Role of T-cell tolerance in the persistence of hepatitis B virus infection.
Infants born to hepatitis B e antigen (HBeAg)-positive hepatitis B virus (HBV) carrier mothers 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 (B10.S-Tg31e). These mice were tolerant to both HBeAg and the nonsecreted HBcAg at the T-cell level. Furthermore, nontransgenic littermates born to HBeAg-expressing mothers showed lowered T-cell responses to HBc/HBe antigens, suggesting that tolerogenic HBeAg may cross the placenta. Tg mice did not produce antibody to HBeAg but did produce immunoglobulin M (IgM) antibodies to HBcAg via a T cell-independent pathway. The coexistence of tolerance to HBc/HBe T-cell determinants and production of antibody to HBcAg in vivo parallels the immunologic status of neonates born to carrier mothers. These observations suggest that expression of HBeAg may represent a viral strategy to guarantee persistence after perinatal infection. Further studies in F1 hybrid Tg mice (B10 x B10.S-Tg31e) illustrated that "self" tolerance to HBeAg is variable, depending on the major histocompatibility complex (MHC) genotype. A proportion of T cells recognizing e129-140 in the context of I-Ab evade induction of tolerance, persist in the periphery, and can be activated in vivo by a single injection of the 12 residue T-cell self-peptide. Furthermore, the self-reactive T cells can cooperate with self-reactive, HBeAg-specific B cells to mediate in vivo production of autoantibody sufficient to neutralize detection of the autoantigen in serum.(ABSTRACT TRUNCATED AT 250 WORDS)
Milich
D R
DR
Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037.
Jones
J
J
Hughes
J
J
Maruyama
T
T
D000818:Animals; D000918:Antibody Specificity; D002353:Carrier State; D002908:Chronic Disease; D006509:Hepatitis B / Q000276:immunology*; D006513:Hepatitis B e Antigens / Q000097:blood*; D006801:Humans; D007108:Immune Tolerance; D007231:Infant, Newborn; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*
D006513:Hepatitis B e Antigens