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Neonatal NK cells target the mouse duct epithelium via Nkg2d and drive tissue-specific injury in experimental biliary atresia
Pranavkumar Shivakumar, … , Claire A. Chougnet, Jorge A. Bezerra
Pranavkumar Shivakumar, … , Claire A. Chougnet, Jorge A. Bezerra
Published July 6, 2009
Citation Information: J Clin Invest. 2009;119(8):2281-2290. https://doi.org/10.1172/JCI38879.
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Research Article Hepatology

Neonatal NK cells target the mouse duct epithelium via Nkg2d and drive tissue-specific injury in experimental biliary atresia

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Abstract

Biliary atresia is a neonatal obstructive cholangiopathy that progresses to end-stage liver disease. Although the etiology is unknown, a neonatal adaptive immune signature has been mechanistically linked to obstruction of the extrahepatic bile ducts. Here, we investigated the role of the innate immune response in the pathogenesis of biliary atresia. Analysis of livers of infants at diagnosis revealed that NK cells populate the vicinity of intrahepatic bile ducts and overexpress several genes involved in cytotoxicity. Using a model of rotavirus-induced biliary atresia in newborn mice, we found that activated NK cells also populated murine livers and were the most abundant cells in extrahepatic bile ducts at the time of obstruction. Rotavirus-primed hepatic NK cells lysed cholangiocytes in a contact- and Nkg2d-dependent fashion. Depletion of NK cells and blockade of Nkg2d each prevented injury of the duct epithelium after rotavirus infection, maintained continuity of duct lumen between the liver and duodenum, and enabled bile flow, despite the presence of virus in the tissue and the overexpression of proinflammatory cytokines. These findings identify NK cells as key initiators of cholangiocyte injury via Nkg2d and demonstrate that injury to the duct epithelium drives the phenotype of experimental biliary atresia.

Authors

Pranavkumar Shivakumar, Gregg E. Sabla, Peter Whitington, Claire A. Chougnet, Jorge A. Bezerra

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Figure 10

Improved outcome after blocking Nkg2d.

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Improved outcome after blocking Nkg2d.
(A) Development of symptoms, weig...
(A) Development of symptoms, weight gain, and survival after daily i.p. injections of 100 μg of anti-Nkg2d neutralizing antibodies (or IgG isotype control) into neonatal mice injected with saline or RRV on the first day of life. Saline, Nkg2d Ab: n = 8; RRV, Nkg2d Ab: n = 38; RRV, control IgG: n = 13. *P < 0.01. (B) H&E staining of representative longitudinal sections of murine extrahepatic bile ducts at different time points after injection of RRV on the first day of life, followed by the daily administration of 100 μg of blocking anti-Nkg2d antibodies. Scale bars: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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