Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 200, Issue 11, Pages 1511-1517Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20041035
Keywords
chemokines; integrins; inflammation; hepatitis; colitis
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Funding
- MRC [G84/6524] Funding Source: UKRI
- Medical Research Council [G84/6524] Funding Source: researchfish
- Medical Research Council [G84/6524] Funding Source: Medline
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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 I 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.
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