Chapter 20 - Pathogenesis of Bile Duct Lesions in Primary Biliary Cirrhosis: Role of Autophagy Followed by Cellular Senescence

Abstract

Primary biliary cirrhosis (PBC), an organ-specific autoimmune disease, is histologically characterized by chronic non-suppurative destructive cholangitis in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. A high prevalence of serum antimitochondrial autoantibodies (AMAs) is also a feature of PBC. The autoimmune-mediated pathogenesis of bile duct lesions has been studied, but the mechanism has not been fully clarified. We have revealed for the first time that autophagy, deregulated autophagy, and cellular senescence are involved in bile duct lesions in PBC. Accumulation of microtubule-associated protein light chain 3β (LC3)-positive autophagic vesicles and aggregation of p62, a marker of deregulated autophagy, are observed in damaged small bile ducts in PBC, whereas such findings are not seen in small bile ducts in control livers. Interestingly, granular expression of the mitochondrial antigen PDC-E2 is co-localized with LC3, suggesting autophagy of mitochondria. In our hypothesis, deregulated autophagy may contribute to the abnormal expression of mitochondrial antigens and may be involved in the autoimmune pathogenesis of bile duct lesions in PBC. Furthermore, deregulated autophagy may precede the process of biliary epithelial senescence in PBC. Biliary epithelial cells in damaged bile ducts show characteristics of cellular senescence and may modulate the microenvironment around the bile ducts by expressing various chemokines and cytokines called senescence-associated secretory phenotypes, and contribute to the pathogenesis in PBC.