Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B
Jean Publicover, … , Stewart Cooper, Jody L. Baron
Jean Publicover, … , Stewart Cooper, Jody L. Baron
Published August 8, 2013
Citation Information: J Clin Invest. 2013;123(9):3728-3739. https://doi.org/10.1172/JCI68182.
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Research Article Immunology

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

Abstract

Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV.

Authors

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

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Figure 7

Adult human liver shows greater CXCL13 expression than infant liver, and plasma CXCL13 expression is significantly increased in patients who clear a-HBV.

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Adult human liver shows greater CXCL13 expression than infant liver, and...
(A) Fresh frozen paraffin-embedded liver biopsy samples from infants 6–12 weeks of age (n = 24) and adults (n = 9) was used for RNA extraction using RNeasy FFPE kit (Qiagen), and expression of CXCL13 relative to GAPDH was determined by RT-PCR. Infant liver tissue was obtained from liver biopsies performed to rule out a diagnosis of biliary atresia; of the 24 patients, 6 had biliary atresia, 6 had neonatal nonviral hepatitis, 10 had nonspecific liver disease diagnosis including cholestatsis and ductopenia, and 2 had an unknown diagnosis. Adult liver samples were obtained from donor livers prior to transplant. (B) Plasma was obtained from 5 patients with confirmed a-HBV infection at the time of active hepatitis and with confirmed subsequent viral clearance and HBsAb seroconversion, 5 patients with confirmed chronic HBV infection exhibiting a flare of disease, and 6 healthy volunteers and assayed for CXCL13 levels by ELISA. ***P < 0.001, Mann-Whitney test; **P = 0.0016, Tukey’s ANOVA multiple-comparison test.