Molecular mechanisms of cholangiopathy in primary biliary cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is histologically characterized by chronic nonsuppurative destructive cholangitis (CNSDC) and the progressive loss of intrahepatic small bile ducts.Cellular immune mechanisms involving T cell-reaction are thought to be significantly involved in the formation of CNSDC and bile duct loss. In inflammed portal tracts of PBC, CD4+ T cells of Th1-type expressing IFN-γ or CXCR3 are aggregated and more commonly detected around injured bile ducts than Th2-type CD4 + T cells expressing IL-4 or CCR4,indicating that Th1-dominant cellular immunity play a more prominent role in recruitment of memory T cell subsets in PBC and may be responsible for the progressive bile duct damage.Biliary epithelial apoptosis is demonstrated to be a major pathogenic process of bile duct loss in PBC. In CNSDC, several biliary apoptotic cells, an aberrant expression of Fas antigen (pro-apoptotic molecule), and decreased expression of bcl-2 and mcl-1 (anti-apoptotic molecules) are found, though interlobular bile ducts express bcl-2 and mcl-2, but lack Fas. In addition, the up-regulation of WAF1 and p53 related with biliary apoptosis is found in biliary epithelial cells of PBC, which may be due to cell senescence in response to genotoxic damages such as oxidative stress. Several steps and mechanisms during induction and progression of cholangitis and biliary apoptosis followed by bile duct loss are now being proposed in PBC, but future analysis of an etiopathogenesis explainable for these characteristic histopathogenesis of PBC will be required.HARADA -3 -

Increased expression of Toll-like receptor 3 in intrahepatic biliary epithelial cells at sites of ductular reaction in diseased livers

“…), costimulatory molecules (B7, PD-L1, PD-L2, etc. ), and TLR4, have also been reported in biliary epithelial cells in livers affected by PBC [34][35][36][37][38]. In addition to these molecules involved in innate and acquired immune response, we here demonstrated for the first time that RIG-I/MDA5-MAVS signaling pathway is operative in the strong induction of IFN-b by dsRNA stimulation in HIBECs.…”

Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms

“…Previous studies described the profiles of inflammatory cells surrounding bile ducts in PBC (9,(14)(15)(16)(17). Cellular profiles may change depending on the process of biliary inflammation.…”

Characterisation of TNF-related apoptosis-inducing ligand in peripheral blood in patients with primary biliary cirrhosis

“…There is concrete evidence indicating that apoptosis is possibly the most important mechanism of biliary epithelial cell loss. Apoptotic cells are frequently found on biliary epithelial cells, particularly more cholangitic bile ducts in PBC, but very few occur in control livers [1]. Markers of ongoing apoptosis have been reported within affected portal tracts, including down-regulation of the anti-apoptotic protein bcl-2 [2,3], increased expression of Fas in BECs from PBC patients, as well as elevated expression of FasL in infiltrating mononuclear cells [4].…”