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


CONCLUSIONS
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.
Shimoda
Shinji
S
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. sshimoda@intmed1.med.kyushu-u.ac.jp
Harada
Kenichi
K
Niiro
Hiroaki
H
Yoshizumi
Tomoharu
T
Soejima
Yuji
Y
Taketomi
Akinobu
A
Maehara
Yoshihiko
Y
Tsuneyama
Koichi
K
Nakamura
Minoru
M
Komori
Atsumasa
A
Migita
Kiyoshi
K
Nakanuma
Yasuni
Y
Ishibashi
Hiromi
H
Selmi
Carlo
C
Gershwin
M Eric
ME
D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000276:immunology* / Q000473:pathology; D019013:CD40 Antigens / Q000032:analysis; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000473:pathology; D008297:Male; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism
D019013:CD40 Antigens; D018925:Chemokines; D006684:HLA-DR Antigens; D051193:Toll-Like Receptors