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Affiliation(s)
- David E J Jones
- Centre for Liver Research, University of Newcastle, School of Clinical Medical Sciences, 4th Floor William Leech Building, Medical School, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK.
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Abstract
Further insights into the cellular and molecular mechanisms underlying hepatobiliary transport function and its regulation now permit a better understanding of the pathogenesis and treatment options of cholestatic liver diseases. Identification of the molecular basis of hereditary cholestatic syndromes will result in an improved diagnosis and management of these conditions. New insights into the pathogenesis of extrahepatic manifestations of cholestasis (eg, pruritus) have facilitated new treatment strategies. Important new studies have been published about the pathogenesis, clinical features, diagnosis, and treatment of primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis of pregnancy, total parenteral nutrition-induced cholestasis, drug-induced cholestasis, and viral cholestatic syndromes.
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Affiliation(s)
- Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Karl-Franzens University, School of Medicine, Graz, Austria
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