Jiang Yujie, Qin Shuang, Wei Xin, Liu Xiaoyuan, Guan Jingjing, Zhu Hengyue, Chang Guolin, Chen Yingxiao, Lu Hong, Qian Jingjing, Wang Zhongyong, Shen Mo, Lin Xiangyang
Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China.
Immunol Lett. 2021 Apr;232:9-19. doi: 10.1016/j.imlet.2020.12.008. Epub 2021 Jan 27.
Chronic hepatitis B-related liver cirrhosis(HBV-LC)is the most common cirrhosis in China, which is characterized as liver damage and high mortality. We aim to investigate the characteristics of TRAILNK cells in patients with HBV-LC and their relationship with liver damage in patients with HBV-LC.
Thirty cases each of chronic hepatitis B (CHB), HBV-related compensated liver cirrhosis (HBV-CLC) and HBV-related decompensated liver cirrhosis (HBV-DLC) patients were recruited in this study. Thirty age-and sex-matched healthy individuals were recruited as healthy controls (HCs). NK cell phenotypes were determined using flow cytometry. Serum chemokine concentrations were ascertained using the CBA Flex set. Cell apoptosis was analyzed using the Annexin V-PE/7-AAD apoptosis Kit.
CD56 NK cells increased, but CD56 NK cells reduced in HBV-LC patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was mainly expressed on CD56 NK cells. As the degree of liver damage increased, the frequency and activation of total TRAILNK cells and TRAILNK cell subsets continued to increase, especially in the HBV-LC patients. Furthermore, the difference in frequency and activation of total TRAILNK cells between the HBV-CLC and HBV-DLC groups was mainly due to the highly activation and increase of TRAILCD56 NK cells. With the increasing degree of liver damage, CXCR3-associated chemokines (including CXCL9, CXCL10 and CXCL11) were constantly increased, particularly in the HBV-DLC group. The expression of CXCR3 on CD56 NK cells was almost 100 % in all enrolled cohorts. CXCR3-associated chemokines were negatively correlated with liver function and positively correlated with fibrosis degree. TRAILCD56 NK cells were negatively correlated with liver function, and positively correlated with fibrosis degree and CXCR3-associated chemokines. The apoptosis of K562 cells and hepatocytes was suppressed partially by the TRAIL-neutralizing antibodies.
The increase of CXCR3-related chemokines (including CXCL9, CXCL10 and CXCL11) might be related to the migration of TRAIL CD56 NK cells to the liver. Highly activated TRAIL CD56 NK cells were associated with the liver damage in HBV-LC patients. These findings may provide new perspectives and theoretical basis for future immunotherapy of HBV-LC patients.
慢性乙型肝炎相关肝硬化（HBV-LC）是中国最常见的肝硬化类型，其特点是肝损伤且死亡率高。我们旨在研究HBV-LC患者中TRAIL⁺NK细胞的特征及其与HBV-LC患者肝损伤的关系。
本研究招募了30例慢性乙型肝炎（CHB）患者、30例HBV相关代偿期肝硬化（HBV-CLC）患者和30例HBV相关失代偿期肝硬化（HBV-DLC）患者。招募30名年龄和性别匹配的健康个体作为健康对照（HCs）。使用流式细胞术测定NK细胞表型。使用CBA Flex套装测定血清趋化因子浓度。使用Annexin V-PE/7-AAD凋亡试剂盒分析细胞凋亡。
HBV-LC患者中CD56⁺NK细胞增加，但CD56⁻NK细胞减少。肿瘤坏死因子相关凋亡诱导配体（TRAIL）主要表达于CD56⁺NK细胞上。随着肝损伤程度增加，总TRAIL⁺NK细胞和TRAIL⁺NK细胞亚群的频率和活化持续增加，尤其是在HBV-LC患者中。此外，HBV-CLC组和HBV-DLC组之间总TRAIL⁺NK细胞频率和活化的差异主要归因于TRAIL⁺CD56⁺NK细胞的高度活化和增加。随着肝损伤程度的增加，CXCR3相关趋化因子（包括CXCL9、CXCL10和CXCL11）持续增加，特别是在HBV-DLC组中。在所有纳入队列中，CD56⁺NK细胞上CXCR3的表达几乎为100%。CXCR3相关趋化因子与肝功能呈负相关，与纤维化程度呈正相关。TRAIL⁺CD56⁺NK细胞与肝功能呈负相关，与纤维化程度和CXCR3相关趋化因子呈正相关。TRAIL中和抗体部分抑制了K562细胞和肝细胞的凋亡。
CXCR3相关趋化因子（包括CXCL9、CXCL10和CXCL11）的增加可能与TRAIL⁺CD56⁺NK细胞向肝脏的迁移有关。高度活化的TRAIL⁺CD56⁺NK细胞与HBV-LC患者的肝损伤有关。这些发现可能为未来HBV-LC患者的免疫治疗提供新的视角和理论基础。
