Chronic hepatitis B : immunological, virological and clinical aspects in the natural course and during the combined prednisolone and interferon-alpha-2b therapy

Sammanfattning: The aims of this study were to characterize the IgM and IgG antibody responses to well-defined B-cell epitopes within the preS2 region of the HBV envelope proteins in sera from Chinese and Caucasian patients with chronic HBV infection in relation to viral load and liver disease activity. In addition, the effects of the combined prednisolone and interferon- alpha-2b therapy on these parameters, as well as on the peripheral lymphocyte subsets, were studied in Chinese patients with chronic hepatitis B. By using peptide-based ELISA systems, we demonstrated that patients with chronic HBV infection frequently exhibited serum antibodies of both IgM and IgG classes to linear peptides mimicking specific regions derived from the preS2 region of the HBV envelope protein. The prevalence of the antibody of the IgM class to the peptide preS2 (14-21), which represents an irnmunodominant B-cell epitope within the preS2 region, was observed in 38% (22/58) HBeAg+ patients, compared with 10% (2/21) anti-HBe+ patients with chronic hepatitis B (p < 0.05). Similarly, IgM anti-preS2 (1-55) (the whole preS2 region) was also significantly more frequently observed in serum from HBeAg+ patients, compared with anti-HBe+ patients [48% (16/33) vs. 0% (0/12), p < 0.011]. IgG class antibody responses to the preS2 (14-21) and (1-34) regions were observed in sera from 85% (40/47) and 89% (42/47) of HBeAg+ patients with chronic HBV infection, respectively. Significantly lower frequencies of IgG anti-preS2 (14-21) and (1-34) were found in anti-HBe+ patients [47% (9/19) and 58% (11/19), respectively, p < 0.011. Moreover, IgG anti-preS2 (14-21) and (1-34) reactivities were more frequently observed in patients with a high degree of viremia, or high biochemical or histological evidence of liver disease. A significantly lower HBV viral load was observed in HBeAg+ patients with chronic hepatitis B, who exhibited serum IgM anti-preS2 (14-21) reactivity, compared with those without (p < 0.05). In contrast, a high degree of viremia was observed in HBeAg+ patients with serum IgM anti-HBc antibody; in particular, the highest levels of serum HBV DNA were noted in patients who exhibited IgM anti-HBc but lacked detectable levels of IgM anti-preS2 (14-21) reactivity. The ratios of peripheral CD4/CD8 (helper/suppressor) positive lymphocytes were significantly lower in Chinese patients with chronic active hepatitis B proven by liver biopsy, compared with healthy individuals (p < 0.01). An inverse correlation between the CD4/CD8 ratios and the serum HBV DNA levels was observed (r = -0.8, p < 0.05) in patients with chronic HBV infection. Profound modulatory effects of the combined prednisolone and interferon alpha-2b therapy on the antibody responses to the preS2 regions (e.g. aa14-21 and aa1-55) and the core region of HBV, as well as peripheral lymphocyte subpopulations were observed in Chinese patients with chronic hepatitis B during therapy. Taken together, the humoral immune responses in patients with chronic HBV infection, as studied here by quantitative measurement of the serum IgM and IgG reactivities to linear synthetic peptides derived from the preS2 regions (e.g. aa 14-21), differed from the immune response to the HBV core and e antigens. The presence of pre-treatment IgM antibody to the preS2 (14-21) and (1-55) in circulation was associated with a beneficial response to the combined prednisolone and interferon alpha-2b therapy when studied in a small group of treated patients.