Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B

Publicover, Jean; Gaggar, Anuj; Nishimura, Stephen L.; Horn, Christine M. Van; Goodsell, Amanda; Muench, Marcus O.; Reinhardt, R. Lee; Rooijen, Nico van; Wakil, Adil E.; Peters, Marion; Cyster, Jason G.; Erle, David J.; Rosenthal, Philip; Cooper, Stewart; Baron, Jody L.

doi:10.1172/jci68182

Cited by 75 publications

(80 citation statements)

References 42 publications

(51 reference statements)

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“…CXCL13 fused with green fluorescent protein (GFP) was found to enhance the level of GFP antibody detected and to elicit higher levels of specific IgG1 antibodies than of IgG2a antibodies, which indicates a Th2 response and a contribution factor to humoral immunity (37). Recent studies have also shown that CXCL13 recruits B cells to nonlymphoid organs, contributing to the organization of local immune responses against influenza and hepatitis B virus infections (53,54). In our present study, CXCL13 was inserted into the genome of the RABV and expressed in a considerable quantity both in vitro and in vivo, which was shown to have strong biological activity in a transwell model and to help recruit the cells expressing CXCR5 to the injection sites in vivo.…”

Section: Discussionmentioning

confidence: 99%

A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting both T Follicular Helper and Germinal Center B Cells

Zhao

Zhou

et al. 2017

J Virol

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Rabies remains a public health threat in most parts of the world, and approximately 99% of the cases are transmitted by dogs. There is an urgent need to develop an efficacious and affordable vaccine to control canine-transmitted rabies in developing countries. Our previous studies demonstrate that overexpression of chemokines/cytokines such as CCL-3 (MIP-1␣) and granulocyte-macrophage colonystimulating factor (GM-CSF) can enhance the immunogenicity of rabies vaccines. In the present study, the chemokine CXCL13 was inserted into the genome of the recombinant rabies virus (rRABV) strain LBNSE, and the effect of the chemokine CXCL13 on the immunogenicity of RABV was investigated. It was found that LBNSE-CXCL13 recruited follicular helper T (Tfh) and germinal center (GC) B cells, promoted the formation of GCs, and increased the population of plasma cells in immunized mice. Further studies showed that mice immunized with LBNSE-CXCL13 produced more rabies virus-neutralizing antibodies (VNAs) and developed better protection than those immunized with the parent virus LBNSE or the GM-CSF-expressing RABV (LBNSE-GM-CSF). Collectively, these findings provide a better understanding of the role of CXCL13 expression in the immunogenicity of the RABV, which may help in designing more-efficacious rabies vaccines.IMPORTANCE Rabies is endemic in most parts of the world, and more effort is needed to develop affordable and effective vaccines to control or eliminate this disease. The chemokine CXCL13 recruits both Tfh and B cells, which is essential for the homing of Tfh cells and the development of B cell follicles. In this study, the effect of the overexpression of CXCL13 on the immunogenicity of the RABV was evaluated in a mouse model. We found that CXCL13 expression promoted humoral immunity by recruiting Tfh and GC B cells, facilitating the formation of GCs, and increasing the number of plasma cells. As expected, the overexpression of CXCL13 resulted in enhanced virus-neutralizing antibody (VNA) production and protection against a virulent RABV challenge. These findings provide a better understanding of the role of CXCL13 in RABV-induced immune responses, which will help in designing more efficacious rabies vaccines.KEYWORDS CXCL13, rabies virus, T follicular helper cells, germinal center B cells, humoral immunity R abies, a fatal and ancient neurological disease that occurs in both humans and warm-blooded animals (1, 2), still causes more than 59,000 human deaths every year and poses a potential threat to more than 3.3 billion people (3, 4). Its pathogen,

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Section: Discussionmentioning

confidence: 99%

A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting both T Follicular Helper and Germinal Center B Cells

Zhao

Zhou

et al. 2017

J Virol

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“…In a transgenic mouse model, Publicover et al demonstrated that KCs in 8-to 12-wk-old C57BL/6 mice facilitated lymphoid organization and immune priming and promoted successful immunity against HBV. In contrast, lymphoid organization and immune priming was substantially diminished in 3-to 4-wk-old and KC-depleted 8-to 12-wk-old C57BL/6 mice, leading to abrogated HBV immunity (31). Therefore, it is reasonable to speculate that changing gut microbiota profiles at various stages of gut development provides signals that affect the outcomes of immune activation in the liver and determines the transition from HBV tolerance to clearance.…”

