The immunological landscape of primary biliary cholangitis: Mechanisms and therapeutic prospects

Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease characterized by the progressive destruction of intrahepatic bile ducts, leading to fibrosis, and potentially cirrhosis. PBC has been considered a prototypical autoimmune condition, given the presence of specific autoantibodies and the immune response against well-defined mitochondrial autoantigens. Further evidence supports the interaction of immunogenetic and environmental factors in the aetiology of PBC. An immunological attack on biliary epithelial cells (BECs) with secondary failure of biliary transporters, e.g. the anion exchange protein 2 (AE2), is traditionally considered the primum movens. A recent hypothesis proposes a primary failure of BECs with the downregulation of AE2 secondary to epigenetic mechanisms (miR-506 overexpression) which then triggers the immunological storm. This highlights the secretory defect as culprit and sustaining factor in the pathogenesis of PBC with UDCA helping to restore this protective mechanism by promoting bicarbonate secretion and reducing bile acid toxicity. In this review we aim to provide the most recent evidence on the immunopathogenesis of PBC. We will analyse the immune function of the biliary epithelium, assessing the immunomodulatory functions of the bile acids and the evidence of the immunological roles of the secretory pathways targeted by the current treatments.