Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: Connecting xenobiotics with primary biliary cirrhosis

In primary biliary cirrhosis (PBC), the major autoepitope recognized by bot h T and B cells is the inner lipoyl domain of the E2 component of pyruvate dehydrogenase. To address the hypothesis that PBC is induced by xenobiotic exposure, we took advantage of ab initio quantum chemistry and synthesized the inner lipoyl domain of E2 component of pyruvate dehydrogenase, replacin g the lipoic acid moiety with synthetic structures designed to mimic a xeno biotically modified lipoyl hapten, and we quantitated the reactivity of the se structures with sera from PBC patients. Interestingly, antimitochondrial Abs from all seropositive patients with PBC, but no controls, reacted agai nst 3 of the 18 organic modified autoepitopes significantly better than to the native domain. By structural analysis, the features that correlated wit h autoantibody binding included synthetic domain peptides with a halide or methyl halide in the meta or para position containing no strong hydrogen bo nd accepting groups on the phenyl ring of the lysine substituents, and synt hetic domain peptides with a relatively low rotation barrier about the link age bond. Many chemicals including pharmaceuticals and household detergents have the potential to form such halogenated derivatives as metabolites. Th ese data reflect the first time that an organic compound has been shown to serve as a mimeotope for an autoantigen and further provide evidence for a potential mechanism by which environmental organic compounds may cause PBC.