title: Epithelial cell specificity and apotope recognition by serum autoantibodies in primary biliary cirrhosis.
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.
  
  
  CONCLUSIONS
  We submit that the biliary specificity of PBC is secondary to the unique processes of biliary apoptosis.
authors.affiliation: Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA 95616, USA.
authors.forename: Guanghua
authors.initials: G
authors.lastname: Rong
authors.forename: Renqian
authors.initials: R
authors.lastname: Zhong
authors.forename: Ana
authors.initials: A
authors.lastname: Lleo
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Bowlus
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Chen-Yen
authors.initials: CY
authors.lastname: Yang
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Dean A
authors.initials: DA
authors.lastname: Cuebas
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.forename: Gary
authors.initials: G
authors.lastname: Norman
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: He
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000217:Acyltransferases / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000918:Antibody Specificity / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008297:Male; D042361:Mammary Glands, Human / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000276:immunology / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D024101:Mitochondrial Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; C100153:2,4-dienoyl-CoA reductase; D000217:Acyltransferases; C033588:dihydrolipoamide acyltransferase; C021515:dihydrolipoamide succinyltransferase