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

J Viral Hepat. 2014 Dec;21(12):860-72. doi: 10.1111/jvh.12216. Epub 2014 Feb 5.

Abstract

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.

Keywords: adaptive immunity; chronic hepatitis B; immunoregulation; innate immunity; non-parenchymal liver cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blotting, Western
  • Cytokines / metabolism*
  • Endothelial Cells / immunology
  • Female
  • Gene Expression Profiling
  • Hepatitis B Surface Antigens / analysis*
  • Hepatitis B, Chronic / immunology*
  • Hepatitis B, Chronic / virology*
  • Humans
  • Kupffer Cells / immunology
  • Leukocytes, Mononuclear / immunology
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Real-Time Polymerase Chain Reaction
  • Toll-Like Receptors / immunology*

Substances

  • Cytokines
  • Hepatitis B Surface Antigens
  • Toll-Like Receptors