MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).
Mucosal addressin cell adhesion molecule (MAdCAM-1) plays a pivotal role in T-lymphocyte homing to the gut. Given the strong association between the autoimmune liver diseases primary sclerosing cholangitis and autoimmune hepatitis and inflammatory bowel disease, we investigated the role of MAdCAM-1 in recruiting mucosal lymphocytes to the liver. MAdCAM-1 was strongly expressed on inflamed portal vein/sinusoidal endothelium in autoimmune mediated liver disease. In modified Stamper-Woodruff assays, MAdCAM-1 on hepatic vessels supported adhesion of alpha4beta7+ lymphocytes (i.e., gut-derived T cells) from patients with inflammatory bowel disease and primary sclerosing cholangitis. This adhesion was inhibited by pretreatment with blocking antibodies to MAdCAM-1, alpha4beta7, or the integrin alpha4 chain indicating that MAdCAM-1 in inflamed liver is functionally active. Circulating lymphocytes from patients with primary sclerosing cholangitis showed rolling adhesion on MAdCAM-1 transfectants in a flow-based adhesion assay that could be blocked by anti-MAdCAM-1 or anti-alpha4beta7 mAbs. These findings indicate that, under certain circumstances, vessels in the human liver support adhesion of alpha4beta7+ mucosal lymphocytes via binding to aberrantly expressed MAdCAM-1 on liver endothelium. This provides a mechanism to explain the hepatic recruitment of mucosal lymphocytes in inflammatory liver disease complicating inflammatory bowel disease.
Grant
A J
AJ
MRC Centre for Immune Regulation, Liver Research Laboratories, Queen Elizabeth Hospital, Birmingham, UK. A.J.Grant@bham.ac.uk
Lalor
P F
PF
Hübscher
S G
SG
Briskin
M
M
Adams
D H
DH
D001773:Blood Cells / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules; D015209:Cholangitis, Sclerosing / Q000473:pathology / Q000503:physiopathology; D002908:Chronic Disease; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D006505:Hepatitis / Q000503:physiopathology*; D006801:Humans; D007136:Immunoglobulins / Q000502:physiology*; D015212:Inflammatory Bowel Diseases / Q000473:pathology / Q000503:physiopathology; D016023:Integrins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology / Q000503:physiopathology*; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008214:Lymphocytes / Q000502:physiology*; D009088:Mucoproteins / Q000502:physiology*
D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D016023:Integrins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; C071777:integrin alpha4beta7