Differential immune response to xenobiotic‐modified self‐molecule in simple and connective tissue disease‐associated primary biliary cholangitis

Abstract

Background and Aims: Our previous studies demonstrated that 2-octynoic acid (2OA) might alter the conformational structure of the inner lipoic acid (LA) binding domain (ILD) in the E2 subunit of pyruvate dehydrogenase complex (PDC-E2), leading to the loss of immune tolerance in simple primary biliary cholangitis (S-PBC). Here, we further explore if this etiological mechanism also accounts for connective tissue diseaseassociated PBC (CTD-PBC).Methods: Intein-mediated protein ligation was used to prepare ILD, LA-ILD and 2OA-ILD, and their reactivity with serum samples from 124 S-PBC and 132 CTD-PBC patients was examined. The antibodies to LA, 2OA, LA-ILD and 2OA-ILD, the isotypes of antibodies to LA, 2OA and ILD, were comparatively detected between the two patient groups by enzyme-linked immunosorbent assay and immunoblotting.Results: Both the percentage and reactivity of antibody to 2OA in S-PBC were significantly higher than in CTD-PBC. Antibodies to 2OA and to LA between the two groups separately shared the same characteristics. Remarkably, coexistence of the antibodies to LA-ILD and to 2OA, and coexistence of the antibodies to LA and to 2OA in S-PBC were both significantly more frequent than in CTD-PBC, whereas the percentage of anti-LA antibody without anti-2OA antibody in S-PBC was markedly lower than in CTD-PBC. Moreover, the isotype of antibody to LA was predominantly IgG in CTD-PBC, whilst this isotype was mainly IgM in S-PBC. Conclusion:Xenobiotic 2OA might play less important pathogenic role in CTD-PBC than in S-PBC, suggesting that different underlying mechanisms are involved in their immune intolerance to PDC-E2.

New insights into the pathogenesis of primary biliary cholangitis asymptomatic stage

“…The importance of chemical xenobiotics capable of modifying lipoic acid in E2 PDC has been previously shown for the appearance of serologic reactivity of this complex[ 81 , 82 ]. Alteration of the conformational structure of the lipoyl domain of E2 PDC, due to chemical modification of lipoic acid may contribute to the loss of immune tolerance[ 83 , 84 ].…”