38 Furthermore, only patients with PBC and serum AMA react with HiBEC Abs, yet patients with PBC without detectable AMA still have biliary damage. This suggests that biliary damage in PBC may not only be mediated by autoantibodies but also be cell-mediated responses, which would not have been detected in the experimental approach used here. Data from this study reinforces the hypothesis of apoptosis-related learn more immune tolerance as a mechanism in the initiation and perpetuation in PBC. Clearly, the etiology of PBC is unknown. However, both genetic susceptibility and environmental factors contribute to the onset

of disease. Interestingly, a number of candidate gene studies have reported critical PF-6463922 concentration links involving both MHC and non-MHC genes.39-44 More recently, genome-wide case–control association studies in PBC have identified a significant association with IL-12A (interleukin-12A), IL-12RB2 (interleukin-12

receptor, beta2 subunit), and STAT4 (signal transducer and activator of transcription 4) polymorphisms.45, 46 Interestingly, IL-12A polymorphism is associated with celiac disease47 and multiple sclerosis,48 and STAT4 polymorphism is also found in patients with SLE and rheumatoid arthritis.49 The association of these pleiotropic immune function–related genes in PBC and other autoimmune diseases illustrates that multiple genes are shared between clinical immune-related diseases, and the immune-mediated pathogenesis may be secondary upon breaking of tolerance by environmental xenobiotics.50 The challenge is to translate these genetic differences with functional human immunopathology. The pattern of antigens found within ABs is determined not by disease but rather by the evolutional characters of each cell type. Given this perspective, no cell that is subject of an autoimmune attack is really an innocent victim. Rather, development of disease, whether systemic or organ-specific, isometheptene is largely dependent

on the genetics and/or environment-induced susceptibility of each individual to the loss of tolerance of a specific apotope. Thus, in the case of PBC, autoimmunity does not target epithelial cells of the bronchia or mammary glands, despite the failure of these epithelial cells to completely clear all self-antigens under the same experimental conditions. HiBECs are targeted and destroyed for the selective presence of special apoptotic antigens—PDC-E2 and sometimes others—that are sensitive to the preexisting immunologic defect in patients with PBC. In addition to the three known mitochondrial autoantigens in PBC, we identified another mitochondrial enzyme, DECR1, as exclusively intact within HiBEC ABs. DECR1 was also immunologically recognized by antibodies in a small number of serum samples from patients with PBC.