Biliary Atresia

Biliary atresia represents a phenotypic endpoint of progressive obliterative cholangiopathy driven by the convergence of viral triggers, dysregulated innate and adaptive immunity, and aberrant developmental signaling. Current molecular evidence supports a two-hit model: an initial viral insult (reovirus type 3, rotavirus group C, or CMV) infects cholangiocytes via apical membrane receptors, triggering innate immune activation through pattern recognition receptors (Toll-like receptors TLR3 and TLR7 recognizing viral dsRNA and ssRNA respectively). This initial inflammatory response activates resident hepatic macrophages (Kupffer cells) and recruits circulating monocytes, NK cells, and dendritic cells to the periductal region. The second hit involves a maladaptive adaptive immune response. Molecular mimicry between viral epitopes and cholangiocyte surface antigens (particularly enolase-α and annexin A2) drives autoreactive CD4+ Th1 cell activation. These Th1 cells produce IFN-γ and TNF-α that upregulate MHC class II expression on cholangiocytes, rendering them targets for CD8+ cytotoxic T lymphocyte-mediated killing via perforin-granzyme pathways and Fas-FasL-mediated apoptosis. Simultaneously, IL-17-producing Th17 cells amplify neutrophil recruitment and periductal inflammation. Regulatory T cell (Treg) dysfunction, characterized by decreased FOXP3 expression, fails to suppress this autoimmune cascade. At the...