Age-dependent immune events during HBV infection from birth to adulthood: An alternative interpretation

Abstract

Immune responses change during the life of an individual. While this concept has been well accepted for adaptive immunity, only recently it is becoming clear that the innate immune responses also acquire distinct features in different phases of life. We believe that this concept can offer a different interpretation of the pathological manifestations that can be observed in HBV-infected subjects during the patient's life. Here, we will review the age-related immunopathological features of HBV infection and discuss how the different virological and clinical manifestations might be linked to the developmental pathway of the immune system from newborns to adults. We will discuss how the age of patients can affect the degree of inflammatory responses, but not the levels of antiviral specific immunity. We then propose that the different clinical manifestations occurring during the natural history of HBV infection are related to the host ability to trigger an inflammatory immune response. Hepatitis B virus is a hepatotropic, non-cytopathic, DNA virus that chronically infects about 300 million people worldwide. It causes acute or chronic liver diseases characterized by different levels of liver inflammation and viral replication. An acute HBV infection can be resolved without clinical symptoms or with an inflammatory disease of the liver (acute hepatitis). Similarly, persistent HBV infection can cause minimal pathological manifestations or trigger a chronic liver inflammation that develops into liver cirrhosis or cancer (1). These clinical and virological profiles do not only vary among individuals in relation to their genetic background, dose, or route of infection but they are also present within the same individual in relation to his age. HBV chronic infection is, particularly in Asia, the result of virus transmission from HBV+ mothers to their infants (1). HBV infection at birth is characterized by an apparent benign phase of disease with high HBV replication levels and absence of markers of liver inflammation [i.e., normal alanine aminotransferase or aminotransferases (ALT) levels; an enzyme released by dying hepatocytes] during childhood. This phase, defined as immune tolerant, is followed by a disease phase in adulthood characterized by liver inflammatory events and fluctuations in ALT levels and viral load, known as the immune active/clearance phase (Figure 1) (1, 2). The favored interpretation of these different virological and clinical patterns is that during childhood there is a phase of immunotolerance, i.e., an absence of antiviral specific immunity that is lost at the start of adulthood when the host immune system actively "combat" HBV infection (2).