期刊
PLOS ONE
卷 8, 期 8, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0073644
关键词
-
资金
- NIDDK [1 RO1 DK078195]
- Children's Hospital Colorado Research Institute
- Cystic Fibrosis Foundation [FELDMA10BO]
- [R01 AI052310]
- [T32-DK06700907]
A leading theory regarding the pathogenesis of biliary atresia (BA) is that bile duct injury is initiated by a virus infection, followed by an autoimmune response targeting bile ducts. In experimental models of autoimmune diseases, B cells have been shown to play an important role. The aim of this study was to determine the role of B cells in the development of biliary obstruction in the Rhesus rotavirus (RRV)-induced mouse model of BA. Wild-type (WT) and B cell-deficient (Ig-alpha(-/-)) mice received RRV shortly after birth. Ig-alpha(-/-) RRV-infected mice had significantly increased disease-free survival rate compared to WT RRV-infected BA mice (76.8% vs. 17.5%). In stark contrast to the RRV-infected BA mice, the RRV-infected Ig-alpha(-/-) mice did not have hyperbilirubinemia or bile duct obstruction. The RRV-infected Ig-alpha(-/-) mice had significantly less liver inflammation and Th1 cytokine production compared to RRV-infected WT mice. In addition, Ig-alpha(-/-) mice had significantly increased numbers of regulatory T cells (Tregs) at baseline and after RRV infection compared to WT mice. However, depletion of Tregs in Ig-alpha(-/-) mice did not induce biliary obstruction, indicating that the expanded Tregs in the Ig-alpha(-/-) mice were not the sole reason for protection from disease. Conclusion: B cell deficient Ig-alpha(-/-) mice are protected from biliary obstruction in the RRV-induced mouse model of BA, indicating a primary role of B cells in mediating disease pathology. The mechanism of protection may involve lack of B cell antigen presentation, which impairs T-cell activation and Th1 inflammation. Immune modulators that inhibit B cell function may be a new strategy for treatment of BA.
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