Lymphocyte homing in the pathogenesis of extra-intestinal manifestations of inflammatory bowel disease

Abstract

-Inflammatory bowel disease is associated with extra-intestinal manifestations which occur either at the same time as flares of bowel inflammation (skin and eye disease) or run a course that is independent to inflammation in the bowel (liver and some joint syndromes). It has been suggested that the skin and eye complications occur as a consequence of the recruitment of activated effector cells released from the gut into the circulation to extra-intestinal site where they cause acute damage. However, this does not explain how patients can develop primary sclerosing cholangitis many years after having their colon removed for colitis. We propose that longlived populations of memory lymphocytes arise as a consequence of bowel inflammation and that these cells express homing receptors that direct their subsequent migration not only to the gut but also to the liver. These long-lived cells may recirculate to the liver for many years and, in the absence of a local activating stimulus, will not cause damage. However, if they are subsequently activated in the liver this will lead to the development of inflammation and tissue damage which promotes the recruitment of more mucosal lymphocytes resulting in persistent inflammation and disease. The recent findings that MAdCAM-1 and CCL25, previously thought to be restricted to the gut, are up-regulated in the liver during inflammatory liver diseases that complicate IBD support the concept that common mechanisms control lymphocyte recruitment to the inflamed liver and gut.

Regulation of dextran sodium sulfate induced colitis by leukocyte beta 2 integrins

“…33,34 Much effort has been focused on determining specific molecular mechanisms responsible for immune cell mediated tissue damage during colitis. Several reports have previously identified leukocyte and endothelial cell adhesion molecules as potentially important regulators of leukocyte recruitment in human IBD and experimental colitis.…”

Rapid and preferential distribution of blood‐borne αCD3εAb to the liver is followed by local stimulation of T cells and natural killer T cells

“…Such an inability of the liver to control activation of memory/ effector T cells is particularly interesting in situations where these T cells are recruited to the liver and have been shown to produce local organ damage. 32,33 However, cytokines released from NKT and T cells after a single application of aCD3eAb did not lead to local inflammation in the liver, because no alanine aminotransferase increase or histological evidence of liver damage was observed (data not shown). However, local release of cytokines exerted antiviral effects in the liver.…”

Current research on the treatment of primary sclerosing cholangitis

“…It has been previously shown that the liverinfiltrating lymphocytes in PSC include mucosal T cells recruited to the liver by aberrant expression of the gutspecific chemokine CCL25 that activates α4/β7 binding to MAdCAM-1 on the hepatic endothelium (63,68). Therefore, targeting the CCL25-MAdCAM-1 axis could be of therapeutic benefit in PSC.…”

“…M u c o s a l a d r e s s i n c e l l a d h e s i o n m o l e c u l e 1 (MAdCAM-1), an endothelial cell adhesion molecule, is expressed in high amounts in the gut of patients with IBD and those with IBD and PSC (62)(63)(64)(65). Vascular adhesion protein 1 (VAP-1) has been found to induce the expression of MAdCAM-1 in the hepatic endothelial cells of human liver tissue (66).…”