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

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 disease-associated 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.