Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*Star), Singapore.
J Hepatol. 2010 Mar;52(3):330-9. doi: 10.1016/j.jhep.2009.12.015. Epub 2010 Jan 13.
BACKGROUND & AIMS: The pathogenesis of hepatic flares (HF) in patients chronically infected with hepatitis B virus (HBV) is controversial. Therefore, we studied the kinetics of innate and adaptive immune activation during HF in chronic hepatitis B.
Soluble (IFN-alpha, IL-1beta, TNF-alpha, IL-6, IL-8, IL-10, CCL-2, CCL-3, CXCL-9, CXCL-10) and cellular (HBV-specific T cells, NK, Treg) immunological parameters were measured longitudinally (10 month-4 week intervals) in patients (n=5) who developed HF after therapy withdrawal and cross-sectionally in chronic (n=29) and acute hepatitis B patients (n=5). Hepatic expression of different chemokines was studied by co-incubating cytokines (IFN-alpha, IFN-gamma, TNF-alpha) and activated T, NK and monocytes with hepatocytes and hepatocyte-like cells.
A progressive increase of HBV replication precedes HF but occurs without detection of innate immune activation, with the exception of increased serum CXCL-8. Despite the absence of increased circulatory HBV-specific T or activated NK cells, HF were temporally associated with high serum levels of IFN-gamma inducible chemokines CXCL-9 and CXCL-10 (but not CCL-2 or CCL-3). CXCL-9 and CXCL-10 displayed different in vitro requirements for activation and are differentially produced in liver injury present in acute or chronic patients.
CXCL-9 and CXCL-10 play a major role in the development of HF. Their differential expression in acute versus chronic patients suggests the presence of different mechanisms that govern liver injury during acute and chronic hepatitis B.
慢性乙型肝炎病毒（HBV）感染者发生肝衰竭（HF）的发病机制仍存在争议。因此，我们研究了慢性乙型肝炎 HF 期间固有和适应性免疫激活的动力学。
对 5 例因停药后发生 HF 的患者（n=5）进行了纵向（10 个月-4 周间隔）研究，并对慢性（n=29）和急性乙型肝炎患者（n=5）进行了横断面研究，测量了可溶性（IFN-α、IL-1β、TNF-α、IL-6、IL-8、IL-10、CCL-2、CCL-3、CXCL-9、CXCL-10）和细胞（HBV 特异性 T 细胞、NK、Treg）免疫参数。通过将细胞因子（IFN-α、IFN-γ、TNF-α）和活化的 T、NK 和单核细胞与肝细胞和肝样细胞共孵育，研究了不同趋化因子在肝内的表达。
HBV 复制的进行性增加先于 HF，但在没有检测到固有免疫激活的情况下发生，除了血清 CXCL-8 增加外。尽管循环中 HBV 特异性 T 细胞或活化的 NK 细胞没有增加，但 HF 与血清中 IFN-γ诱导的趋化因子 CXCL-9 和 CXCL-10 水平升高呈时间相关性（但 CCL-2 或 CCL-3 则没有）。CXCL-9 和 CXCL-10 的激活需要不同的体外条件，在急性或慢性患者的肝损伤中存在不同的产生方式。
CXCL-9 和 CXCL-10 在 HF 的发展中起主要作用。它们在急性与慢性患者中的差异表达表明，在急性和慢性乙型肝炎中，控制肝损伤的机制存在差异。
