Hua-Jie Li1,2, Ning Yang3, Xiuying Mu1,2, Lili Tang2, Song-Shan Wang2, Chun-Bao Zhou2, Jin-Hong Yuan2, Hai-Yan Wang2,4, Ying-Ying Yu1,2, Jing Li1,2, Si-Yuan Chen2, Zhi-Qian Feng5, Tao Yang2, Kai Liu2, Wen-Jing Cao2,4, Ming-Ju Zhou2,6, Chao Zhang2, Ji-Yuan Zhang2, Yan-Mei Jiao2, Jin-Wen Song2, Xing Fan2, Ming Shi2, Ruonan Xu7, Fu-Sheng Wang8,9. 1. Clinical Medical School, Peking University 302, Beijing, 100039, China. 2. Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, 100 Xisihuan Road, Fengtai District, Beijing, 100039, China. 3. Clinical Testing Center, The Fifth Medical Center of General Hospital of Chinese PLA General Hospital, Beijing, 100039, China. 4. The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230000, China. 5. The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, China. 6. Beijing Ditan Hospital, Capital Medical University, Beijing, 100102, China. 7. Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, 100 Xisihuan Road, Fengtai District, Beijing, 100039, China. xuruonan2004@aliyun.com. 8. Clinical Medical School, Peking University 302, Beijing, 100039, China. fswang302@163.com. 9. Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, 100 Xisihuan Road, Fengtai District, Beijing, 100039, China. fswang302@163.com.
Abstract
BACKGROUND AND AIMS: Natural killer (NK) cells are critical innate effectors that respond to viral infections and contribute to immunopathology. Here, we aimed to investigate the role of NK cells in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) and elucidate the underlying mechanism by examining their phenotypic and functional profiles. METHODS: We included patients with HBV-ACLF (n = 37) and chronic hepatitis B (n = 19), and healthy controls (n = 13) in our study. We examined the phenotype and function of different subsets of peripheral NK cells using flow cytometry and RNA-sequencing analysis, and screened liver NK cells using immunohistochemistry. We detected inflammatory cytokines using a Luminex assay. In addition, we analyzed the relationships between these parameters and disease severity. RESULTS: Peripheral NK cells were decreased and characterized by high expression of caspase-3, Ki67, CXCR3, NKG2D, NKp46, CD107a, and GM-CSF, and typified by higher cell migration and immune response by RNA-sequencing analysis in patients with HBV-ACLF than in those with chronic hepatitis B. Accumulations of CXCL-10 and NK cells were found in the liver, and excessive production of CXCL-10 in the peripheral blood contributed to the apoptosis of NK cells in vitro. The decrease in NK cells was associated with the level of HBV DNA and disease severity and had good prognostic performance in predicting the outcome of patients with HBV-ACLF through AUROC analysis. CONCLUSION: NK cells were significantly decreased and showed dysfunction of phenotypic and functional profiles across distinct subsets in the peripheral blood of patients with ACLF. Crosstalk between CXCL-10 and NK cells may mediate the unbalanced distribution of NK cells. Understanding the dysfunction and decrease in NK cells may provide new insights into ACLF pathogenesis.
BACKGROUND AND AIMS: Natural killer (NK) cells are critical innate effectors that respond to viral infections and contribute to immunopathology. Here, we aimed to investigate the role of NK cells in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) and elucidate the underlying mechanism by examining their phenotypic and functional profiles. METHODS: We included patients with HBV-ACLF (n = 37) and chronic hepatitis B (n = 19), and healthy controls (n = 13) in our study. We examined the phenotype and function of different subsets of peripheral NK cells using flow cytometry and RNA-sequencing analysis, and screened liver NK cells using immunohistochemistry. We detected inflammatory cytokines using a Luminex assay. In addition, we analyzed the relationships between these parameters and disease severity. RESULTS: Peripheral NK cells were decreased and characterized by high expression of caspase-3, Ki67, CXCR3, NKG2D, NKp46, CD107a, and GM-CSF, and typified by higher cell migration and immune response by RNA-sequencing analysis in patients with HBV-ACLF than in those with chronic hepatitis B. Accumulations of CXCL-10 and NK cells were found in the liver, and excessive production of CXCL-10 in the peripheral blood contributed to the apoptosis of NK cells in vitro. The decrease in NK cells was associated with the level of HBV DNA and disease severity and had good prognostic performance in predicting the outcome of patients with HBV-ACLF through AUROC analysis. CONCLUSION: NK cells were significantly decreased and showed dysfunction of phenotypic and functional profiles across distinct subsets in the peripheral blood of patients with ACLF. Crosstalk between CXCL-10 and NK cells may mediate the unbalanced distribution of NK cells. Understanding the dysfunction and decrease in NK cells may provide new insights into ACLF pathogenesis.