Trained immunity in newborn infants of HBV-infected mothers

Hong, Michelle; Sandalova, Elena; Low, Diana; Gehring, Adam J.; Fieni, Stefania; Amadei, Barbara; Urbani, Simona; Chong, Yap Seng; Guccione, Ernesto; Bertoletti, Antonio

doi:10.1038/ncomms7588

Cited by 148 publications

(138 citation statements)

References 52 publications

(61 reference statements)

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“…Based on our results, it is tempting to speculate that insufficient DC activation due to low sCD14 levels may be one of the factors contributing to inadequate HBV-specific immunity in HBV-infected newborns. In a seemingly paradoxical observation, Hong and colleagues recently showed that monocytes of HBVexposed newborns had an enhanced activation state compared to those from unexposed neonates (40). Monocytes, however, in contrast to the BDCA1 ϩ DC that we studied here, are not able to induce activation of naive virus-specific T cells and express membrane CD14 and thus do not depend on sCD14 for their activation.…”

Section: Discussioncontrasting

confidence: 38%

Hepatitis B Virus Surface Antigen Activates Myeloid Dendritic Cells via a Soluble CD14-Dependent Mechanism

Montfoort

Bosch

et al. 2016

J Virol

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Hepatitis B virus (HBV) infection can cause chronic liver disease, which is associated with increased risk of liver cirrhosis, liver failure, and liver cancer. Clearance of HBV infection requires effective HBV-specific immunity; however, the immunological mechanisms that determine the development of effective HBV-specific immunity are poorly understood. Dendritic cells (DC) play a pivotal role in the regulation of antiviral immunity. Here, we investigated the interaction between HBV surface antigen (HBsAg), the main envelope glycoprotein of HBV, and BDCA1؉ myeloid dendritic cells (mDC). Exposure of peripheral bloodderived BDCA1؉ mDC to HBsAg resulted in strong DC maturation, cytokine production, and enhanced capacity to activate antigen-specific cytotoxic T cells (CTLs). By using neutralizing antibodies, crucial roles for CD14 and Toll-like receptor 4 (TLR4) in HBsAg-mediated BDCA1 ؉ mDC maturation were identified. Concordantly, HBsAg-mediated DC maturation required fetal calf serum (FCS) or human plasma, naturally containing soluble CD14 (sCD14). Intriguingly, HBsAg-induced DC maturation was significantly reduced in umbilical cord blood plasma, which contained less sCD14 than adult plasma, indicating that sCD14 is an important host factor for recognition of HBsAg by DC and subsequent DC activation. A direct interaction between sCD14 and HBsAg was demonstrated by using enzyme-linked immunosorbent assay (ELISA). Moreover, sCD14-HBsAg complexes were detected both in vitro and in sera of HBV-infected patients. The abundance of sCD14-HBsAg complexes varied between chronic HBV disease stages and correlated with activation of BDCA1 ؉ mDC in vivo. We conclude that HBsAg activates BDCA1 ؉ DC via an sCD14-dependent mechanism. These findings provide important novel insights into the initiation of HBV-specific immunity and facilitate development of effective immunotherapeutic interventions for HBV. Hepatitis B virus (HBV) is a double-stranded DNA (dsDNA) virus that is transmitted via blood and specifically infects hepatocytes. It can cause chronic liver disease and progressive liver injury leading to increased risk of liver cirrhosis, liver failure, and liver cancer (1). The current estimated prevalence of HBV infection is 248 million individuals globally (2). Although the initiation of an effective antiviral immune response is paramount for resolving HBV infection (3), the early steps in the recognition of the virus by immune cells and the functional consequences of this interaction remain to be resolved.A pivotal role for dendritic cells (DC) is anticipated, because these cells play a central role in the orchestration of antiviral immunity due to the expression of a wide variety of different pathogen recognition receptors (PRR) and their unique capacity to initiate virus-specific cytotoxic T cell (CTL) responses (4, 5). Among the different DC subsets, BDCA1 ϩ myeloid DC (mDC) are of particular interest for HBV-specific immunity, since hepatitis B surface antigen (HBsAg)-positive mDC were detected in liver (6) an...

