Biliary epithelial-mesenchymal transition in posttransplantation recurrence of primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) recurs in the allograft after liver transplantation. Study of early tissue changes in the time-course of disease recurrence provides a unique insight into the initial stages of the disease process, which, in nontransplant patients, occurs long before clinical presentation. We describe a patient who developed classical clinical, biochemical, immunological, and histological features of PBC within 9 months after transplantation. Use of tissue from this patient before and during the development of PBC allowed us to identify biliary epithelial cell (BEC) epithelial-mesenchymal transition (EMT) as a key pathogenetic process. BEC expression of S100A4 (an early fibroblast lineage marker established as a robust marker of EMT), vimentin, and pSmad 2/3 [a marker of transforming growth factor beta (TGF-beta) pathway signaling] were identified immunohistochemically in most BECs in liver tissue from this patient at the point of diagnosis of recurrent disease. BEC expression of S100A4 and pSmad 2/3 was seen as early as 24 days after orthotopic liver transplantation (OLT), although no other features of recurrent PBC were present at this time.


CONCLUSIONS
S100A4, vimentin, and pSmad 2/3 expression in early recurrent PBC after OLT suggests that BEC EMT is occurring (potentially explaining BEC loss) and that this process is driven by TGF-beta. S100A4 expression by BEC appears to occur before the development of any other features of recurrent PBC, suggesting that EMT may be an initiating event.
Robertson
Helen
H
Applied Immunobiology and Transplantation Research Group, Newcastle University, Newcastle-upon-Tyne, NE2 4HH, UK.
Kirby
John A
JA
Yip
William W
WW
Jones
David E J
DE
Burt
Alastair D
AD
D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism / Q000473:pathology*; D016031:Liver Transplantation; D012008:Recurrence
D015415:Biomarkers