The pathogenesis of biliary atresia: evidence for a virus-induced autoimmune disease

Abstract

Biliary atresia is a mystifying cause of neonatal cholestasis, manifested by progressive inflammation and fibrosis of both the extrahepatic and intrahepatic bile ducts. It is a devastating disease that leads to cirrhosis and the need for liver transplantation in the majority of children. The etiology is unknown, and one theory is that it may involve a primary perinatal hepatobiliary viral infection and a secondary generation of an autoimmune-mediated bile duct injury. This review will outline the evidence from both human and murine studies supporting a potential cholangiotropic viral infection as the initiator of bile duct injury in biliary atresia and the role of the adaptive immune response and autoimmunity in progression of disease. Delineating the pathways of immune and autoimmune-mediated bile duct injury within biliary atresia could stimulate development of new medical interventions aimed at suppressing the specific immune response, decreasing the inflammatory damage to bile ducts, and delaying or negating the need for liver transplantation.

Figure 1

Proposed model of viral-induced, T cell–mediated autoreactivity leading to bile duct epithelial injury in BA. Viral infection of bile duct epithelia (BDE) (1) causes initial injury to the cells. Virus particles phagocytosed by macrophages or dendritic cells (2) are presented to naïve T cells in local lymph nodes where activation and IL-2 stimulated proliferation of virus-specific CD4⁺ T cells ensues (3). These activated CD4⁺ T cells travel back to the original site of exposure and elicit T-cell effector functions (4) including IFN-γ–induced macrophage stimulation and activation of cytotoxic CD8⁺ T cells. The macrophages release TNF-α, nitric oxide (N.O.), and reactive oxygen species while the CD8⁺ T cells release granzyme and perforin, together resulting in further BDE injury through apoptotic or necrotic pathways. Previously sequestered or altered BDE antigens released from this initial injury are now phagocytosed by macrophages or dendritic cells and presented to autoreactive T cells (5), causing further activation of this T cell–mediated immune cascade (6) and progressive destruction of BDE.