Cited by 222Liver Diseases and ImmunityAutoimmune Bullous Skin DiseasesSystemic Lupus Erythematosus Research

Apotopes and the biliary specificity of primary biliary cirrhosis†

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Lleo, Ana, Selmi, Carlo, Invernizzi, Pietro, Podda, Mauro, Coppel, Ross L., Mackay, Ian R., Gores, Gregory J., Ansari, Aftab A. +2 more·2009·Hepatology

Abstract

UNLABELLED: 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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Crossref · 10.1002/hep.22736

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  • PDC-E2 localizes in apoptotic bodies, being accessible to recognition by AMA.

    “PDC-E2 localizes in the apoptotic bodies, being accessible to recognition by AMA(257) .”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [257]

    The Results report PDC-E2 in apoptotic blebs and isolated apoptotic bodies from human intrahepatic biliary epithelial cells (HIBEC), with staining by AMA-positive sera without permeabilization. The claim omits that cell-type restriction: the Results report no PDC-E2 staining after apoptosis in the other cell lines tested. (LLM, conf=0.86)

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  • Apoptotic biliary epithelial cells uniquely retain intact PDC-E2, while other cells do not due to glutathione modifications of PDC-E2 in their mitochondria.

    “This hypothesis is plausible because apoptotic BECs uniquely retain intact PDC-E2, while other cells do not due to glutathione modifications of PDC-E2 in their mitochondria.1,49”

    From Primary biliary cholangitis. (2024) · cites this paper as [49]

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Research works printed but not linked: 2

  1. [33]Herrmann M Voll RE Zoller OM Hagenhofer M Ponner BB Kalden JR Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus Arthritis Rheum 1998 41 1241 1250 9663482
  2. [38]Yang GX L ZX Chuang YH Moritoki Y Lan RY Wakabayashi K Ansari AA Flavell RA Ridgway WM Coppel RL Tsuneyama K Mackay IR Gershwin ME Adoptive transfer of CD8+ T cells from dnTGFbetaRII mice induces autoimmune cholangitis in Rag1-/- mice Hepatology 2008 47 2 571 580 18452147 PMC2749317

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Authors
Lleo, A., Selmi, C., Invernizzi, P., Podda, M., Coppel, R. L., Mackay, I. R., Gores, G. J., Ansari, A. A., Van de Water, J., & Gershwin, M. E.
Affiliations
  • Humanitas University (IT)
  • IRCCS Humanitas Research Hospital (IT)
  • Monash University (AU)
  • Mayo Clinic (US)
  • Emory University (US)
  • University of California, Davis (US)
Corresponding author
Gershwin, M. Eric
Venue
Hepatology
Published
2009-03
Volume
49
Issue
3
Pages
871-879
ISSN
0270-9139 (ISSN-L)
OpenAlex
W2019481852
Cited by
222
References
53
Citations by year
2026: 9 · 2025: 6 · 2024: 8 · 2023: 12 · 2022: 9 · 2021: 5 · 2020: 11 · 2019: 15 · 2018: 10 · 2017: 18 · 2016: 6 · 2015: 13 · 2014: 13 · 2013: 17 · 2012: 20
FWCI
15.13
Type
journal article
Language
en
Open access
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Funders
  • National Institutes of Health (DK 39588)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 39588, R37DK039588, Z01DK070004, R01DK039588, DK70004, R21DK070004)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Autoimmune Bullous Skin Diseases
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
Keywords
primary biliary cirrhosis, antimitochondrial antibodies, PDC-E2, pyruvate dehydrogenase complex, apoptosis, cholangiocytes, cholangiocyte injury, autoantibody reactivity
MeSH terms
Antibodies, Antibody Specificity, Epitopes, Autoantigens, Bile Ducts, Intrahepatic, Cell Line, Cells, Cultured, Epithelial Cells, HeLa Cells, Humans, Liver Cirrhosis, Biliary, Mitochondria, Autoimmunity, Keratinocytes, Apoptosis, Caco-2 Cells, Mitochondrial Proteins, Dihydrolipoyllysine-Residue Acetyltransferase

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