高水平表面抗原衰减Toll样受体介导的免疫应答

StephenW

Original Article
Toll-like receptor-mediated immune responses are attenuated in the presence of high levels of hepatitis B virus surface antigen
Authors

    M. Jiang,
    R. Broering,
    M. Trippler,
    L. Poggenpohl,
    M. Fiedler,
    G. Gerken,
    M. Lu,
    J. F. Schlaak

    First published: 5 February 2014Full publication history
    DOI: 10.1111/jvh.12216
    Citing literature
    Funding Information

Summary

It has been recently shown that Toll-like receptor (TLR) signalling in murine nonparenchymal liver cells (NPCs) is suppressed in the presence of Hepatitis B virus surface antigen (HBsAg). It is not clear, however, whether this is also relevant for the adaptive immune responses and how this effect is mediated. Peripheral blood mononuclear cells (PBMCs) from Hepatitis B virus (HBV) patients and controls were stimulated by TLR ligands in the absence or presence of autologous serum. Interestingly, TLR-mediated cytokine expression (Interleukin-6 and -10) as well as TLR3-induced interferon (IFN) expression in PBMCs of HBV patients was significantly higher than in the healthy volunteers, showing a negative correlation with the levels of HBsAg. In addition, TLR3-mediated IFN-γ production was inhibited in the presence of HBV-containing serum. To mechanistically analyse this observation, murine Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs) were stimulated with TLR3 ligands in the presence or absence of HBsAg. Mixed lymphocyte reactions were performed to study T-cell activation induced by TLR-stimulated NPCs. Gene expression of cytokines and TLR3 was analysed by quantitative rt-PCR, and activation of transcription factors was assessed by Western blot or reporter gene assays. TLR-induced expression of interferon γ, interferon sensitive genes and proinflammatory cytokines in murine KCs and LSECs was efficiently suppressed in the presence of HBsAg, whereas the expression of anti-inflammatory cytokines was enhanced. Activation of NFκB, IRF-3 and MAPKs in these liver cells was potently suppressed by HBsAg. T-cell activation mediated through TLR3-stimulated KCs or LSECs was suppressed by HBsAg which could be reverted by anti-IL-10 antibodies. These findings may, at least in part, explain how HBV evades innate and adaptive immune responses to maintain a persistent infection.

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• 1Faculty of Medicine, Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany
  
• 2Faculty of Medicine, Institute of Virology, University Duisburg-Essen, Essen, Germany
  
• 3Department of Pathogenic Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  
  

*  Correspondence: Joerg F. Schlaak, MD, Department of Gastroenterology and Hepatology, University Hospital of Essen, Hufelandstr. 55, 45122 Essen, Germany.
E-mail: [email protected]