Contradictory intrahepatic immune responses activated in high-load hepatitis C virus livers compared with low-load livers

• Published in: Archives of virology 2018-04, Vol.163 (4), p.855-865
• Main Authors: Ishibashi, Mariko, Yamaguchi, Hiromi, Hirotani, Yukari, Sakurada, Akihisa, Endo, Toshihide, Sugitani, Masahiko, Takayama, Tadatoshi, Makishima, Makoto, Esumi, Mariko
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Antigen-presenting cells; Antigens; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, CD20 - genetics; Antigens, CD20 - immunology; Antigens, Differentiation, Myelomonocytic - genetics; Antigens, Differentiation, Myelomonocytic - immunology; Apoptosis; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Biomedical and Life Sciences; Biomedicine; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - virology; CD11c antigen; CD11c Antigen - genetics; CD11c Antigen - immunology; CD20 antigen; CD3 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; CD40 Ligand - genetics; CD40 Ligand - immunology; CD40L protein; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; Cell death; Dendritic Cells - immunology; Dendritic Cells - virology; DQA1 protein; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Foxp3 protein; Gene Expression Regulation; Helper cells; Hepacivirus - growth & development; Hepacivirus - immunology; Hepacivirus - pathogenicity; Hepatitis; Hepatitis C; Hepatitis C, Chronic - complications; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - virology; Hepatocytes; Hepatocytes - immunology; Hepatocytes - virology; Histocompatibility antigen HLA; HLA-DQ alpha-Chains - genetics; HLA-DQ alpha-Chains - immunology; Humans; Immune response; Immune Tolerance; Immunological tolerance; Infectious Diseases; Kupffer cells; Kupffer Cells - immunology; Kupffer Cells - virology; Liver - immunology; Liver - virology; Liver Neoplasms - etiology; Liver Neoplasms - genetics; Liver Neoplasms - immunology; Liver Neoplasms - virology; Load; Lymphocytes B; Lymphocytes T; Macrophages; Medical Microbiology; Original Article; PD-L1 protein; Signal Transduction; T cell receptors; Transcriptome - immunology; Viral Load - genetics; Viral Load - immunology; Virology
• ISSN: 0304-8608; 1432-8798
• DOI: 10.1007/s00705-017-3675-8

We found a HLA class II histocompatibility antigen gene, DQ alpha 1 chain ( HLA-DQA1 ), that was expressed more than 9-fold higher in high-load hepatitis C virus (HCV) livers than low-load HCV livers using transcriptomics of chronic HCV-infected livers. To further investigate this finding, we examined which cells were positive for HLA-DQA1 and what liver immune responses were different between HCV-high and -low livers. HLA-DQA1-positive cells were significantly increased in the HCV-high group, and most positive cells were identified as non-parenchymal sinusoid cells and lymphocytic infiltrates in the portal area. Parenchymal hepatocytes were negative for HLA-DQA1. HLA-DQA1-positive cells in the liver sinusoid were positive for CD68 (macrophages or Kupffer cells); those in the lymphocytic infiltrates were positive for CD20 (B cells) or CD3 (T cells). mRNA levels of antigen-presenting cell (APC) markers such as CD68 and CD11c were significantly upregulated in the HCV-high group and were correlated with HLA-DQA mRNA levels. CD8B mRNA (CD8 + T cells) was upregulated in both HCV-positive livers compared with HCV-negative livers, whereas CD154 mRNA (CD4 + T helper cell) was upregulated in the HCV-high group compared with the HCV-low group. The immune regulatory molecules FOXP3 mRNA (regulatory T cell, T reg) and programmed cell death ligand-1 ( PD-L1 ) mRNA were significantly increased in the HCV-high group. HCV-high livers had two molecular immune responses: increased APC numbers and adaptive immunity and the induction of immune tolerance. The local hepatic imbalance of contradictory immune responses might be responsible for high HCV loads.