Kinetics of hepatitis B surface antigen–specific immune responses in acute and chronic hepatitis B or After HBs vaccination: Stimulation of the in vitro antibody response by interferon gamma

✍ Scribed by Wulf Otto Böcher; Sabine Herzog-Hauff; Jörg Schlaak; Karl-Hermann Meyer zum Büschenfelde; Hanns Friedrich Löhr

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 223 KB
• Volume: 29
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510290120

✦ Synopsis

Because cellular and humoral immune responses against the hepatitis B virus (HBV) surface antigen (HBs) might be crucial to overcome HBV infection, HBs-specific B-and T-cell responses of HBV patients and HBs vaccine recipients were analyzed quantitatively and functionally. In patients with acute hepatitis B (AHB), transient high anti-HBssecreting B-cell frequencies were observed early after clinical onset, whereas 1 patient who probably developed chronic infection and chronic HBV carriers had absent or weak B-and T-cell responses. In HBs vaccine recipients, maximal HBs-specific B-and T-cell responses were detected after the first injection that decreased gradually before anti-HBs antibodies appeared in serum. Years after vaccination, anti-HBs-secreting B cells were enriched in the bone marrow. After in vitro stimulation with HBsAg, peripheral blood mononuclear cells (PBMC) of only 1 of 5 acute and 1 of 6 chronic HBV patients, but of all 6 vaccine recipients, secreted varying amounts of interferon gamma (IFN-␥), but no interleukin-4 (IL-4) or IL-5. Furthermore, the addition of IFN-␥, but not of IL-2, -4, -12, or IFN-␣, resulted in strong increases of anti-HBs-secreting B cells in vaccine recipients and chronic carriers. In conclusion, circulating anti-HBssecreting B cells were significantly higher in early acute hepatitis B or early after HBs vaccination than in chronic hepatitis B and decreased in the follow-up as a result of compartmentalization to lymphoid tissues. Release of IFN-␥ by antigen-stimulated T cells might be critical for anti-HBs formation. (HEPATOLOGY 1999;29:238-244.)

Because hepatitis B virus (HBV) is a noncytopathic virus and T cells dominate the lymphocyte infiltrations of the liver, it is widely assumed that the inflammatory activity is mediated by the host' s cellular immune responses. In acute self-limited HBV infection, CD8-positive cytotoxic T cells were observed that recognized epitopes on the core, surface, and polymerase antigens in an HLA class I-restricted manner. [1][2][3][4] Furthermore, strong HLA class II-restricted T-helper cell (TH cell) responses against recombinant HBV core antigens and derived peptides have been demonstrated in acute infection and during exacerbations of chronic HBV infection. [5][6][7][8][9] Chronic HBV carriers widely recognized the same antigens, although the cellular immune responses were significantly weaker. 8-10 Thus, insufficient T-cell responses are thought to contribute to viral persistence and chronic liver disease.

In addition to HBV-specific cellular immune reactions, the humoral immune response might be critical in the pathogenesis of HBV infection by binding extracellular viral particles and therefore limiting the spread of the infection. The occurrence of neutralizing surface antigen-specific antibodies indicates complete recovery from acute HBV infection, whereas these antibodies are usually undetectable in patients with viral persistence using conventional assays. Because hepatitis B surface antigen (HBsAg) is expressed on hepatocellular surfaces, 11 antibody-mediated cytotoxicity might also contribute to hepatocellular damage. 12,13 Moreover, it has been shown extensively in vitro and in vivo that anti-HBs antibodies can neutralize extracellular viral particles 14,15 and that active immunization with HBsAg protects from HBV infection. 16 Furthermore, passive immunoprophylaxis with anti-HBs immunoglobulins prevents HBV carriers from reinfection after liver transplantation. 17 Thus, regulation and modulation of the humoral immune response might be relevant to improving vaccine response in primary nonresponders or for treatment of patients with chronic hepatitis B (CHB).

Little is known about the kinetics and regulation of the HBs-specific B-cell response in the clinical course of HBV infection and in vaccine recipients. Thus, the aims of this study were: 1) the quantification and characterization of the cellular and humoral immune responses in the follow-up of patients with acute hepatitis B (AHB) or CHB and in vaccine recipients; 2) the comparison of anti-HBs-secreting B cells in the peripheral blood and the bone marrow; and 3