Cellular and humoral autoimmunity directed at bile duct epithelia in murine biliary atresia

Abstract

Biliary atresia is an inflammatory fibrosclerosing lesion of the bile ducts that leads to biliary cirrhosis and is the most frequent indication for liver transplantation in children. The pathogenesis of biliary atresia is not known; one theory is that of a virus-induced, subsequent autoimmune-mediated injury of bile ducts. The aim of this study was to determine whether autoreactive T cells and autoantibodies specific to bile duct epithelia are present in the rotavirus (RRV)-induced murine model of biliary atresia and whether the T cells are sufficient to result in bile duct inflammation. In vitro analyses showed significant increases in IFN-␥-producing T cells from RRV-diseased mice in response to bile duct epithelial autoantigen. Adoptive transfer of the T cells from RRV-diseased mice into naïve syngeneic SCID recipients resulted in bile duct-specific inflammation. This induction of bile duct pathology occurred in the absence of detectable virus, indicating a definite response to bile duct autoantigens. Furthermore, periductal immunoglobulin deposits and serum antibodies reactive to bile duct epithelial protein were detected in RRV-diseased mice. In conclusion, both cellular and humoral components of autoimmunity exist in murine biliary atresia, and the progressive bile duct injury is due in part to a bile duct epithelia-specific T cell-mediated immune response. The role of cellular and humoral autoimmunity in human biliary atresia and possible interventional strategies therefore should be the focus of future research.

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

“…Instead, it appears that infected cells are secondarily targeted by activated NK cells, which use the Nkg2d receptor to establish contact, injure cholangiocytes, and initiate a break in epithelial integrity. The ability of activated NK cells to also lyse an uninfected cholangiocyte cell line reported here raises the possibility that they may also injure neighboring uninfected cholangiocytes in vivo, perhaps via the recognition of cellular epitopes by molecular mimicry (5,30). This has the potential to extend the mucosal injury and amplify the inflammatory response typical of biliary atresia.…”

Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice

“…The use of low-dose virus can better simulate the experience of BA patients. Importantly, based on studies showing that, even after successful removal of obstructed EHBDs via portoenterostomy and the restoration of adequate bile flow, 80% of patients with BA will ultimately require liver transplantation owing to the progressive nature of this disease, 1,5 we propose that CMV-induced autoimmune-mediated and inflammatory response may account for the progressive biliary injury, cirrhosis and eventual requirement for liver transplantation observed in BA patients. Although LD-CMV infection generated immune activation and specific bile duct injury in Treg-depleted neonatal mice, accompanied with injury to and atresia of intrahepatic bile ducts and partial obstruction of the EHBDs, they did not induce the complete atresia phenotype of duct obstruction.…”

Biliary Atresia: A Multidisciplinary Approach to Diagnosis and Management

“…46 Interestingly, transfer of T cells from rotavirus-induced biliary atresia to severe combined immunodeficiency mice has been shown to be sufficient to cause bile duct-specific inflammation. 51 As with reovirus, however, the detection of rotavirus in human biliary atresia has been inconsistent. 42,52 Therefore, in spite of all the evidence from wellcharacterized experimental models, the role of viral infection in human biliary atresia remains unresolved.…”