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

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Abstract

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.

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Acknowledgements

This work was supported by a grant from the “Open Research Center” Project for Private Universities: matching fund subsidy from MEXT (2005), Nihon University Joint Research Grant for 2006, Grants-in-Aid for Scientific Research (C) 22590350 (2010) and 25430142 (2013) from MEXT, and Nihon University Multidisciplinary Research Grant for 2014. The authors thank Drs. Keiko Takagi, Takuichi Oikawa, and Takao Mamiya, Nihon University Itabashi Hospital, Japan, for providing clinical data of patients.

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  1. Mariko Ishibashi

    Present address: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan

Authors and Affiliations

  1. Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1, Ohyaguchikami-cho, Itabashi-ku, Tokyo, 173-8610, Japan

    Mariko Ishibashi, Hiromi Yamaguchi, Akihisa Sakurada, Toshihide Endo, Makoto Makishima & Mariko Esumi

  2. Department of Pathology, Nihon University School of Medicine, Tokyo, Japan

    Yukari Hirotani & Masahiko Sugitani

  3. Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan

    Tadatoshi Takayama

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  1. Mariko Ishibashi
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Correspondence to Makoto Makishima or Mariko Esumi.

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All authors declare that they have no conflict of interest.

Ethical approval

Our study protocol was previously approved by the ethics committee of our university in accordance with the 1975 Declaration of Helsinki.

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Informed and written consent was obtained from each patient.

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Handling Editor: Michael A. Purdy.

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Ishibashi, M., Yamaguchi, H., Hirotani, Y. et al. Contradictory intrahepatic immune responses activated in high-load hepatitis C virus livers compared with low-load livers. Arch Virol 163, 855–865 (2018). https://doi.org/10.1007/s00705-017-3675-8

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  • DOI: https://doi.org/10.1007/s00705-017-3675-8

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