Tolerance and immunity to pathogens in early life: insights from HBV infection

Abstract

Immunity is not static but varies with age. The immune system of a newborn infant is not "defective" or "immature." Rather, there are distinct features of innate and adaptive immunity from fetal life to adulthood, which may alter the susceptibility of newborn infants to infections compared to adults. Increased protection to certain infectious diseases during early life may benefit from a dampened immune response as a result of decreased immune pathology. This concept may offer an alternative interpretation of the different pathological manifestations clinically observed in hepatitis B virus (HBV)-infected patients during the natural history of infection. Herein, we review the immune pathological features of HBV infection from early life to adulthood and challenge the concept of a generic immune tolerant state in young people. We then discuss how the different clinical and virological manifestations during HBV infection may be related to the differential antiviral immunity and pro-inflammatory capacity generated at different ages. Lastly, we address the potential to consider earlier therapeutic intervention in HBV-infected young patients to achieve effective immune control leading to better outcomes.

Keywords: HBV-specific T cells; Hepatitis B virus; Immune tolerance; Liver inflammation; Trained immunity; Vertical transmission.

Fig. 1

Kinetics of HBV replication and host immune response in self-limited versus chronic infection. Coordinated activation of both innate and adaptive immunity is necessary for successful control of HBV. HBV hepatitis B virus, WHV woodchuck hepatitis virus

Fig. 2

Induction of trained immunity in human neonates of HBV⁺ mothers. HBsAg⁺ cells can be detected in the cord blood of neonates born to HBV-infected mothers, demonstrating in utero exposure to viral products. These HBsAg⁺ cells could be due to transplacental passage of maternal HBsAg⁺ cells or active uptake of serum HBsAg by neonatal cells. HBV exposure in utero is associated with significantly elevated plasma levels of the antiviral cytokine IL-12p40, and in some cases, IFN-α2. Exposure to HBV in utero also induces innate immune cell (monocytes, NK cells) maturation/activation and enhances Th1 T cell development. Importantly, this heightened state of innate immune functionality results in a stronger ability of neonatal immune cells to respond to unrelated pathogen challenge—a process known as “trained immunity”