The outstanding paradox in PBC pathogenesis remains the tissue tropism of the immune attack on the small intrahepatic bile ducts, although the mitochondrial targets are ubiquitously expressed proteins. An increased vulnerability of the primarily affected BECs therefore is a prerequisite in the pathogenesis of PBC. Staining of BECs from PBC livers with monoclonal antibodies against the mitochondrial PDC-E2 autoantigen showed a specific reaction at the apical surface which was not found in controls [206, 207] . Other non-PBC-related mitochondrial proteins show the expected cytoplasmic pattern [208] . It was subsequently demonstrated that the apical staining is due to a complex between (auto-)antimitochondrial IgA and PDC-E2, giving rise to speculations that IgA might be a player in the immune-mediated destruction of BECs [209, 210] . Apoptosis of BECs has been proposed as a cause of aberrant neoantigen presentation, responsible for activation or attraction of autoreactive T lymphocytes or antibodies. Unlike other cell types [211] for which autoantibody recognition of PDC-E2 is abrogated during apoptosis, probably by glutathiolation of the lysine-lipoyl moiety of PDC-E2, the antigenicity of PDC-E2 persists in the apoptotic BECs in which glutathiolation does not occur [211, 212] .