Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Front Immunol. 2021 Nov 11;12:631976. doi: 10.3389/fimmu.2021.631976. eCollection 2021.
We previously showed that overt acute hepatitis B (AHB) was more severe in female patients. Using the same cohort and AHB mouse model, we examined the underlying mechanism.
Baseline biochemistry, virological and cytokine assays, and T helper (Th)1 and Th2 immune markers of 118 consecutive patients were analyzed. The decompensated livers of AHB and chronic hepatitis B (CHB) patients who underwent liver transplantation were analyzed immunohistochemically. B6 mice were hydrodynamically injected with pHBV1.3 plasmids.
Decompensated AHB patients (n=41) were older, more often female, and had higher alanine aminotransferase (ALT), soluble programmed cell death protein 1 (sPD-1) levels, and neutrophil-lymphocyte ratios but lower rates of HBeAg positivity and quantitative HBsAg, interferon (IFN)-γ-inducible protein 10 (IP-10), IFN-γ, and interleukin-4 (IL-4) levels than the compensated patients. Female sex (95% CI OR=1.0754.9), age (1.061.40), and ALT levels (1.001~1.004) were associated with hepatic decompensation. Higher sPD-1 but lower IFN-γ and IL-4 levels were observed in female patients. Compared to CHB, decompensated AHB livers had more IL-17-positive cells but fewer HBsAg-positive cells and lower CD4/CD8 ratios. Higher serum IL-17 levels were noted in the female AHB mice than those in the males.
Females predominated in decompensated AHB, in which downregulated IFN-γ and IL-4 with augmented hepatic IL-17-positive cell development indicated accelerating destructive immunity to enhance viral clearance. The early surge of serum IL-17 was confirmed in the female AHB mice. Targeting the pathway involving IFN-γ, IL-4, and IL-17 might prevent liver transplantation or fatality in decompensated AHB.
我们之前曾表明，女性患者的显性急性乙型肝炎（AHB）更为严重。使用相同的队列和 AHB 小鼠模型，我们研究了潜在的机制。
分析了 118 例连续患者的基线生化、病毒学和细胞因子检测以及辅助性 T（Th）1 和 Th2 免疫标志物。对接受肝移植的 AHB 和慢性乙型肝炎（CHB）失代偿患者的肝脏进行免疫组织化学分析。B6 小鼠用 pHBV1.3 质粒进行水力注射。
失代偿性 AHB 患者（n=41）年龄较大，女性较多，丙氨酸氨基转移酶（ALT）、可溶性程序性死亡蛋白 1（sPD-1）水平和中性粒细胞-淋巴细胞比值较高，但 HBeAg 阳性率和定量 HBsAg、干扰素（IFN）-γ诱导蛋白 10（IP-10）、IFN-γ和白细胞介素-4（IL-4）水平较低。女性（95%CI OR=1.0754.9）、年龄（1.061.40）和 ALT 水平（1.001~1.004）与肝功能失代偿有关。在女性患者中观察到更高的 sPD-1 但更低的 IFN-γ和 IL-4 水平。与 CHB 相比，失代偿性 AHB 肝脏中 IL-17 阳性细胞较多，HBsAg 阳性细胞较少，CD4/CD8 比值较低。在雌性 AHB 小鼠中观察到的血清 IL-17 水平高于雄性。
失代偿性 AHB 中女性占主导地位，其中下调的 IFN-γ和 IL-4 以及增强的肝内 IL-17 阳性细胞发育表明加速破坏性免疫以增强病毒清除。在雌性 AHB 小鼠中证实了血清 IL-17 的早期激增。靶向涉及 IFN-γ、IL-4 和 IL-17 的途径可能有助于预防失代偿性 AHB 患者的肝移植或死亡。
