Abstract
Chronic hepatitis B virus (HBV) infection is characterized by sustained liver inflammation with an influx of lymphocytes, which contributes to the development of cirrhosis and hepatocellular carcinoma. The mechanisms underlying this immune-mediated hepatic pathogenesis remain ill defined. We report in this article that repetitive infusion of anti-CD137 agonist mAb in HBV-transgenic mice closely mimics this process by sequentially inducing hepatitis, fibrosis, cirrhosis, and, ultimately, liver cancer. CD137 mAb initially triggers hepatic inflammatory infiltration due to activation of nonspecific CD8(+) T cells with memory phenotype. CD8(+) T cell-derived IFN-γ plays a central role in the progression of chronic liver diseases by actively recruiting hepatic macrophages to produce fibrosis-promoting cytokines and chemokines, including TNF-α, IL-6, and MCP-1. Importantly, the natural ligand of CD137 was upregulated significantly in circulating CD14(+) monocytes in patients with chronic hepatitis B infection and closely correlated with development of liver cirrhosis. Thus, sustained CD137 stimulation may be a contributing factor for liver immunopathology in chronic HBV infection. Our studies reveal a common molecular pathway that is used to defend against viral infection but also causes chronic hepatic diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / pathology
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / immunology*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Carcinoma, Hepatocellular / virology
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Cytokines / genetics
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Cytokines / immunology
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Cytokines / metabolism
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Hepatitis B virus / genetics
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Hepatitis B virus / immunology*
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Hepatitis B, Chronic / genetics
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Hepatitis B, Chronic / immunology
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Hepatitis B, Chronic / metabolism
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Humans
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Immunologic Memory / drug effects
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Immunologic Memory / genetics
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Immunologic Memory / immunology
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Lipopolysaccharide Receptors / genetics
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Lipopolysaccharide Receptors / immunology
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Lipopolysaccharide Receptors / metabolism
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Liver Neoplasms, Experimental / genetics
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Liver Neoplasms, Experimental / immunology*
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Liver Neoplasms, Experimental / metabolism
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Liver Neoplasms, Experimental / pathology
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Liver Neoplasms, Experimental / virology
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Mice
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Mice, Transgenic
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Monocytes / immunology*
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Monocytes / metabolism
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Monocytes / pathology
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / agonists
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / biosynthesis
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology*
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism
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Up-Regulation / drug effects
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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Antibodies, Monoclonal
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Cytokines
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Lipopolysaccharide Receptors
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Tumor Necrosis Factor Receptor Superfamily, Member 9