Environmental shaping of tolerance failure in autoimmune liver diseases: a phenotype-specific framework with primary...

Autoimmune liver diseases (primary biliary cholangitis, PBC; primary sclerosing cholangitis, PSC; autoimmune hepatitis, AIH) are three distinct, organ-specific autoimmune disorders that share loss of tolerance as the central pathophysiological mechanism but differ in target tissue, age of onset, genetic background, and environmental susceptibility. This review examines how environmental exposures modulate tolerance failure and tissue-directed injury across the three phenotypes. The signal is most coherent in PBC, where epidemiological evidence (smoking, recurrent urinary tract infections), neoantigen-focused mechanistic work on xenobiotic modification of PDC-E2, cholangiocyte apotope biology, and emerging exposomic data converge. PSC is better understood through gut-liver-microbiome interactions. AIH, including pediatric AIH, shows a weaker and more heterogeneous environmental signature complicated by overlap with drug-induced autoimmune-like hepatitis (DI-ALH). We outline the limitations of current exposomic methodology and propose phenotype-resolved research priorities. Environmental modulation does not replace loss of tolerance as the central paradigm; it provides context for how tolerance failure becomes durable and tissue-selective.