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

Shivakumar, P., et al. 2009. J. Clin. Invest. 119, 2281-2290.

Speaker: Chia-Chun Tsai (蔡佳純)                                        Time: 15:10~16:10, Oct. 28, 2009

Commentator: Dr. Ching-Chuan Liu (劉清泉醫師)             Place: Room 601

Abstract：

Biliary atresia (BA) is the most common cause of end-stage liver disease in infants and is the major pediatric indication for liver transplantation in the United States (1). The pathogenesis of BA is correlated with infection-mediated fibrosis of the extrahepatic and intrahepatic bile ducts in most patients. However, the etiology is still unknown. Previous studies found that CD4⁺ and CD8⁺ T cells infiltrated around the bile ducts of patients with BA and showed adaptive immunity was associated with the pathogenesis of BA (2). In this study, the authors investigated the role of innate immunity in the pathogenesis of BA. They found that NK cells populated in the livers of patients and the activation and cytotoxicity genes of NK cells were overexpressed. They used a neonatal mouse model with BA induced by rotavirus to address this issue. They found that activated NK cells were the most abundant immune cells in the livers and extrahepatic bile ducts of mice with BA. They found that cholangiocytes were lysed by rotavirus-primed hepatic NK cells by NKg2d receptor-dependent contact. They used antibodies to deplete NK cells and block the binding of NKg2d and prevented the disease progression effectively. However, the viral titers and the levels of proinflammatory cytokines were similar regardless the presence of NK cells in rotavirus-infected mice. Therefore, they proved that the cytotoxicity of NK cells is an important initiator in the mouse model of experimental BA. NK cells may be a target for therapy in the early stage of BA.

References:

1.     Sokol, R.J. , et al. 2007. Screening and outcomes in biliary atresia: summary of a National Institutes of Health workshop. Hepatology. 46, 566-81.

2.     Mack, C.L., et al. 2007. Oligoclonal expansions of CD4⁺ and CD8⁺ T cells in the target organ of patients with biliary atresia. Gastroenterology. 133, 278-87.