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Section: Discussioncontrasting

confidence: 38%

Hepatitis B Virus Surface Antigen Activates Myeloid Dendritic Cells via a Soluble CD14-Dependent Mechanism

Montfoort

Bosch

et al. 2016

J Virol

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“…The identification of these nonspecific (or heterologous) effects suggests that these vaccines induce trained immunity that protects against unrelated pathogens. This hypothesis was proposed in proof-of-principle trials with BCG vaccine in healthy adult volunteers (37), and thereafter validated in clinical trials in newborn children vaccinated with BCG (38) or exposed in utero to hepatitis B vaccine (39). Secondly, certain infections such as malaria can also induce a state of hyper-responsiveness that is functionally equivalent to the induction of trained immunity (40, 41).…”

Section: Innate Immune Memory In Vertebratesmentioning

confidence: 99%

Trained immunity: A program of innate immune memory in health and disease

Netea

Joosten

Latz

et al. 2016

Science

1,962

1,845

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The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed trained immunity or innate immune memory. Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, for new therapeutic strategies for the treatment of immune deficiency states, and for modulation of exaggerated inflammation in autoinflammatory diseases.

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“…The clinical course of acute HBV infection with a substantial rise of liver enzymes and bilirubin, the need for the elimination of covalently closed circular DNA, as well as recent findings in cell culture models, however, also supports the contribution of cytolytic effector mechanisms such as perforin and granzyme secretion and induction of the apoptotic Fas/FasL pathway [5, 15,16] . Interestingly, the mechanism of viral persistence in the vast majority of HBV-infected newborns and children remains unclear; T-cells in these young patients are not generally compromised or tolerogenic [17,18] . In HCV infection, findings in patients, chimpanzees as well as a cell culture model indicate that non-cytolytic effector functions have a dominant role [8,10,11,19] .…”

Section: Successful Hbv-and Hcv-specific Cd8+ T-cell Responsementioning

confidence: 99%

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

Nitschke

Luxenburger

Kiraithe

et al. 2016

Dig Dis

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Approximately 500 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV) worldwide and are thus at high risk of progressive liver disease, leading to liver fibrosis, cirrhosis and ultimately hepatocellular cancer. Virus-specific CD8+ T-cells play a major role in viral clearance in >90% of adult patients who clear HBV and in approximately 30% of patients who clear HCV in acute infection. However, several mechanisms contribute to the failure of the adaptive CD8+ T-cell response in those patients who progress to chronic infection. These include viral mutations leading to escape from the CD8+ T-cell response as well as exhaustion and dysfunction of virus-specific CD8+ T-cells. Antiviral efficacy of the virus-specific CD8+ T-cell response also strongly depends on its restriction by specific human leukocyte antigens (HLA) class I alleles. Our review will summarize the role of HLA-A, B and C-restricted CD8+ T-cells in HBV and HCV infection. Due to the current lack of a comprehensive database of HBV- and HCV-specific CD8+ T-cell epitopes, we also provide a summary of the repertoire of currently well-described HBV- and HCV-specific CD8+ T-cell epitopes. A better understanding of the factors that contribute to the success or failure of virus-specific CD8+ T-cells may help to develop new therapeutic options for HBV eradication in patients with chronic HBV infection (therapeutic vaccination and/or immunomodulation) as well as a prophylactic vaccine against HCV infection.

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Trained immunity in newborn infants of HBV-infected mothers

Cited by 148 publications

References 52 publications

Hepatitis B Virus Surface Antigen Activates Myeloid Dendritic Cells via a Soluble CD14-Dependent Mechanism

Hepatitis B Virus Surface Antigen Activates Myeloid Dendritic Cells via a Soluble CD14-Dependent Mechanism

Trained immunity: A program of innate immune memory in health and disease

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

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