23, 27, 28 Although serum autoantibodies against the E2 subunits of mitochondrial 2-oxo-dehydrogenase have been well characterized in PBC,1, 6 the discovery that these proteins are intact only in ABs from HiBECs helps to explain the selective destruction of biliary cells in the disease. We previously reported a HiBEC-specific failure in the postapoptotic degradation (PAD) of antigenic PDC-E2, the major autoantigen.4 In this study, we demonstrated that defective PAD in HiBECs is not limited to PDC-E2, but also involves OGDC-E2 and BCOADC-E2 that are also intact

in HiBEC ABs. We identified in ABs from HiBECs the other PBC-specific mitochondrial autoantigens, OGDC-E2 and BCOADC-E2, which are recognized by serum antibodies in approximately 23% and 57%, respectively, of patients.9 Thus, all three mitochondrial 2-oxo acid Selleck Olaparib AZD1152 HQPA dehydrogenase complexes that are autoantigens in PBC can be traced to HiBEC ABs. These findings highlight the involvement of inappropriate PAD as the source of autoantigens and perhaps in the pathogenesis of biliary-selective damage in PBC. This study focused on the tissue specificity of the apotope. Upon being taken up by local professional phagocytotic cells, these incompletely processed proteins may critically challenge the balance between tolerance and autoimmunity, thus providing a structural basis for the eventual biliary

epithelial cell (BEC)-selective immune response of PBC. However, we hypothesize that the unique PAD pattern of HiBECs is not sufficient to initiate the pathologic damage in

PBC, not only because the HiBECs studied here are from donors without PBC and the autoantigen-loaded ABs may therefore occur in anyone, but because PBC frequently recurs even after allogenic liver transplantation. In addition, the constant leakage of intact cellular components may cause antigen accumulation in regions near BECs. Epithelial cells can either uptake and process ABs from their neighboring apoptotic cells as nonprofessional phagocytes29, 30 or present pathologic epitopes onto their surface as nonprofessional antigen-presenting cells.31-33 In PBC, the atypical distribution of PDC-E2 on the surface of BECs in patients has been described.34-37 The presence of pathological epitopes on the surface of BECs may selleck compound serve as targets to attract the autoantibody-mediated immunologic attack if tolerance has been broken. Our data suggest that the defect of cellular protein PAD is not unique to HiBECs. We found several intact autoantigens in ABs of different epithelial cells, implying human epithelial cells variably process their apoptotic leftovers due to factors yet to be determined. We found BCOADC-E2, a PBC autoantigen, to be immunologically intact in epithelial cells other than HiBECs. This finding would suggest that cells other than biliary epithelium could be targeted by the immune response in patients with PBC and anti–BCOADC-E2 autoantibodies.