Conclusions
Resolution of an AH-B infection and the associated liver injury are believed to be immune mediated. Therefore, the inability to resolve an HBV infection reflects a defect(s) in the HBV-specific immune response resulting in chronic infection. A number of studies suggest that the immunological defect may reside at the level of T cell responsiveness. Although any number of defects in the complex interactions between the host immune response and HBV may result in persistent infection, a likely candidate is an inefficient HBeAg-specific Th cell response. For example, we have proposed a model in which exposure to HBeAg in utero tolerizes the HBe/HBcAg-specific Th cell response and results in chronicity after neonatal or perinatal HBV infection [53]. Immunosuppression or genetic T cell nonresponsiveness to HBe/HBcAg may explain chronicity after adult HBV infection. However, the chronicity rate after symptomatic HBV infection in adults is relatively low (i.e., < 10%). Chronic or persistent HBV infection encompasses a heterogeneous patient population ranging from severe to limited liver disease to the asymptomatic carrier state. Presumably, chronic liver disease reflects ongoing HBV-specific immune responses sufficient to cause liver cell injury but insufficient to clear the infection completely. Nevertheless, the currently available serological assays suggest that the humoral immune responses to HBeAg and HBsAg during CH-B infection are universally negative regardless of clinical status or degree of liver injury. To resolve this apparent contradiction, we and others have designed more sensitive serological assays capable of detecting anti-HBe and anti-HBs antibodies in the presence of excess circulating antigens. Using sensitive experimental immunoassays it is clear that chronically infected HBV patients produce a variety of antibodies and that the quantity and quality of antibody production correlates with the degree of liver disease. In fact, HBV-specific humoral immune responses in chronic infection appear remarkably intact considering the degree to which Th cell function can be compromised and the excess production of subviral particles and proteins during chronic HBV infection. However, at least one study did suggest a B cell defect during HBV infection [78]. It was suggested that envelope-specific cytotoxic T lymphocytes may lyse HBsAg-specific B cells that present envelope peptides in the context of the MHC class I pathway. Such a mechanism would be expected to suppress anti-HBs production.
In summary, the serological responses of CH-B patients serve as efficient “markers’ of the degree and specificity of underlying T cell responsiveness. This information is relevant to the diagnosis and prognosis of CH-B patients and may be useful in determining appropriate treatment modalities. For example, the use of the experimental immunoassays can distinguish between asymptomatic and symptomatic CH-B patients and between AH-B patients and CH-B patients undergoing an AE of liver disease. Furthermore, a survey of a large number of CH-B patients using the more sensitive immunoassays suggested that the balance between HBV-specific Th1 and Th2-type cells may be important in preventing and/or resolving chronic HBV infection. Lastly, use of the sensitive experimental immunoassays may allow the selection of CH-B patients most likely to benefit from immunomodulatory therapy. For example, asymptomatic as well as symptomatic CH-B patients with evidence of pre-existing HBV-specific immune responses may be more responsive to immune-enhancing therapies (i.e., IFN-α).
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Milich, D.R., Sallberg, M. & Maruyama, T. The humoral immune response in acute and chronic hepatitis B virus infection. Springer Semin Immunopathol 17, 149–166 (1995). https://doi.org/10.1007/BF00196163
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DOI: https://doi.org/10.1007/BF00196163