Toward solving the etiological mystery of primary biliary cholangitis

Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature AMA autoantibody, female predominance and relatively specific portal infiltration and cholestasis. The identification and cloning of the major mitochondrial autoantigens, recognized by AMA, have served as an immunologic platform to identify the earliest events involved in loss of tolerance. Despite the relative high concordance rate in identical twins, genome wide association studies have not proven clinically useful and have led to suggestions of epigenetic events. To understand the natural history and etiology of PBC, several murine models have been developed including spontaneous models, models induced by chemical xenobiotic immunization and by "designer" mice with altered interferon metabolism. Herein, we describe five such models including 1) NOD.c3c4 mice, 2) dominant negative form of transforming growth factor (TGF)-β receptor type II (dnTGFβRII) mice, 3) interleukin (IL)-2Rα^-/- mice 4) ARE Del^-/-mice and 5) 2-octynoic acid conjugated bovine serum albumin (2OA-BSA) immunized mice. Individually there is no perfect murine model but collectively the models point to loss of tolerance to PDC-D2, the major mitochondrial autoantigen, as the earliest event that occurs before clinical disease is manifest. Although there is no direct association of AMA titer and PBC disease progression it is noteworthy that the triad of PBC monocytes, biliary apotopes and AMA leads to an intense proinflammatory cytokine burst. Further the recurrence of PBC after liver transplantation indicates that, due to MHC restriction, disease activity must include not only adaptive immunity but also innate immune mechanisms. We postulate that successful treatment of PBC may require a personalized approach with therapies designed for different stages of disease.