32 This is achieved by constant forming and breaking of the disulfide bond with subsequent electron transfer of an acetyl group from pyruvate to coenzyme A (CoA) to produce acetyl-CoA. We have recently shown that the modification of this disulfide bond renders PDC-E2 more immunogenic and proposed that this modification can interrupt ATP synthesis, causing cell death and exposing modified PDC-E2 to the immune system. This could initiate breakdown

of self-tolerance to native PDC-E2 in genetically susceptible individuals by presentation of a crossreactive moiety.12 This finding is supported by the observation that PDC-E2 is more immunogenic in its reduced and unmasked form,33 a structure equivalent to SAc-PDC-E2. Additionally, diacetyl derivatives buy Obeticholic Acid of PDC-E2 (SAc-PDC-E2) cannot participate in the enzymatic reaction to form acetyl-CoA as efficiently as monoacetyl derivatives, the physiological form of PDC-E2,34 again rendering the cell more susceptible to exogenous damage. Thus, direct alteration of the lipoyl ring—i.e., disruption of the S-S linkage—renders the lipoic acid “activated” and receptive to xenobiotic modification, which in turn presents a crossreactive neo-epitope. Although it is not clear how xenobiotics or the modified cellular proteins initiate autoimmunity in PBC, analysis of serum samples from subjects with acute liver failure indicate that a severe liver oxidant injury can lead to AMA production.21,

35 In particular, AMA with the same antigen and epitope specificity MS-275 molecular weight as in patients check details with PBC was found in almost 35% of individuals poisoned by ingesting excessive amounts of acetyl-para-aminophenol (commonly known as acetaminophen), suggesting that the PDC-E2 lipoyl domain is likely a target of acetaminophen-induced reactive oxygen species. Thus, in genetically susceptible individuals, prolonged exposure to electrophilic agents such as acetaminophen may initiate and/or enhance the breakdown of self-tolerance to PDC-E2.13 We propose such

modified-self comes to the attention of the immune system in apoptotic blebs from biliary epithelial cells during the normal turnover of the cellular lining of intrahepatic bile ducts in an environment of xenobiotic exposure.36 Previous work has demonstrated that protein modification can be an initiating point to the breach of tolerance. Indeed, in one study it was estimated that the majority of human proteins are susceptible to posttranslational modification, including, for example, acetylation, lipidation, citrullination, and glycosylation.37, 38 The clinical significance of these modifications has been demonstrated in rheumatoid arthritis, Sjogren’s syndrome, systemic lupus, and celiac disease.39-42 The earliest work reflecting the clinical significance of xenobiotics with respect to modification and environmental factors was the relative induction of lupus-like diseases experimentally by mercury.