3. Most data on genetic associations with disease point to loci or genes involved in immune function. Altered regulation of self-tolerance can possibly support or induce immune reaction against self-PDC-E2, expressed normally or aberrantly by BECs. 4. Primary events of cholangiocellular apoptosis or cell damage have been suggested that could lead to aberrant presentation of self-antigens or create an inflammatory environment potentially triggering immune dysregulation. Suggested mechanisms include metabolic stress, possibly triggered by dysfunction of transporters involved in cell maintenance like AE2. This mechanism was suggested [179] based on the finding that an AE2 variant is a strong and independent prognostic factor for disease progression in PBC under UDCA therapy [112] . Furthermore, secretion of directly toxic environmental compounds into the bile or viral infection would trigger cholangiocellular damage.