Autoimmune, Cholestatic and Biliary Disease
Article first published online: 24 JUN 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 1, pages 196–203, July 2011
How to Cite
Rong, G., Zhong, R., Lleo, A., Leung, P. S.C., Bowlus, C. L., Yang, G.-X., Yang, C.-Y., Coppel, R. L., Ansari, A. A., Cuebas, D. A., Worman, H. J., Invernizzi, P., Gores, G. J., Norman, G., He, X.-S. and Gershwin, M. E. (2011), Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis. Hepatology, 54: 196–203. doi: 10.1002/hep.24355
Potential conflict of interest: Nothing to report.
Financial support provided by National Institutes of Health grant DK39588 (to M.E.G.).
- Issue published online: 24 JUN 2011
- Article first published online: 24 JUN 2011
- Accepted manuscript online: 12 APR 2011 08:17AM EST
- Manuscript Accepted: 2 APR 2011
- Manuscript Received: 18 FEB 2011
A major enigma of primary biliary cirrhosis (PBC) is the selective targeting of biliary cells. Our laboratory has reported that after apoptosis, human intrahepatic biliary epithelial cells (HiBECs) translocate the E2 subunit of the pyruvate dehydrogenase complex immunologically intact into apoptotic bodies, forming an apotope. However, the cell type and specificity of this reaction has not been fully defined. To address this issue, we investigated whether the E2 subunit of the pyruvate dehydrogenase complex, the E2 subunit of the branched chain 2-oxo acid dehydrogenase complex, the E2 subunit of the oxo-glutarate dehydrogenase complex, four additional inner mitochondrial enzymes, and four nuclear antigens remain immunologically intact with respect to postapoptotic translocation in HiBECs and three additional control epithelial cells. We report that all three 2-oxo acid dehydrogenase enzymes share the ability to remain intact within the apotope of HiBECs. Interestingly, the E2 subunit of the branched chain 2-oxo acid dehydrogenase complex also remained intact in the other cell types tested. We extended the data, using sera from 95 AMA-positive and 19 AMA-negative patients with PBC and 76 controls, by testing for reactivity against the seven mitochondrial proteins studied herein and also the ability of AMA-negative sera to react with HiBEC apotopes. Sera from 3 of 95 AMA-positive sera, but none of the controls, reacted with 2,4-dienoyl coenzyme A reductase 1, an enzyme also present intact only in the HiBEC apotope, but which has not been previously associated with any autoimmune disease. Finally, the specificity of HiBEC apotope reactivity was confined to AMA-positive sera. Conclusion: We submit that the biliary specificity of PBC is secondary to the unique processes of biliary apoptosis. (HEPATOLOGY 2011)