Laurence Amiot1, Nicolas Vu2, Michel Rauch2, Annie L'Helgoualc'h2, Frédéric Chalmel2, Hugues Gascan3, Bruno Turlin4, Dominique Guyader5, Michel Samson2. 1. Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement & Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Fédération de Recherche BioSit de Rennes UMS 3480, F-35043 Rennes, France; Department of Biology, University Hospital Pontchaillou, CHU Pontchaillou, Rennes, France. Electronic address: laurence.amiot@univ-rennes1.fr. 2. Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement & Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Fédération de Recherche BioSit de Rennes UMS 3480, F-35043 Rennes, France. 3. CNRS, UMR 6290, Institute of Genetics and Development of Rennes, Rennes, France. 4. Université de Rennes 1, F-35043 Rennes, France; Department of Pathology, University Hospital Pontchaillou, CHU Pontchaillou, Rennes, France. 5. Université de Rennes 1, F-35043 Rennes, France; Department of Hepatology, University Hospital Pontchaillou, CHU Pontchaillou, Rennes, France.
Abstract
BACKGROUND & AIMS: Infection with hepatitis C virus is a worldwide health problem. An inadequate Th2 cytokine response promotes the fibrosis-cirrhosis fate. Immune-modulating molecules favoring a Th2 profile, such as HLA-G molecules of the HLA class Ib family, may play a role in chronic hepatitis. HLA-G contributes to the escape of tumors, and their involvement in viral infections has been increasingly described. The aim of this work was to study the expression of HLA-G in the liver, its cellular source and its regulation in cases of chronic C hepatitis. METHODS: HLA-G cells in blocks of liver derived from patients infected with HCV were labeled by immunohistochemistry and enumerated. Double immunofluorescence allowed the identification of the cellular source. HLA-G secretion by a human mast cell line was quantified by ELISA after various stimulations. After treatment with IFN-α, real-time PCR was performed to determine the kinetics of cytokine expression profiles, followed by heat map clustering analysis. RESULTS: The number of HLA-G+ cells was significantly associated with the area of fibrosis. For the first time, we identify the HLA-G+ cells as being mast cells. HLA-G secretion was significantly induced in human mast cells stimulated by IL-10 or interferons of class I. The transcriptome of the secretome of this cell line stimulated by IFN-α revealed that (i) the HLA-G gene is upregulated late, and that (ii) T lymphocytes and NK cells are recruited. CONCLUSIONS: These findings suggest an autocrine loop in the genesis of HCV liver fibrosis, based on mast cells expressing HLA-G.
BACKGROUND & AIMS: Infection with hepatitis C virus is a worldwide health problem. An inadequate Th2 cytokine response promotes the fibrosis-cirrhosis fate. Immune-modulating molecules favoring a Th2 profile, such as HLA-G molecules of the HLA class Ib family, may play a role in chronic hepatitis. HLA-G contributes to the escape of tumors, and their involvement in viral infections has been increasingly described. The aim of this work was to study the expression of HLA-G in the liver, its cellular source and its regulation in cases of chronic C hepatitis. METHODS:HLA-G cells in blocks of liver derived from patients infected with HCV were labeled by immunohistochemistry and enumerated. Double immunofluorescence allowed the identification of the cellular source. HLA-G secretion by a human mast cell line was quantified by ELISA after various stimulations. After treatment with IFN-α, real-time PCR was performed to determine the kinetics of cytokine expression profiles, followed by heat map clustering analysis. RESULTS: The number of HLA-G+ cells was significantly associated with the area of fibrosis. For the first time, we identify the HLA-G+ cells as being mast cells. HLA-G secretion was significantly induced in human mast cells stimulated by IL-10 or interferons of class I. The transcriptome of the secretome of this cell line stimulated by IFN-α revealed that (i) the HLA-G gene is upregulated late, and that (ii) T lymphocytes and NK cells are recruited. CONCLUSIONS: These findings suggest an autocrine loop in the genesis of HCV liver fibrosis, based on mast cells expressing HLA-G.
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