T Lymphocyte Sensitization to Hbcag and T Cell–Mediated Unresponsiveness to Hbsag in Hepatitis B Virus–Related Chronic Liver Disease

Abstract

Using a newly developed indirect T lymphocyte migration inhibition test, cell-mediated immunity to HBsAg and HBcAg was directly and simultaneously examined in a total of 21 patients with HBsAg-positive chronic liver disease (CLD), and in seven subjects whose sera contained anti-HBs (2 previous acute hepatitis B; 4 hepatitis B vaccine recipients and 1 chronic active hepatitis). T cell sensitization to HBcAg was invariably detected in the HBsAg-positive CLD patients tested (12/12), whereas T cell sensitization to HBsAg was not present in any of the patients (0/21). In contrast, T cell sensitization to HBsAg was present in all anti-HBs-positive subjects. These results support the hypothesis that the cellular immune response to HBcAg, rather than to HBsAg, is implicated in the pathogenesis of HBsAg-positive CLD. Moreover, the observation that the addition of T cells from patients with HBsAg-positive CLD to T cells from anti-HBs positive subjects in a ratio of 1 to 9 reversed their sensitization to HBsAg, suggests that a hyperactivity of HBsAg-specific suppressor T cell population may be responsible for persistent HBs antigenemia.

The serology of chronic hepatitis B infection revisited.

“…This observation together with the fact that HBe/HBcAg-specific Th cells have been shown to elicit anti-envelope antibody production (26), suggest that HBeAg-specific Th cells may mediate anti-envelope antibody production in CH-B infection. This hypothesis is consistent with a number of recent reports that have demonstrated HBe/ HBcAg-specific T cell proliferative responses but not HBsAg or pre-S-specific T cell proliferation in CH-B patients (37)(38)(39)(40). Furthermore, increasing levels of HBe/HBcAg-specific T cell proliferation were reported to occurjust before acute exacerbations of liver injury (37), which correlates precisely with the timing of increases in anti-HBc, anti-HBe, and anti-envelope antibody levels in CAH patients (Fig.…”

Variations in codons 84-101 in the core nucleotide sequence correlate with hepatocellular injury in chronic hepatitis B virus infection.

“…2. Serum ALT levels were within nearly normal range for [3][4][5][6][7][8] yr in the healthy carriers despite active virus replication (all patients were seropositive for HBeAg). In contrast, in the chronic liver disease group serum enzyme levels continuously fluctuated (Fig.…”

“…We decided to analyze the C gene of HBV, because it was previously suggested that the core peptide (HBcAg) could be an immunological target ofcytotoxic T cells in HBV infection (2)(3)(4)(5). It was recently shown that hyperimmune globulin against HBsAg may force the antigenic epitope of "a" determinant of surface antigen to mutate (28).…”

“…Previous studies have suggested that the hepatic injury due to HBV is immune-mediated, and that the hepatitis B core antigen (HBcAg) could be an immunological target (1)(2)(3)(4)(5). HBV DNA contains four open reading frames, one of them being the C gene coding for a core peptide (HBcAg) (6).…”

Novel pre-C/C gene mutants of hepatitis B virus in chronic active hepatitis: naturally occurring escape mutants

“…HBV core antigen (HBcAg) has been postulated to be an immunological target for cytotoxic T lymphocytes (CTLs) (Penna et al, 1987;Milich et al, 1989;Vento et al, 1985). Selective pressure from CTLs may result in substitutions in the amino acids in a restricted segment of the core protein containing the CTL epitope (Rotzschke & Falk, 1991).…”