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

Hong, Michelle; Bertoletti, Antonio

doi:10.1007/s00281-017-0641-1

Cited by 52 publications

(46 citation statements)

References 88 publications

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“…Further, HBV-specific T cells could be detected in mice with persistent HBV replication after hydrodynamic injection, but did not enter the liver unless an intrahepatic immune activation was triggered by TLR3 stimulation (160). A recent report also showed that HBV-specific T cells are detectable in the peripheral blood of young patients in the immune tolerant phase (103,161). HBVspecific T cells were found to possess the ability to proliferate and produce cytokines (162).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 98%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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Functional cure" is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. "Functional cure" can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 98%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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“…Since the phenomenon of chickens with congenital infection with ALV-J showing persistent viremia was discovered and defined as immune tolerance, the pathogenesis of immune tolerance induced by ALV-J has been studied continuously. Because the immune tolerance caused by ALV-J, HBV, and HIV has many common features in the pathological process [27,28], it has drawn a great attraction to study the pathogenesis of immune tolerance induced by these viruses. It has been found that the damage of lymphocytes [29], the abnormal secretion of cytokines [30], the variation of viral epitopes [31], and the expression of EAV-HP gene in embryo [32] all play more or less roles in the induction of immune tolerance by ALV-J.…”

Section: Discussionmentioning

confidence: 99%

Lyn inhibited BCR signal pathway mediates B-cell anergy induced by avian leukosis virus subgroup J

Zheng

Yang

et al. 2020

Preprint

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Background: Immune tolerance induced by retrovirus is a prerequisite for tumorigeness. We had reported that B-cell anergy was the main reason for immune tolerance induced by avian leukosis virus subgroup J (ALV-J). However, the molecular mechanism remains unclear. Results: Initially, we found that Lyn showed down-regulation in chick embryo fibroblasts (CEF) and up-regulation in B-cells infected by ALV-J. So, we speculated that tyrosine kinase Lyn plays a key role in B-cell anergy induced by ALV-J. Confocal laser scanning microscopy (CLSM) and co-immunoprecipitation (Co-IP) results demonstrated that ALV-J indirectly regulated the expression of Lyn. To further investigate the role and regulatory mechanism of Lyn in B-cell anergy induced by ALV-J, the expression levels of Lyn and Syk at different phosphorylation site, the Ca 2+ mobilization, and the expression levels of NF-κB p65 protein in vitro and vivo were detected in B-cells. The result showed that Ca 2+ mobilization was delayed and p65 expression level was decreased in B-cells after ALV-J infection. Consistently, the retrieve of Ca 2+ mobilization, expression levels of NF-κB p65 were found after RNA interference of Lyn. Subsequently, we demonstrated that the activation of phosphorylated Lyn protein at Tyr507 site played a critical role in B-cells anergy, which were verified by the fact of the significantly up-regulation of the expression levels of phosphorylated Syk protein at Tyr525/526 site when RNA interference for Lyn were performed in B-cells. Furthermore, immunohistochemical (IHC) staining results confirmed that the expression levels of Lyn phosphorylated protein at Tyr507 site in bursal cells were increased, while the expression levels of Syk phosphorylated protein at Tyr525/526 sites were decreased. Conclusions: These findings suggested that Lyn inhibited BCR signal pathway mediates B-cell anergy under ALV-J infection，which will provide a new insight for revealing the molecular mechanism of immune tolerance induced by ALV-J. Keywords: avian leukosis virus subgroup J , B-cell anergy, immune tolerance, Lyn, Syk

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“…Immunization starting with a first dose within 24 hours of birth is recommended 10 due to the high risk (90%) of developing lifelong, chronic HBV infection in neonates, with the risk decreasing to approximately 20% to 30% by 1 to 5 years of age. 11 Approximately 95% of immunocompetent infants vaccinated with 3 doses of HBV vaccine demonstrate seroprotective anti-HBs levels (≥10 mIU/mL), with levels >100 mIU/mL considered to provide an enduring response. 7 Following primary immunization, protective antibody levels may decrease to low or undetectable levels.…”

mentioning

confidence: 99%

“… 23 The Th2/regulatory T cell-type response and reduced B cell somatic hypermutation that predominates in early infancy results in immune tolerance and a diminished humoral response, which shifts to a Th1-type response and a progressive maturation of immunoglobulin class switching and responses through the first year of life. 11 Although pro-inflammatory responses are diminished in neonates, synergistic stimulation of specific Toll-like receptors (TLR) and C-type lectin receptors (CLR) offers immune activation that varies with age, being greatest in newborns. 11 , 14 This neonatal characteristic immune profile is now being increasingly thought of as highly specialized and uniquely adapted to contend with the various forces the newborn immune system is subjected to.…”

mentioning

confidence: 99%

From infancy and beyond… ensuring a lifetime of hepatitis B virus (HBV) vaccine-induced immunity

Osiowy

2018

Human Vaccines & Immunotherapeutics

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Despite the long-term efficacy and immune persistence observed following HBV vaccination of infants, the need for a booster dose following infant immunization continues to be deliberated. Evidence from HBV booster dose response studies and long-term immunization program reviews are the basis for the recommendation that a vaccine booster is not necessary. However, further studies continue to emerge and highlight the need for standardization among observational studies in order to appropriately compare outcomes. There is an assumption that neonatal and infant (within 12 months of age) vaccine immune responses are equivalent; however, evidence exists for distinct vaccine responses within the first year of life. HBV vaccine programs have evolved over time, particularly regarding the type and dosage of vaccine used. Several universal neonatal immunization programs initially incorporated a 2.5 μg dosage (Recombivax-HB, Merck). This dosage has been shown in multiple long-term studies and meta-analyses to be associated with a lower primary response, decreased antibody persistence over time, and a reduced booster response 10 to 20 years following immunization. Ongoing surveillance of this and other HBV neonatally-vaccinated populations, particularly in low endemic regions, is necessary to understand the impact on long-term protection in order to ensure lifelong protection against hepatitis B infection.

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

Cited by 52 publications

References 88 publications

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Lyn inhibited BCR signal pathway mediates B-cell anergy induced by avian leukosis virus subgroup J

From infancy and beyond… ensuring a lifetime of hepatitis B virus (HBV) vaccine-induced immunity

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