Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis.
Primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease characterized by progressive bile duct destruction, develops as an extra-intestinal complication of inflammatory bowel disease (IBD) (Chapman, R.W. 1991. Gut. 32:1433-1435). However, the liver and bowel inflammation are rarely concomitant, and PSC can develop in patients whose colons have been removed previously. We hypothesized that PSC is mediated by long-lived memory T cells originally activated in the gut, but able to mediate extra-intestinal inflammation in the absence of active IBD (Grant, A.J., P.F. Lalor, M. Salmi, S. Jalkanen, and D.H. Adams. 2002. Lancet. 359:150-157). In support of this, we show that liver-infiltrating lymphocytes in PSC include mucosal T cells recruited to the liver by aberrant expression of the gut-specific chemokine CCL25 that activates alpha4beta7 binding to mucosal addressin cell adhesion molecule 1 on the hepatic endothelium. This is the first demonstration in humans that T cells activated in the gut can be recruited to an extra-intestinal site of disease and provides a paradigm to explain the pathogenesis of extra-intestinal complications of IBD.
Eksteen
Bertus
B
Liver Research Laboratories, Institute for Biomedical Research, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TT, England, UK.
Grant
Allister J
AJ
Miles
Alice
A
Curbishley
Stuart M
SM
Lalor
Patricia F
PF
Hübscher
Stefan G
SG
Briskin
Michael
M
Salmon
Mike
M
Adams
David H
DH
D002465:Cell Movement; D019742:Chemokines, CC / Q000502:physiology*; D015209:Cholangitis, Sclerosing / Q000209:etiology*; D004727:Endothelium / Q000502:physiology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications; D007422:Intestines / Q000473:pathology*; D008099:Liver / Q000473:pathology*; D008214:Lymphocytes / Q000502:physiology*; D054388:Receptors, CCR; D019707:Receptors, Chemokine / Q000032:analysis / Q000502:physiology*
C119309:CC chemokine receptor 9; C108074:CCL25 protein, human; D019742:Chemokines, CC; D054388:Receptors, CCR; D019707:Receptors, Chemokine