Section: Discussionmentioning

confidence: 99%

Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota

Chou

Chien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

168

154

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A unique feature of hepatitis B virus (HBV) infection in humans is that viral clearance heavily depends on the age of exposure. However, the reason for this remains unclear. Here we show that gut microbiota contribute to the age dependence of HBV immunity in a hydrodynamic transfection mouse model. Although adult (12-wkold) C3H/HeN mice cleared HBV within 6 wk postinjection (wpi), their young (6-wk-old) counterparts remained HBV-positive at 26 wpi. Sterilization of gut microbiota from 6 to 12 wk of age using antibiotics prevented adult mice from rapidly clearing HBV. Young mice with the Toll-like-receptor (TLR) 4 mutation (C3H/HeJ) exhibited rapid HBV clearance. The results suggest that an immuno-tolerating pathway to HBV prevailed in young mice, before the establishment of gut bacteria, through a TLR4-dependent pathway and that the maturation of gut microbiota in adult mice stimulated liver immunity, resulting in rapid HBV clearance.liver tolerance | Toll-like 4 receptor | temporal-temperature gel electrophoresis | chronic hepatitis B | Kupffer cells

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“…Therefore, whilst CXCL13 and macrophages facilitate lymphoid organization and successful HBV immunity of the adult, the young mice have abrogated HBV immunity due to greatly diminished CXCL13/macrophage-mediated immune priming [7]. Nonetheless, neonatal immune system is not intrinsically defective and enhanced TLR responses of the neonatal DCs as compared with the adult have been reported [8,9].…”

Section: Hepatitis B Virus (Hbv) Is Known To Cause Age-dependent Infementioning

confidence: 99%

Feedback regulation of IFN‐α/β signaling by Axl receptor tyrosine kinase modulates HBV immunity

Huang

Liu

et al. 2015

Eur J Immunol

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Hepatitis B virus (HBV) is known to cause age-dependent infection outcomes wherein most infections during young age result in chronicity.The mechanism underlying the differential outcome remains elusive. By using hydrodynamic injection of the replicationcompetent pAAV-HBV, we established a mouse model in which HBV persistence was generated in 4-5 w/o C57BL/6 young mice, but not in adult mice over 10 w/o. HBV-tolerant young mice expressed higher interferon (IFN)-α/β levels in hepatocytes and intrahepatic plasmacytoid DCs (pDCs) than adult mice after pAAV-HBV injection. Excessive IFN-α/β expression in young mice was associated with induction of the Axl regulatory pathway and expansion of intrahepatic Treg cells. In line with these findings, augmented IFN-β expression increased Axl expression in the liver and HBV persistence in adult mice, whereas IFN-α/β signaling blockage decreased Axl expression and HBV persistence in young mice. Accordingly, Axl overexpression decreased HBV clearance of adult mice whereas Axl silencing enhanced HBV clearance of young mice. In vitro, IFN-β priming of pDCs and Axl-overexpressing macrophages enhanced Treg-cell differentiation. These findings suggest that age-dependent HBV chronicity is attributed to IFN-β-Axl immune regulation, which is selectively induced in young mice by excessive IFN-α/β production at early stage of HBV infection.Keywords: Axl receptor tyrosine kinase r hepatitis B virus (HBV) r immune regulation r TAM receptor tyrosine kinase r type I interferons Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Miao-Tzu Huang; Dr. Ding-Shinn Chen e-mail: mthuang@ntu.edu.tw; chends@ntu.edu.tw Eur. J. Immunol. 2015Immunol. . 45: 1696Immunol. -1705 Immunity to infection 1697 liver cirrhosis, and hepatocellular carcinoma. In contrast, most HBV infection in the adult often resolves [1,2]. In chronic HBV infection, the host's immune system fails to mount effective anti-HBV immunity [3]. Increased regulatory T (Treg) cells [4] and PD-1-expressing CD8 + T cells [5] have been found in both circulation and livers of the HBV carriers. Neonatal immune responses are characterized by low antibody production, poor cytotoxicity, and Th2-skewed immune responses [6]. Immaturity of the immune system and neonatal tolerance to HBV are currently held responsible for the greatly increased HBV persistence during young age.To this aspect, a recent study has shown that CXCL13, which is involved in B-lymphocyte trafficking and lymphoid development, is expressed in an age-dependent manner in both mouse and human liver macrophages. Therefore, whilst CXCL13 and macrophages facilitate lymphoid organization and successful HBV immunity of the adult, the young mice have abrogated HBV immunity due to greatly diminished CXCL13/macrophage-mediated immune priming [7]. Nonetheless, neonatal immune system is not intrinsically defective and enhanced TLR responses of the neonatal DCs as compared with the adult have been reported [8,9...

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Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B

Cited by 75 publications

References 42 publications

A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting both T Follicular Helper and Germinal Center B Cells

A Novel Rabies Vaccine Expressing CXCL13 Enhances Humoral Immunity by Recruiting both T Follicular Helper and Germinal Center B Cells

Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota

Feedback regulation of IFN‐α/β signaling by Axl receptor tyrosine kinase modulates HBV immunity

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