Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Immunol. 2010 Jan 1;184(1):466-75. doi: 10.4049/jimmunol.0900687. Epub 2009 Nov 30.
The role of liver NK cells in virus-induced severe viral hepatitis and, subsequently, hepatic failure is not well defined. In this study, we investigated the role of liver NK cells in the development of hepatocyte necrosis in fulminant hepatic failure (FHF) and acute-on-chronic liver failure (ACLF) because of viral infection. A mouse model of FHF induced by murine hepatitis virus strain 3 (MHV-3) was used to study the role of liver NK cells. Samples from patients with hepatitis B virus-related ACLF (HBV-ACLF) were examined. After MHV-3 infection, the number of NK cells in livers of BALB/cJ mice increased markedly, peaked at 48 h postinfection, and remained at a high level until sacrifice. In peripheral blood, spleen, and bone marrow, this number decreased significantly. Expression of CD69, cytotoxic activity, and intracellular IFN-gamma and TNF-alpha production by liver NK cells at 48 h postinfection were all significantly upregulated. Depletion of NK cells 24 h post-MHV-3 infection increased the mice survival from 0 of 18 (0%) to 4 of 18 (22.2%). Highly activated liver NK cells were cytotoxic to MHV-3-infected hepatocytes and this effect was markedly inhibited by anti-Fas ligand (FasL) plus anti-NKG2D mAbs. Furthermore, the accumulation of hepatic NK cells and increased expression of FasL and natural cytotoxicity receptors (NKp30 and NKp46) on the peripheral NK cells from patients with HBV-ACLF were correlated with disease progression. These results indicate NK cells play a pivotal role in the pathogenesis of FHF and HBV-ACLF, in which process Fas/FasL and NKG2D/NKG2D ligand pathway contribute to the liver NK cell-mediated hepatocyte injury.
肝 NK 细胞在病毒诱导的重型病毒性肝炎，随后的肝衰竭中的作用尚未明确。本研究旨在探讨肝 NK 细胞在病毒感染导致的暴发性肝衰竭（FHF）和慢加急性肝衰竭（ACLF）中引起肝细胞坏死中的作用。我们使用小鼠肝炎病毒 3 型（MHV-3）诱导的 FHF 模型来研究肝 NK 细胞的作用。并检测了乙型肝炎病毒相关 ACLF（HBV-ACLF）患者的样本。MHV-3 感染后，BALB/cJ 小鼠肝脏 NK 细胞数量显著增加，感染后 48 小时达到峰值，并持续处于高水平直至处死。在外周血、脾脏和骨髓中，其数量显著减少。感染后 48 小时，肝 NK 细胞的 CD69 表达、细胞毒性活性以及细胞内 IFN-γ和 TNF-α的产生均显著上调。MHV-3 感染后 24 小时 NK 细胞耗竭可将小鼠存活率从 0/18（0%）提高至 4/18（22.2%）。高度活化的肝 NK 细胞对 MHV-3 感染的肝细胞具有细胞毒性作用，抗 Fas 配体（FasL）加抗 NKG2D mAb 可显著抑制该作用。此外，HBV-ACLF 患者外周血 NK 细胞中肝 NK 细胞的积聚和 FasL 及自然细胞毒性受体（NKp30 和 NKp46）表达的增加与疾病进展相关。这些结果表明，NK 细胞在 FHF 和 HBV-ACLF 的发病机制中发挥关键作用，其中 Fas/FasL 和 NKG2D/NKG2D 配体途径有助于肝 NK 细胞介导的肝细胞损伤。
