Milich D R, Jones J E, Hughes J L, Price J, Raney A K, McLachlan A
Department of Molecular Biology, Scripps Clinic and Research Foundation, La Jolla 92037.
Proc Natl Acad Sci U S A. 1990 Sep;87(17):6599-603. doi: 10.1073/pnas.87.17.6599.
Infants born to hepatitis B virus carrier mothers, who express a secreted form of the nucleocapsid antigen designated HBeAg, invariably become persistently infected. To investigate the role of immunologic tolerance mechanisms in chronic infection of the newborn, we have generated HBeAg-expressing transgenic mice. HBeAg-expressing transgenic mice were tolerant to both HBeAg and the nonsecreted nucleocapsid (hepatitis B cor antigen/HBcAg) at the T-cell level. Transgenic mice did not produce antibody to HBeAg but did produce anti-HBc antibody in vivo and in vitro. The coexistence of tolerance to HBc/HBe T-cell determinants and anti-HBc antibody production in vivo parallels the immunologic status of neonates born to carrier mothers. It was also demonstrated that the maintenance of T-cell tolerance to HBcAg/HBeAg required the continued presence of the tolerogen and in its absence persisted for less than 16 weeks. The reversibility of T-cell tolerance to HBcAg/HBeAg may explain the inverse correlation between age of infection and rates of viral persistence. These observations suggest that a function of the HBeAg may be to induce immunologic tolerance in utero. Expression of HBeAg may represent a viral strategy to guarantee persistence after perinatal infection.
乙肝病毒携带者母亲所生的婴儿，若其表达一种名为HBeAg的核衣壳抗原分泌形式，往往会持续感染。为了研究免疫耐受机制在新生儿慢性感染中的作用，我们培育了表达HBeAg的转基因小鼠。表达HBeAg的转基因小鼠在T细胞水平上对HBeAg和非分泌性核衣壳（乙肝核心抗原/HBcAg）均具有耐受性。转基因小鼠不产生针对HBeAg的抗体，但在体内和体外均能产生抗HBc抗体。对HBc/HBe T细胞决定簇的耐受性与体内抗HBc抗体产生并存，这与携带者母亲所生新生儿的免疫状态相似。还证明了对HBcAg/HBeAg的T细胞耐受性的维持需要耐受原的持续存在，若缺乏耐受原，耐受性持续时间不到16周。对HBcAg/HBeAg的T细胞耐受性的可逆性可能解释了感染年龄与病毒持续率之间的负相关。这些观察结果表明，HBeAg的一个功能可能是在子宫内诱导免疫耐受。HBeAg的表达可能代表一种病毒策略，以确保围产期感染后病毒的持续存在。
