Evolution of our understanding of PBC.

The discovery of mitochondrial autoantigens recognized by antimitochondrial antibodies (AMAs) in 1987 marked the dawn of a new era in primary biliary cholangitis (PBC) research. Since then, there has been substantial progress in our understanding of PBC partly bestowed by the development of innovative technologies in molecular biology, immunology, and genetics. Here, we review this evolutionary progress in understanding PBC. We now recognize that the epitopes of AMAs, CD4+, and CD8+ T cells are all mapped to the same region of the inner lipoyl domain of pyruvate dehydrogenase complex E2 subunit (PDC-E2), and that intrahepatic biliary epithelial cells (BECs) are exclusively targeted in PBC. BECs express PDC-E2 on apotopes in an immunologically intact form during apoptosis, but not other epithelial cells, which could explain the tissue specificity of PBC. In addition, genetic factors, environmental triggers, and epigenetic modifications play crucial roles in the development of PBC. Intact lipoylated PDC-E2, presumably after modification with xenobiotics such as 2-octynamide or 2-nonyamide that are abundantly present in the environment, is endocytosed by antigen-presenting cells and are presented to CD4+ or CD8+ T cells. An immune complex consisting of PDC-E2 and anti-PDC-E2 autoantibodies cross-present autoantigens in a more efficient manner. Finally, an adenylate uridine-rich element (ARE) Del -/- mouse model has been established, which presents a disease modeling human PBC, including female dominance as one of its most important features, and can be used to dissect the immunopathology of PBC. Expanding our knowledge of the pathology from a very early stage of the disease will provide the key to cure PBC.