chapter  Chapter 29
27 Pages

Immunopathogenesis of Vanishing Bile Duct Syndromes

WithJohn M. Vierling, Marius Braun, Haimei Wang

Vanishing Bile Duct Syndrome is a term used to describe progressive loss of small intra-hepatic ducts in a variety of different diseases. It is increasingly clear that immunopathogenetic mechanisms involving innate and adaptive immune responses contribute to ductopenia in most of these diseases. Although immunopathogenesis of ductopenia remains incompletely understood, substantial progress has been made in diseases associated with nonsuppurative destructive cholangitis and fibrous obliterative cholangitis. Nonsuppurative cholangitis is mediated by T-cells in the autoimmune disease primary biliary cirrhosis and the alloimmune diseases chronic graft-versus-host disease and hepatic allograft rejection. In contrast, fibrous obliterative cholangitis is associated with mixed portal inflammatory infiltrates and generation of concentric layers of periductal fibrosis. Fibrosis emanating from the intrahepatic bile ducts displaces peribiliary capillary plexi and leads to progressive ischemia and disruption of the cholehepatic circulation. Recent evidence in both nonsuppurative cholangitis and fibrous obliterative cholangitis indicate a pathogenic role for innate immune activation by bacterial cell wall products. This activation, which also modulates the adaptive immune responses of autoimmunity and alloimmunity, culminates in cytokine and/or bacterial activation of biliary epithelial cells lining small caliber bile ducts. The activated phenotype of these biliary epithelial cells renders them capable of possible antigen presenting functions and enhances their susceptibility to apoptosis mediated by T-effector cells and their cytokines. Recent evidence that activated biliary epithelial cells also secrete polarizing cytokines and chemokines indicates they directly participate in the generation of distinct peribiliary inflammatory and cytokine milieus. Variations in the types of cytokines and chemokines secreted by activated biliary epithelial cells may underlie differences in the immunopathology resulting in vanishing bile duct syndromes.