Apotopes and the biliary specificity of primary biliary cirrhosis

Ana Lleo, Carlo Selmi, Pietro Invernizzi, Mauro Podda, Ross L. Coppel, Ian R. Mackay, Gregory J. Gores, Aftab A. Ansari, Judith A Van de Water, M. Eric Gershwin

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Abstract

Primary biliary cirrhosis (PBC) is characterized by antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Notwithstanding the presence of mitochondria in virtually all nucleated cells, the destruction in PBC is limited to small intrahepatic bile ducts. The reasons for this tissue specificity remain unknown, although biliary epithelial cells (BECs) uniquely preserve the PDC-E2 epitope following apoptosis. Notably, PBC recurs in an allogeneic transplanted liver, suggesting generic rather than host PBC-specific susceptibility of BEC. We used cultured human intrahepatic BECs (HIBECs) and other well-characterized cell lines, including, HeLa, CaCo-2 cells, and nontransformed human keratinocytes and bronchial epithelial cells, to determine the integrity and specific localization of PDC-E2 during induced apoptosis. All cell lines, both before and after apoptosis, were tested with sera from patients with PBC (n=30), other autoimmune liver and rheumatic diseases (n= 20), and healthy individuals (n = 20) as well as with a mouse monoclonal antibody against PDC-E2 and AMA with an immunoglobulin A isotype. PDC-E2 was found to localize unmodified within apoptotic blebs of HIBECs, but not within blebs of various other cell lineages studied. The fact that AMA-containing sera reacted with PDC-E2 on apoptotic BECs without a requirement for permeabilization suggests that the autoantigen is accessible to the immune system during apoptosis. Conclusion: Our data indicate that the tissue (cholangiocyte) specificity of the autoimmune injury in PBC is a consequence of the unique characteristics of HIBECs during apoptosis and can be explained by exposure to the immune system of intact immunoreactive PDC-E2 within apoptotic blebs.

Original languageEnglish (US)
Pages (from-to)871-879
Number of pages9
JournalHepatology
Volume49
Issue number3
DOIs
StatePublished - 2009

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Biliary Liver Cirrhosis
Epithelial Cells
Apoptosis
Blister
Organ Specificity
Antibodies
Immune System
Dihydrolipoyllysine-Residue Acetyltransferase
Intrahepatic Bile Ducts
Cell Line
Caco-2 Cells
Immunoglobulin Isotypes
Autoantigens
Cell Lineage
Rheumatic Diseases
Serum
Keratinocytes
Immunoglobulin A
Autoimmune Diseases
Liver Diseases

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Lleo, A., Selmi, C., Invernizzi, P., Podda, M., Coppel, R. L., Mackay, I. R., ... Gershwin, M. E. (2009). Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology, 49(3), 871-879. https://doi.org/10.1002/hep.22736

Apotopes and the biliary specificity of primary biliary cirrhosis. / Lleo, Ana; Selmi, Carlo; Invernizzi, Pietro; Podda, Mauro; Coppel, Ross L.; Mackay, Ian R.; Gores, Gregory J.; Ansari, Aftab A.; Van de Water, Judith A; Gershwin, M. Eric.

In: Hepatology, Vol. 49, No. 3, 2009, p. 871-879.

Research output: Contribution to journalArticle

Lleo, A, Selmi, C, Invernizzi, P, Podda, M, Coppel, RL, Mackay, IR, Gores, GJ, Ansari, AA, Van de Water, JA & Gershwin, ME 2009, 'Apotopes and the biliary specificity of primary biliary cirrhosis', Hepatology, vol. 49, no. 3, pp. 871-879. https://doi.org/10.1002/hep.22736
Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR et al. Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology. 2009;49(3):871-879. https://doi.org/10.1002/hep.22736
Lleo, Ana ; Selmi, Carlo ; Invernizzi, Pietro ; Podda, Mauro ; Coppel, Ross L. ; Mackay, Ian R. ; Gores, Gregory J. ; Ansari, Aftab A. ; Van de Water, Judith A ; Gershwin, M. Eric. / Apotopes and the biliary specificity of primary biliary cirrhosis. In: Hepatology. 2009 ; Vol. 49, No. 3. pp. 871-879.
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AU - Selmi, Carlo

AU - Invernizzi, Pietro

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AU - Mackay, Ian R.

AU - Gores, Gregory J.

AU - Ansari, Aftab A.

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AU - Gershwin, M. Eric

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AB - Primary biliary cirrhosis (PBC) is characterized by antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Notwithstanding the presence of mitochondria in virtually all nucleated cells, the destruction in PBC is limited to small intrahepatic bile ducts. The reasons for this tissue specificity remain unknown, although biliary epithelial cells (BECs) uniquely preserve the PDC-E2 epitope following apoptosis. Notably, PBC recurs in an allogeneic transplanted liver, suggesting generic rather than host PBC-specific susceptibility of BEC. We used cultured human intrahepatic BECs (HIBECs) and other well-characterized cell lines, including, HeLa, CaCo-2 cells, and nontransformed human keratinocytes and bronchial epithelial cells, to determine the integrity and specific localization of PDC-E2 during induced apoptosis. All cell lines, both before and after apoptosis, were tested with sera from patients with PBC (n=30), other autoimmune liver and rheumatic diseases (n= 20), and healthy individuals (n = 20) as well as with a mouse monoclonal antibody against PDC-E2 and AMA with an immunoglobulin A isotype. PDC-E2 was found to localize unmodified within apoptotic blebs of HIBECs, but not within blebs of various other cell lineages studied. The fact that AMA-containing sera reacted with PDC-E2 on apoptotic BECs without a requirement for permeabilization suggests that the autoantigen is accessible to the immune system during apoptosis. Conclusion: Our data indicate that the tissue (cholangiocyte) specificity of the autoimmune injury in PBC is a consequence of the unique characteristics of HIBECs during apoptosis and can be explained by exposure to the immune system of intact immunoreactive PDC-E2 within apoptotic blebs.

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