A three-tier framework for interacting immune-tolerance defects in primary biliary cholangitis

Primary biliary cholangitis (PBC) combines autoimmune susceptibility with selective injury to small intrahepatic bile ducts. We use a three-tier framework of central, peripheral, and tissue-level tolerance to examine how immune dysregulation interacts with defective epithelial secretion and intracellular pH regulation. This narrative review integrates human genetic, tissue, and functional studies with clinical trials and experimental models, distinguishing patient observations from model-dependent mechanisms and untested hypotheses. Human evidence supports peripheral immune abnormalities, cholangiocyte stress, reduced anion exchanger 2 (AE2) expression, and impaired stimulated biliary bicarbonate secretion. Experimental studies connect AE2 deficiency to altered intracellular pH, cholangiocyte susceptibility to apoptosis, and enhanced CD8+ T-cell activation. Proposed links to defective mitophagy, mitochondrial autoantigen exposure, and female predominance remain incompletely tested in PBC. Evidence for a primary thymic defect is substantially weaker. Ursodeoxycholic acid and peroxisome proliferator-activated receptor (PPAR)-directed therapies address bile-acid homeostasis and tissue injury, whereas tolerance-directed cellular therapies remain investigational. The framework integrates immune and epithelial mechanisms without imposing a fixed sequence of disease initiation. It supports research into residual injury under treatment but is not a validated treatment-selection algorithm. Clinical escalation should follow biochemical response, symptoms, and established prognostic measures; prospective studies must test whether AE2, pH, and immune phenotypes improve stratification.