Huang Yi-Wen, Hsu Cheng-Kai, Lin Shih-Chang, Wei Shu-Chen, Hu Jui-Ting, Chang Han-Yu, Liang Cher-Wei, Chen Ding-Shinn, Chen Pei-Jer, Hsu Ping-Ning, Yang Sien-Sing, Kao Jia-Horng
Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan.
Antivir Ther. 2014;19(7):637-43. doi: 10.3851/IMP2762. Epub 2014 Mar 12.
Chronic hepatitis B (CHB) patients display Toll-like receptor 9 (TLR9)-dependent defective immune responses. We aimed to study TLR9 expression on CHB patients and its alteration during therapy.
We compared TLR9 expression on fresh peripheral CD14+ monocytes from a cohort of 97 CHB patients and 35 HBsAg-negative, anti-HCV-negative controls, during pegylated interferon or entecavir therapy. TLR9 expression on liver tissue was also investigated.
Compared with controls, peripheral CD14+ monocytes of CHB patients displayed reduced expression of TLR9 mean fluorescence intensity (MFI; 9.90 ±3.64 versus 7.95 ±3.61; P=0.007) independent of age, gender and alanine aminotransferase (ALT; -2.09, 95% CI -3.568, -0.613; P=0.006). Furthermore, age, gender, ALT, HBeAg status, quantitative HBsAg (qHBsAg) or HBV DNA did not predict the TLR9 expression (P=0.863). Hepatic TLR9 messenger RNA (mRNA) was significantly reduced in 54 patients compared with 3 controls (0.45 ±0.32 versus 1-fold). Using response-guided therapy by qHBsAg levels and pretreatment TLR9 MFI as a reference, TLR9 MFI restored to a mean of 1.7- to 2.7-fold in pegylated interferon responders and reduced to a mean of 0.6- to 0.7-fold in non-responders starting from treatment week 12. Among 10 entecavir-treated patients, TLR9 MFI gradually restored to a mean of 1.2- to 2.1-fold starting from treatment week 48.
CHB patients display reduced TLR9 expression on peripheral CD14+ monocytes, which is independent of host and viral markers, and on liver tissue. Responders to pegylated interferon and those under entecavir demonstrate restoration of TLR9 expression. On-treatment TLR9 expression on peripheral monocytes might predict response to pegylated interferon therapy.
慢性乙型肝炎（CHB）患者表现出Toll样受体9（TLR9）依赖性免疫反应缺陷。我们旨在研究CHB患者的TLR9表达及其在治疗过程中的变化。
我们比较了97例CHB患者和35例HBsAg阴性、抗HCV阴性对照者在接受聚乙二醇干扰素或恩替卡韦治疗期间新鲜外周血CD14+单核细胞上的TLR9表达。还研究了肝组织中的TLR9表达。
与对照组相比，CHB患者外周血CD14+单核细胞的TLR9平均荧光强度（MFI）表达降低（9.90±3.64对7.95±3.61；P=0.007），与年龄、性别和丙氨酸氨基转移酶（ALT；-2.09，95%CI -3.568，-0.613；P=0.006）无关。此外，年龄、性别、ALT、HBeAg状态、定量HBsAg（qHBsAg）或HBV DNA不能预测TLR9表达（P=0.863）。与3例对照者相比，54例患者的肝组织TLR9信使核糖核酸（mRNA）显著降低（0.45±0.32对1倍）。以qHBsAg水平和治疗前TLR9 MFI为参考进行反应导向治疗，从治疗第12周开始，聚乙二醇干扰素应答者的TLR9 MFI恢复至平均1.7至2.7倍，无应答者降至平均0.6至0.7倍。在10例接受恩替卡韦治疗的患者中，从治疗第48周开始，TLR9 MFI逐渐恢复至平均1.2至2.1倍。
CHB患者外周血CD14+单核细胞和肝组织上的TLR9表达降低，这与宿主和病毒标志物无关。聚乙二醇干扰素应答者和接受恩替卡韦治疗者的TLR9表达恢复。外周单核细胞治疗期间的TLR9表达可能预测聚乙二醇干扰素治疗的反应。
