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.
Highlights
Biliary atresia (BA) is the leading cause of neonatal cholestasis, occurring in approximately 1 out of 10,000 live births in the United States [1]
Many experimental models of autoimmune diseases have demonstrated an important role of B cells in disease pathogenesis [17,18,19,20] and trials of B-cell modulating agents are being conducted in human autoimmune diseases [21]
The B cell receptor (BCR) is composed of membrane-bound Ig and the non-covalently associated signal transduction moiety Ig-α/Ig-β
Summary
Biliary atresia (BA) is the leading cause of neonatal cholestasis, occurring in approximately 1 out of 10,000 live births in the United States [1]. In order to perform mechanistic studies, the Rhesus rotavirus (RRV)-induced mouse model of BA has been employed by many investigators [11,12,13,14] In this model, the bile duct injury is associated with Th1-mediated inflammation and with bile duct epithelial autoreactive T cells [15,16]. Many experimental models of autoimmune diseases have demonstrated an important role of B cells in disease pathogenesis [17,18,19,20] and trials of B-cell modulating agents are being conducted in human autoimmune diseases [21] In both humans and in the mouse model of BA, periductal immunoglobulin deposits and circulating autoantibodies have been described [15,22]. One such autoantibody reactive to cytosolic enolase from bile duct epithelia has been identified in both mouse and human BA [23], as well as in other autoimmune biliary diseases [23,24], lending further evidence to the role of autoimmunity in the pathogenesis of BA
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