Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized serologically by the high prevalence of anti-mitochondrial autoantibodies (AMAs) and histologically by the cholangitis of small bile ducts, eventually followed by extensive loss of the small bile duct. An autoimmune pathogenesis is suggested by clinical and experimental studies, but there remain issues regarding the etiology, the significance of AMAs in the pathogenesis of bile duct lesions, and so on. The unique properties of apoptosis in biliary epithelial cells (BECs), in which there is exposure of autoantigen to the effectors of the immune system, are proposed to be a cause of bile duct lesions in PBC. Recent progress disclosed that cellular senescence and autophagy are involved in bile duct lesions in PBC. Senescent BECs may modulate the periductal microenvironment by expressing senescence-associated secretory phenotypes, including various chemokines, and contribute to the pathogenesis of bile duct lesions in PBC.
Highlights
Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease in which autoimmune pathogenesis is suggested [1,2,3,4]
The inhibition of autophagy suppressed cellular senescence in cultured cells [28]. These findings suggest that autophagy may mediate the process of biliary epithelial senescence and be involved in the pathogenesis of bile duct lesions in PBC
We have reported the cellular senescence of biliary epithelial cells (BECs) with shortened telomeres, the expression of SA-β-gal, and the augmented expression of p16INK4a and p21WAF1/Cip in damaged small bile ducts in PBC (Figure 3) and suggested that cellular senescence may be involved in the pathogenesis of progressive bile duct loss in PBC [24, 27]
Summary
Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease in which autoimmune pathogenesis is suggested [1,2,3,4]. The most accepted hypothesis states that PBC results from an environmental insult on a genetically susceptible background In this scenario, adaptive immunity, both humoral and cellular (CD4 and CD8 T cells), and innate immunity have been proposed as coplayers in immune-mediated liver damage; there remain many mysteries in the etiology and pathogenesis of PBC; in particular, the significance of AMAs and autoantigenspecific T-cell response in the pathogenesis of bile duct lesions remains unknown. Our recent studies disclosed that cellular senescence and autophagy are involved in the bile duct lesion in PBC [24,25,26,27,28] These two novel cellular processes may be related to the immunopathology of BECs together with AMAs in PBC. Hepatitis Research and Treatment in PBC and its possible involvement in the progression of diseases
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