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Editorial
. 2016 Nov;151(5):801-804.
doi: 10.1053/j.gastro.2016.09.037. Epub 2016 Oct 1.

The Concept of Immune Tolerance in Chronic Hepatitis B Virus Infection Is Alive and Well

David R Milich  1
Affiliations
Editorial

The Concept of Immune Tolerance in Chronic Hepatitis B Virus Infection Is Alive and Well

David R Milich. Gastroenterology. 2016 Nov.
No abstract available

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Conflict of interest statement

Conflicts of interest

The author discloses no conflicts.

Figures

Figure 1.
Figure 1.
T-cell tolerance is clonal in hepatitis B virus (HBV) infection. A variety of T-cell clones of different specificities and affinities are available to respond to HBV infection in adults, who clear >90% of infections. In contrast, in the setting of neonatal infection, the HBV antigens behave as neo–self-antigens and elicit tolerance as opposed to activation of HBV-specific T cells, resulting in chronicity in >90% of infections. As depicted, T-cell tolerance is mediated by clonal deletion or by nondeletional mechanisms based on clonal affinities. The deletion or down-regulation of high-affinity T-cell clones results in lower numbers of low-affinity T cells remaining to represent the HBV-specific repertoire in chronic infection. These functionally impaired T cells are not directly detectable ex vivo and require in vitro clonal expansion of peripheral blood mononuclear cell to detect. In utero infection permits all structural and nonstructural HBV antigens (HBs, HBe/HBc, Pol, and X) to gain access to the developing thymus of the fetus potentially eliciting T-cell tolerance to the entire virion. In postnatal infection only the HBeAg may have access to the fetus in utero. Lesser rates of chronicity occur in perinatal infections depending on age at the time of infection. Chronic neonatal infection can progress from the immune tolerant (IT) phase characterized by high serum viral loads and no-to-minimum liver injury to the HBeAg+, immune active (IA+) phase in early adulthood characterized by fluctuating and decreased serum virus and increased liver injury yet failure to clear the infection. The IA− phase is characterized by anti-HBe seroconversion and greater reductions in serum virus and more apparent liver injury, which can result in spontaneous clearance in a minority of infections. The timing of the transition from the IT to the IA phases correlates with the age-dependent involution of the thymus and may be analogous to the waning of self-tolerance. Neonates are not born tolerant to HBV antigens or infection and can respond to HBs vaccination and clear an acute infection if infected with the HBeAg− mutant, respectively. Therefore, T-cell tolerance to HBV is an active process requiring exposure to HBV neo–self-antigens before or early in infection. Vaccination after chronic infection is established is ineffective in adults and children, and demonstrates the existence and relevance of immune tolerance in all phases of chronic infection.
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References

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