Peripheral blood and intrahepatic natural killer cells in chronic hepatitis C : relation to disease activity and hepatic fibrosis

Abstract EN

Background / Aim : Hepatitis C virus (HCV) infection is an important cause of chronic liver disease.

Cellular immune responses are thought to play a key role in the pathogenesis of liver damage.

Increasing attention has been drawn towards components of the innate immune system to HCV, including natural killer (NK) cells.

The present work was designed to study peripheral blood and intrahepatic NK cells in patients with chronic hepatitis C in relation to disease activity and severity of hepatic fibrosis.

Methods : Fifteen untreated patients with chronic hepatitis C and 12 healthy subjects were included in the present study.

All patients had seropositivity of circulating HCV antibodies and detectable serum HCV RNA.

The NK and NKT cells in fresh whole blood samples were identified using two-color flow cytometry as CD3-CD56+ and CD3+CD56+ cells respectively and the results were expressed as percentages of the total lymphocyte count.

Liver biopsies were taken from all patients and the specimens were evaluated as regards the histological activity grade (A) and fibrosis stage (F) according to METAVIR scoring system and for the presence and grade of steatosis.

Immunohistochemical staining was done using antibodies against CD56 for detection of intrahepatic NK cells and smooth muscle actin (SMA) for identification of activated hepatic satellite cells (HSCs).

A semi-quantitative method was used to score the intensity of immunostaining.

Results : The percentages of CD3-CD56+ NK cells and CD3+CD56+ NKT cells in peripheral blood showed significant decreases in patients with chronic hepatitis C compared with healthy subjects (P<0.01) and were positively correlated with the intensity of CD56+ NK cells in the liver (P = 0.001).

The NK cell infiltrate was found to be absent or minimal in about 70% of the liver biopsies of patients with chronic hepatitis C.

Patients presenting with chronic fatigue showed significantly lower percentages of circulating NK and NKT cells and intensity of intrahepatic NK cells than patients who were asymptomatic (P<0.05).

The percentages of peripheral blood NK cells and NKT cells and the intensity of intrahepatic NK cells showed significant inverse correlations with serum HCV RNA levels, steatosis grade, METAVIR fibrosis stage and intensity of activated HSCs (P<0.05).

On the contrary, there were no statistically significant correlations between NK cell populations in peripheral blood and in the liver on one hand and the age of the patient, apparent duration of disease, serum levels of aminotransferases or the histological activity grade on the other hand (P>0.05).

Conclusions : The deficiency of peripheral blood and intra-hepatic NK cells in patients with chronic hepatitis C may provide a mechanism for immune suppression resulting in viral persistence, disease chronicity and progression of hepatic fibrosis.

Restoration of the NK cell population may be one of the potential manipulations for resolution of HCV infection and for therapeutic modulation of hepatofibrogenesis.