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Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis
Author(s) -
Rong Guanghua,
Zhong Renqian,
Lleo Ana,
Leung Patrick S.C.,
Bowlus Christopher L.,
Yang GuoXiang,
Yang ChenYen,
Coppel Ross L.,
Ansari Aftab A.,
Cuebas Dean A.,
Worman Howard J.,
Invernizzi Pietro,
Gores Gregory J.,
Norman Gary,
He XiaoSong,
Gershwin M. Eric
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24355
Subject(s) - pyruvate dehydrogenase complex , protein subunit , autoantibody , primary biliary cirrhosis , enzyme , biology , biochemistry , chemistry , microbiology and biotechnology , antibody , immunology , gene
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. (H EPATOLOGY 2011)