Apotopes and the Biliary Specificity of Primary Biliary Cirrhosis

• Authors: Ana Lleo, University of California; Carlo Selmi, University of California; Pietro Invernizzi, University of California; Mauro Podda, University of Milan; Ross L. Coppel, Monash University; Ian R. Mackay, Monash University; Gregory J. Gores, Mayo Clinic College of Medicine; Aftab A Ansari, Emory University; Judy Van de Water, University of California; M. Eric Gershwin, University of California
• Journal Title: Hepatology
• Volume: Volume 49, Number 3
• Publisher: Wiley | 2009-03, Pages 871-879
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/hep.22736
• Subjects: Health Sciences, Immunology
• Keywords: autoimmunity; antimitochondrial antibodies; apoptosis; apoptotic bodies; cell clearance

Abstract

Primary biliary cirrhosis (PBC) is characterized by antimitochondrial antibodies (AMA), 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 (BEC) 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 BEC (HIBEC) and other well-characterized cell lines, including, HeLa, CaCo-2 cells, and non transformed human keratinocytes and bronchial epithelial cells (BrEpC), 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), a mouse monoclonal antibody against PDC-E2, and AMA with an IgA isotype. PDC-E2 was found to localize unmodified within apoptotic blebs of HIBEC, but not within blebs of various other cell lineages studied. The fact that AMA- containing sera reacted with PDC-E2 on apoptotic BEC without a requirement for permeabilization suggests that the autoantigen is accessible to the immune system during apoptosis. In conclusion, our data indicate that the tissue (cholangiocyte) specificity of the autoimmune injury in PBC is a consequence of the unique characteristics of HIBEC during apoptosis and can be explained by exposure to the immune system of intact immunoreactive PDC-E2 within apoptotic blebs.