Biliary epithelial cells and primary biliary cirrhosis: the role of liver-infiltrating mononuclear cells.

Abstract

UNLABELLED:

Primary biliary cirrhosis (PBC) is characterized by the highly selective autoimmune injury of small intrahepatic bile ducts, despite widespread distribution of mitochondrial autoantigens. On this basis, it has been suggested that the targeted biliary epithelial cells (BECs) play an active role in the perpetuation of autoimmunity by attracting immune cells via chemokine secretion. To address this issue, we challenged BECs from patients with PBC and controls using multiple Toll-like receptor (TLR) ligands as well as autologous liver-infiltrating mononuclear cells (LMNCs) with subsequent measurement of BEC phenotype and chemokine production and LMNC chemotaxis by quantifying specific chemokines. Our data reflect that BECs from PBC patients and controls express similar levels of TLR subtypes, CD40, and human leukocyte antigen DRalpha (HLA-DRalpha) and produce equivalent amounts of chemokines in our experimental conditions. Interestingly, however, BEC-expressed chemokines elicit enhanced transmigration of PBC LMNCs compared with controls. Furthermore, the addition of autologous LMNCs to PBC BECs led to the production of higher levels of chemokines and enhanced the expression of CD40 and HLA-DRalpha.

CONCLUSION:

We submit that the proinflammatory activity of BECs in PBC is secondary to the intervention of LMNCs and is not determined per se. These data support the hypothesis that BECs are in fact "innocent victims" of autoimmune injury and that the adaptive immune response is critical in PBC.

• Authors: Shinji Shimoda, Kenichi Harada, Hiroaki Niiro, Tomoharu Yoshizumi, Yuji Soejima, Akinobu Taketomi, Yoshihiko Maehara, Koichi Tsuneyama, Minoru Nakamura, Atsumasa Komori, Kiyoshi Migita, Yasuni Nakanuma, Hiromi Ishibashi, Carlo Selmi, M Eric Gershwin
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 47 Issue 3 Pg. 958-65 (Mar 2008) ISSN: 1527-3350 [Electronic] United States
• PMID: 18181218 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CD40 Antigens
• Chemokines
• HLA-DR Antigens
• Toll-Like Receptors

Topics

• Autoimmune Diseases (immunology, pathology)
• Bile Ducts, Intrahepatic (immunology, pathology)
• CD40 Antigens (analysis)
• Cells, Cultured
• Chemokines (metabolism)
• Chemotaxis
• Epithelial Cells (pathology)
• Female
• HLA-DR Antigens (analysis)
• Humans
• Leukocytes, Mononuclear (immunology)
• Liver (immunology, pathology)
• Liver Cirrhosis, Biliary (immunology, pathology)
• Male
• Toll-Like Receptors (agonists, metabolism)