Madcam–1 Expressed in Chronic Inflammatory Liver Disease Supports Mucosal Lymphocyte Adhesion to Hepatic Endothelium (Madcam–1 in Chronic Inflammatory Liver Disease)

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Abstract
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 α4β7+ 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, α4β7, or the integrin α4 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–α4β7 mAbs. These findings indicate that, under certain circumstances, vessels in the human liver support adhesion of α4β7+ 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.

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