Hepatic Endothelial CCL25 Mediates the Recruitment of CCR9+ Gut-homing Lymphocytes to the Liver in Primary Sclerosing Cholangitis

Abstract

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 α4β7 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.

Phenotype and Effector Function of CC Chemokine Receptor 9-Expressing Lymphocytes in Small Intestinal Crohn’s Disease

“…A previous study has also reported the aberrant expression of CCL25 in the liver in patients with primary sclerosing cholangitis. CCL25 could trigger adhesion of liver-infiltrating lymphocytes that expressed CCR9 to immobilized MAdCAM-1 in vitro, establishing a link between IBD and primary sclerosing cholangitis through CCR9 ϩ T cell-mediated inflammation (23). In this study, we demonstrate that CCL25 triggers the adhesion of CD SB LPL and MLN lymphocytes to VCAM-1/Fc in vitro.…”

Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury

“…CCR2 and CCR9 are thought to be involved in the migration and accumulation of immune cells in the liver. 18,19 Migration of the clones in response to CCR4 and CCR9 ligands demonstrated that the receptor expression was functionally relevant. In contrast to our previous studies with clones from patients with anticonvulsant-induced cutaneous eruptions, [20][21][22] the skin homing lymphocyte receptors CCR10 and CLA were detected at low levels.…”

“…They were reconstituted in ammonium bicarbonate buffer (50 mM), digested with trypsin overnight at 37 C, and then desalted using C 18 ZipTips (Millipore). Samples (2.4-5 pmole) were delivered into a QTRAP 5500 hybrid quadrupole-linear ion trap mass spectrometer (ABSciex) by automated in-line liquid chromatography (U3000 HPLC System, 5 mm C18 nano-precolumn, and 75 lm  15 cm C 18 PepMap column [Dionex, Sunnyvale, CA]) by way of a 10-lm inner diameter PicoTip (New Objective, Woburn, MA). A gradient from 2% ACN/0.1% FA (v/v) to 50% ACN/0.1% FA (v/v) in 70 minutes was applied at a flow rate of 280 nL/min.…”

Genes and (auto)immunity in primary biliary cirrhosis

“…Further, a process similar to that recently observed for a closely related disease such as primary sclerosing cholangitis should be verified in PBC. 136 …”