A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B.
OBJECTIVE
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-alpha, IL-1beta, TNF-alpha, 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 (10 month-4 week 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-alpha, IFN-gamma, TNF-alpha) 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-gamma 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.
Tan
Anthony T
AT
Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*Star), Singapore.
Koh
Sarene
S
Goh
Winnie
W
Zhe
Heng Yee
HY
Gehring
Adam J
AJ
Lim
Seng Gee
SG
Bertoletti
Antonio
A
D000208:Acute Disease; D056704:Adaptive Immunity / Q000502:physiology*; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000378:metabolism; D006509:Hepatitis B / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D006515:Hepatitis B virus / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007694:Killer Cells, Natural / Q000502:physiology; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D008137:Longitudinal Studies; D013601:T-Lymphocytes / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D014779:Virus Replication / Q000502:physiology
D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D016207:Cytokines