Mucosal lymphocytes in the pathogenesis of the hepatic complications of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is associated with extraintestinal manifestations which occur either at the same time as bowel inflammation (joint, skin and eye) or run an independent course (autoimmune hepatitis and primary sclerosing cholangitis (PSC)). It has been suggested that eye, skin and joint manifestations are driven by the trapping of gut-derived effector cells in capillaries in these sites; however, this cannot explain the liver diseases that develop when bowel inflammation is quiescent or even after colectomy.1,2 This led us to propose that long-lived memory lymphocytes that arise as a consequence of bowel inflammation express homing receptors that direct their subsequent migration not only to the gut but also the liver.3 Such cells could recirculate between the liver and gut without causing damage for many years but if they subsequently encounter an antigen in the liver this could result in their activation and the promotion of tissue damage and disease. This could explain how a patient can develop liver disease many years after their IBD has become quiescent. In order to prove the hypothesis we needed to: • demonstrate that lymphocytes in the liver of patients with PSC were originally activated in the gut • provide a mechanism to explain how these cells are recruited to the liver • show that they are critical for disease pathogenesis. