Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?
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.
Department of Molecular Biology, Scripps Clinic and Research Foundation, La Jolla 92037.
D R
DR
Milich
J E
JE
Jones
J L
JL
Hughes
J
J
Price
A K
AK
Raney
A
A
McLachlan
D000818:Animals; D000831:Animals, Newborn; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006512:Hepatitis B Core Antigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D006513:Hepatitis B e Antigens / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D015183:Restriction Mapping; D013601:T-Lymphocytes / Q000276:immunology*
D006512:Hepatitis B Core Antigens; D006513:Hepatitis B e Antigens; D011994:Recombinant Proteins