标题: DDW2012:Intrahepatic NK Cell Activation Is Dependent on Levels of HBsAg in Chron [打印本页] 作者: StephenW 时间: 2012-5-23 17:08 标题: DDW2012:Intrahepatic NK Cell Activation Is Dependent on Levels of HBsAg in Chron
本帖最后由 StephenW 于 2012-5-23 17:12 编辑
Intrahepatic NK Cell Activation Is Dependent on Levels of HBsAg in Chronic HBeAg-Negative Hepatitis B
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Eric T. Tjwa, Roeland Zoutendijk, Gertine van Oord, Joanne Verheij, Paula J. Biesta, Andrea Woltman, Andre Boonstra, Harry L. Janssen
Affiliation
Erasmus Medical Centre Rotterdam, Rotterdam, Netherlands
Abstract:
Background
Chronic hepatitis B (CHB) is the result of a failing immune response towards the virus. Blood natural killer (NK) cells serve as first-line defence against viral intruders, and these cells are functionally impaired in blood of CHB patients. Since little is known on liver NK cells in CHB, we aimed to investigate the activation status and function of intrahepatic NK cells in both HBeAg positive and negative CHB.
Methods Liver cells were isolated from biopsy specimens of 56 CHB patients. Liver leukocytes were stimulated for 24 h with IL-12/-18. Specimens were also processed for routine histopathological grading and staging according to Ishak scoring. NK cell frequencies, activation status (CD69) and function of NK cells were analysed by flow cytometry.
Results
Our cohort consisted of 21 HBeAg positive and 35 HBeAg negative CHB patients. As expected, the levels of HBV-DNA and HBsAg were significantly higher in HBeAg positive disease (p<0.01). There was a moderate to strong correlation between HBV-DNA and HBsAg in both HBeAg positive and -negative disease. Frequency of liver NK cells and activated liver NK cells, as evidenced by CD69 positivity, was resp. 1.5 and 6-fold higher than in blood (p<0.001). Upon stimulation, the frequency of CD69 positive liver NK cells increased less in liver than in blood (1.1 vs 4.5-fold) regardless of HBeAg status. In line with this, the frequency of IFN-γ expressing NK cells upon stimulation was 3 fold higher in blood than in liver (p<0.001). There was no difference between HBeAg positive and -negative CHB. Liver NK cell activation and IFN-γ expression was significantly correlated in HBeAg negative CHB (r=0.50, p<0.05). In this population, also HBsAg quantification correlated with liver NK cell activation (r=-0.60, p<0.05), but not with cytokine-expression or with levels of HBV-DNA. Liver histology (grading and staging) correlated neither with liver NK cell activation nor cytokine-expression in both HBeAg positive and -negative disease.
Conclusions
Our findings demonstrate that frequency and activation of NK cells differ strongly between the liver and blood. We further show that in chronic HBV patients, IFN-γ production is
compromised despite a high NK cell activation status, which suggests exhaustion of specific functions of liver NK cells in CHB. We demonstrate for the first time that in HBeAg-negative CHB but not in HBeAg positive CHB, increasing HBsAg levels coincide with less liver NK cell activation, suggesting a role for HBsAg in inflammation but not in pathology. As a consequence, monitoring HBsAg levels during antiviral therapy may reflect modulation of the antiviral intrahepatic immune response.
Disclosure(s):
Harry L. Janssen - Consulting: Bristol-Myers Squibb Co. , Gilead Sciences Inc, Novartis Pharmaceuticals, Roche Pharma AG, Santaris, Medtronic Inc. , Kirin, Abbott, DebioPharm S.A.; Grant/Research Support: Bristol-Myers Squibb Co. , Gilead Sciences Inc, Novartis Pharmaceuticals, Roche Pharma AG, Santaris, Medtronic Inc. , Anadys, Innogenetics
The following people have nothing to disclose: Eric T. Tjwa, Roeland Zoutendijk, Gertine van Oord, Joanne Verheij, Paula J. Biesta, Andrea Woltman, Andre Boonstra