Department of Medical Laboratory Science, College of Medicine, I-Shou University, Kaohsiung, Taiwan.
Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
PLoS One. 2019 Nov 26;14(11):e0225482. doi: 10.1371/journal.pone.0225482. eCollection 2019.
As debate rumbles on about whether anti-hepatitis B virus (HBV) nucleos(t)ide analogue treatments modulate host immune system during end-stage liver diseases, we studied effects of two potent anti-HBV agents, telbivudine or entecavir, on humoral immune activities including cytokine secretion, immunoglobulin production, and IgG-Fc agalactosylation, which is known to induce proinflammatory responses, in liver cirrhosis. Serum IgG-Fc N-glycan structures in patients with HBV-related liver cirrhosis, who had received either telbivudine treatment or entecavir treatment for at least 48 weeks were analyzed using liquid chromatography tandem-mass spectrometry. Levels of cytokines and each immunoglobulin isotype were measured using enzyme-linked immunosorbent assays. Results showed that 48 weeks of entecavir treatment caused HBV DNA loss, alanine aminotransferase normalization, and an amelioration of hypergammaglobulinemia in cirrhotic patients; however, telbivudine treatment, though possessing similar efficacies on HBV suppression and an improvement in liver inflammation to entecavir treatment, did not mitigate IgG-related hypergammaglobulinemia. Levels of IgG and transforming growth factor (TGF)-β1 in sera of the cirrhotic patients before and during treatment were positively correlated. In vitro assays revealed that telbivudine treatment induced TGF-β1 expression in human macrophagic cells. Moreover, recombinant TGF-β1 treatment stimulated cell proliferation and IgG overproduction in human IgG-producing B cell lines. Finally, we found that telbivudine treatment enhanced the proportion of serum IgG-Fc agalactosylation in cirrhotic patients, which was associated with enhanced levels of TGF-β1 and IgG. In conclusion, telbivudine therapy was associated with TGF-β1 hyperactivity, IgG-related hypergammaglobulinemia, and IgG-Fc agalactosylation in HBV-related liver cirrhosis.
在关于抗乙型肝炎病毒 (HBV) 核苷 (酸) 类似物治疗是否在终末期肝病中调节宿主免疫系统的争论中，我们研究了两种强效抗 HBV 药物，替比夫定或恩替卡韦，对包括细胞因子分泌、免疫球蛋白产生和 IgG-Fc 半乳糖基化在内的体液免疫活性的影响，已知 IgG-Fc 半乳糖基化可诱导炎症反应。使用液相色谱串联质谱法分析了接受替比夫定或恩替卡韦治疗至少 48 周的 HBV 相关肝硬化患者的血清 IgG-Fc N-糖链结构。使用酶联免疫吸附试验测量细胞因子和每种免疫球蛋白同种型的水平。结果表明，48 周的恩替卡韦治疗导致 HBV DNA 丢失、丙氨酸氨基转移酶正常化和肝硬化患者的高球蛋白血症改善；然而，替比夫定治疗虽然对 HBV 抑制和改善肝炎症与恩替卡韦治疗具有相似的疗效，但不能减轻 IgG 相关的高球蛋白血症。肝硬化患者治疗前后血清 IgG 和转化生长因子 (TGF)-β1 水平呈正相关。体外试验显示替比夫定诱导人巨噬细胞中 TGF-β1 的表达。此外，重组 TGF-β1 处理刺激人 IgG 产生 B 细胞系中的细胞增殖和 IgG 过度产生。最后，我们发现替比夫定治疗增强了肝硬化患者血清 IgG-Fc 半乳糖基化的比例，这与 TGF-β1 和 IgG 水平的升高有关。总之，替比夫定治疗与 HBV 相关肝硬化中的 TGF-β1 过度活跃、IgG 相关高球蛋白血症和 IgG-Fc 半乳糖基化有关。
