Milich D R, Chen M K, Hughes J L, Jones J E
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Immunol. 1998 Feb 15;160(4):2013-21.
The hepatitis B precore Ag (HBeAg) is a secreted nonparticulate version of the viral nucleocapsid hepatitis B core Ag (HBcAg), and its function is unknown. A proportion of HBeAg-specific Th cells evade deletion/anergy in HBeAg-transgenic (Tg) mice and mediate anti-HBe "autoantibody" (autoAb) production after in vivo activation with the appropriate Th cell peptide. This model system was used to determine how secretory HBeAg may effect deletion of Th cells in the periphery. For this purpose, HBeAg-Tg mice were bred with Fas and Fas ligand (FasL)-defective lpr/lpr and gld/gld mutant mice. Fas-FasL interactions mediate activation-induced apoptosis in the periphery. In HBeAg-Tg/+ mice, high-titrated anti-HBe autoAb was produced that was exclusively composed of the IgG1 isotype (i.e., Th2-like profile). In contrast, HBeAg-Tg/lpr and HBeAg-Tg/gld mice produced significantly less anti-HBe autoAb, and the IgG isotype patterns were broadened to include IgG2a, IgG2b and IgG3 as well as IgG1 (i.e., mixed Th1/Th2-like profile). These results suggest that HBeAg-specific Th1 cells are preferentially depleted by Fas-FasL-mediated interactions. The effect of circulating HBeAg on HBcAg-specific Th1 cells was also examined by transferring HBe/HBcAg-specific Th cells into dual HBeAg- and HBcAg-expressing Tg recipient mice. The presence of serum HBeAg ablated the expected Th1-mediated anti-HBc Ab response and shifted it toward a Th2 phenotype. These results suggest that in the context of a hepatitis B viral infection, circulating HBeAg has the potential to preferentially deplete inflammatory HBeAg- and HBcAg-specific Th1 cells that are necessary for viral clearance, thereby promoting hepatitis B virus persistence.
乙肝前核心抗原（HBeAg）是病毒核衣壳乙肝核心抗原（HBcAg）的一种分泌型非颗粒形式，其功能尚不清楚。在HBeAg转基因（Tg）小鼠中，一部分HBeAg特异性Th细胞逃避了缺失/失能，在用适当的Th细胞肽进行体内激活后，介导抗HBe“自身抗体”（autoAb）的产生。该模型系统用于确定分泌型HBeAg如何影响外周Th细胞的缺失。为此，将HBeAg-Tg小鼠与Fas和Fas配体（FasL）缺陷的lpr/lpr和gld/gld突变小鼠进行杂交。Fas-FasL相互作用在外周介导激活诱导的细胞凋亡。在HBeAg-Tg/+小鼠中，产生了高滴度的抗HBe自身抗体，其仅由IgG1同种型组成（即类似Th2的特征）。相比之下，HBeAg-Tg/lpr和HBeAg-Tg/gld小鼠产生的抗HBe自身抗体明显较少，并且IgG同种型模式扩大到包括IgG2a、IgG2b和IgG3以及IgG1（即混合的Th1/Th2样特征）。这些结果表明，HBeAg特异性Th1细胞优先通过Fas-FasL介导的相互作用而被清除。还通过将HBe/HBcAg特异性Th细胞转移到同时表达HBeAg和HBcAg的Tg受体小鼠中，研究了循环HBeAg对HBcAg特异性Th1细胞的影响。血清HBeAg的存在消除了预期的Th1介导的抗HBc Ab反应，并使其向Th-2表型转变。这些结果表明，在乙肝病毒感染的情况下，循环HBeAg有可能优先清除病毒清除所必需的炎性HBeAg和HBcAg特异性Th1细胞，从而促进乙肝病毒的持续存在。
