Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis

Guanghua Rong, Renqian Zhong, Ana Lleo, Patrick S Leung, Christopher Bowlus, Guo Xiang Yang, Chen Yen Yang, Ross L. Coppel, Aftab A. Ansari, Dean A. Cuebas, Howard J. Worman, Pietro Invernizzi, Gregory J. Gores, Gary Norman, Xiaosong He, M. Eric Gershwin

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)196-203
Number of pages8
JournalHepatology
Volume54
Issue number1
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Hepatology

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    Rong, G., Zhong, R., Lleo, A., Leung, P. S., Bowlus, C., 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., & Gershwin, M. E. (2011). Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis. Hepatology, 54(1), 196-203. https://doi.org/10.1002/hep.24355