A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B

Tan, Anthony T.; Koh, Sarene; Goh, Winnie; Zhe, Heng Yee; Gehring, Adam J.; Lim, Seng Gee; Bertoletti, Antonio

doi:10.1016/j.jhep.2009.12.015

« Previous Next »Journal of Hepatology
Volume 52, Issue 3 , Pages 330-339, March 2010

A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B

Anthony T. Tan
- Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*Star), Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Sarene Koh
- Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*Star), Singapore
Winnie Goh
- Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*Star), Singapore
Heng Yee Zhe
- Faculty of Science, National University of Singapore, Singapore
Adam J. Gehring
- Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*Star), Singapore
Seng Gee Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Antonio Bertoletti
- Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*Star), Singapore
- Singapore Immunology Network, Agency of Science Technology and Research (A*Star), Singapore
- Program Emerging Viral Diseases Unit, Duke-NUS Graduate Medical School, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Corresponding author. Address: Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609, Singapore. Tel.: +65 6407 0091; fax: +65 6776 6837.

Received 20 August 2009; received in revised form 24 September 2009; accepted 13 October 2009. published online 13 January 2010.

Background & Aims

The pathogenesis of hepatic flares (HF) in patients chronically infected with hepatitis B virus (HBV) is controversial. Therefore, we studied the kinetics of innate and adaptive immune activation during HF in chronic hepatitis B.

Methods

Soluble (IFN-α, IL-1β, TNF-α, IL-6, IL-8, IL-10, CCL-2, CCL-3, CXCL-9, CXCL-10) and cellular (HBV-specific T cells, NK, Treg) immunological parameters were measured longitudinally (10month–4week intervals) in patients (n=5) who developed HF after therapy withdrawal and cross-sectionally in chronic (n=29) and acute hepatitis B patients (n=5). Hepatic expression of different chemokines was studied by co-incubating cytokines (IFN-α, IFN-γ, TNF-α) and activated T, NK and monocytes with hepatocytes and hepatocyte-like cells.

Results

A progressive increase of HBV replication precedes HF but occurs without detection of innate immune activation, with the exception of increased serum CXCL-8. Despite the absence of increased circulatory HBV-specific T or activated NK cells, HF were temporally associated with high serum levels of IFN-γ inducible chemokines CXCL-9 and CXCL-10 (but not CCL-2 or CCL-3). CXCL-9 and CXCL-10 displayed different in vitro requirements for activation and are differentially produced in liver injury present in acute or chronic patients.

Conclusions

CXCL-9 and CXCL-10 play a major role in the development of HF. Their differential expression in acute versus chronic patients suggests the presence of different mechanisms that govern liver injury during acute and chronic hepatitis B.

Abbreviations: HBV, hepatitis B virus, HF, hepatic flares, PBMC, peripheral blood mononuclear cells, HBsAg, hepatitis B surface antigen, HCV, hepatitis C virus, HIV-1, human immunodeficiency virus type 1, HDV, hepatitis D virus, NK, natural killer cell, Treg, regulatory T cells, ALT, alanine amino-transferase, MCMV, murine cytomegalovirus