Severe dendritic cell perturbation is actively involved in the pathogenesis of acute-on-chronic hepatitis B liver failure

Background/Aims: Functionally impaired dendritic cells (DCs) play important roles in suppressing host immune responses and facilitating viral persistence in chronic hepatitis B virus (HBV) infection. However, little is known regarding the status of intrahepatic DCs in HBV infection. Methods: Based on availability, 11 recipient liver samples were obtained from acute-on-chronic hepatitis B fiver failure (ACHBLF) patients who had undergone liver transplantation. The frequencies, phenotypes, and functions of intrahepatic DC subsets were analyzed. Results: Both plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) extensively infiltrated the liver of the ACHBLF patients and expressed mature phenotypes therein. In particular, activated hepatic pDCs produced interferon (IFN)-alpha, which subsequently induced interleukin (IL)-12 and IL-10 production via toll-like receptor-9 ligation in liver-infiltrating lymphocytes cultured in vitro. However, blockade of IFN-alpha production significantly reduced the cytokine production of the LILs. Further, a significantly low frequency of peripheral pDCs and highly reduced IFN-alpha production were observed in a large cohort of the ACHBLF patients, particularly in the non-survivors. Moreover, a persistently upregulated expression of hepatic IFN-alpha-associated genes was observed in the ACHBLF patients during disease progression. Conclusions: Activated pDCs accumulated in large numbers in the liver of the ACHBLF patients and regulated local immune responses in chronic HBV infection. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.