Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?

Abstract

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. HBeAgexpressing 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 <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.

Hepatitis B-specific T helper cell responses in uninfected infants born to HBsAg+/HBeAg− mothers

“…7,15,16 In neonates born to HBsAg 1 /HBeAg 1 mothers, immune tolerance is further induced by transplacental passage of HBeAg that can result in specific tolerance of T helper cells to both HBeAg and HBcAg because these two antigens are crossreactive. 6,17 However, intrauterine infection and immunoprophylactic failure have also been reported in infants of HBsAg 1 /HBeAg 2 mothers. 7,18 Most studies of neonatal T-cell responses against HBV have focused on the immune responses elicited by HBsAg in vaccinated healthy infants.…”

“…3,4 Although the exact mechanism of vertical transmission is still unclear, it has been postulated that passage of HBV virions or infected PBMCs through the placenta or during the perinatal period is involved. [5][6][7] Identified risk factors for the development of infection include high maternal perinatal viremia and the transplacental passage of HBeAg. 8,9 Both infected and uninfected infants have been shown to encounter HBeAg in utero, but exposure to hepatitis B core antigen (HBcAg), which would indicate possible exposure to virions, has not been documented in babies of either HBeAg 1 or HBeAg 2 mothers.…”

Viruses, Immunity, and Cancer: Lessons from Hepatitis B

“…14,18 -25 The nascent precore protein contains the entire core protein plus a leader sequence that directs it to the ER, where it undergoes limited proteolysis and is secreted into the plasma as hepatitis B e antigen (HBeAg). Its role in the viral life cycle is poorly understood, although it may have tolerogenic properties that would favor viral persistence, 26,27 and it appears to be able to modulate nucleocapsid stability, and therefore replication, by forming heterodimers with the core protein. 28 -30 The 2.4-and 2.1-kb transcripts produce the large, middle, and small envelope proteins.…”

Effect of viral load on T-lymphocyte failure in patients with chronic hepatitis B

“…Hepatitis B e antigen (HBeAg) may play an important role in the interaction of the virus with the immune system. Data from transgenic mice indicate neonatal tolerance to HBeAg is a crucial mechanism responsible for the lack of an antiviral immune response following mother to infant transmission [10,11] . Milich et al [12] have further demonstrated an immunomodulator y role of HBeAg in antig en presentation and recognition by CD4 + cells.…”