Xenobiotics and loss of tolerance in primary biliary cholangitis

Figure 1 Schematic representation of the pyruvate dehydrogenase E2 lipoyl domain. Including the 19 residues (LLAEI-ETDKA-TIGFE-VQEE), lipoic acid is covalently attached to the ε group of lysine (K) via an amide bond.

Figure 2 Xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen pyruvate dehydrogenase E2, lead to the loss of self-tolerance and eventually biliary lesions in primary biliary cholangitis. PDC-E2: Pyruvate dehydrogenase E2; AMA: Anti-mitochondrial autoantibody.

Figure 3 APAP metabolism and proposed mechanism of APAP-mediated breaking of immune tolerance. APAP is metabolized in the liver to nontoxic compounds via conjugation of the aromatic ring to sulfate or glucuronic acid. APAP is converted into a highly electrophilic metabolite, NAPQI by microsomal cytochrome P450 oxidation. Reactive NAPQI accumulates and can form adducts with cellular proteins, leading to disruption of cellular functions, generation of neo-antigens, and loss of tolerance.