Pathogenesis of biliary tract injury in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is histologically characterized by chronic nonsuppurative destructive cholangitis (CNSDC) associated with destruction of small bile ducts. The pathogenesis of PBC, predominance of female, or the reason why biliary duct is selectively involved, however, remains unknown. Infectious or non-infectious noxious insults such as xenobiotic chemicals may precipitate in the individual having a genetic background of PBC. Activation of innate immune response seems to be a key event in early PBC, leading to the autoimmune injury of small intrahepatic bile duct. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). In PBC, dysregulated biliary innate immunity, namely hyper-responsiveness to PAMPs, is associated with the pathogenesis of cholangiopathy. Moreover, the targeted biliary epithelial cells (BEC) may play an active role in the perpetuation of autoimmunity by attracting immune cells via chemokine secretion. Biliary innate immune responses induce the production of two chemokines, CX3CL1 (fractalkine) and several Th1 shift chemokines, causing the migration of inflammatory cells including NK cells. TLR 4 ligand-stimulated NK cells destroy autologous BECs in the presence of interferon alpha (IFN-a) synthesized by TLR 3 ligand-stimulated monocytes. These findings give new insights in the pathogenesis of this mysterious disease, PBC.