title: B cell deficient mice are protected from biliary obstruction in the rotavirus-induced mouse model of biliary atresia.
abstract: 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-α(-/-)) mice received RRV shortly after birth. Ig-α(-/-) 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-α(-/-) mice did not have hyperbilirubinemia or bile duct obstruction. The RRV-infected Ig-α(-/-) mice had significantly less liver inflammation and Th1 cytokine production compared to RRV-infected WT mice. In addition, Ig-α(-/-) 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-α(-/-) mice did not induce biliary obstruction, indicating that the expanded Tregs in the Ig-α(-/-) mice were not the sole reason for protection from disease. Conclusion : B cell deficient Ig-α(-/-) 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.
authors.affiliation: Department of Pediatrics, Section of Pediatric Gastroenterology, Children's Hospital, Colorado, Aurora, Colorado, USA. afeldman@luriechildrens.org
authors.forename: Amy G
authors.initials: AG
authors.lastname: Feldman
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Tucker
authors.forename: Erika K
authors.initials: EK
authors.lastname: Fenner
authors.forename: Roberta
authors.initials: R
authors.lastname: Pelanda
authors.forename: Cara L
authors.initials: CL
authors.lastname: Mack
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D001656:Biliary Atresia / Q000150:complications / Q000276:immunology* / Q000821:virology; D002779:Cholestasis / Q000517:prevention & control*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051379:Mice; D012401:Rotavirus / Q000472:pathogenicity*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology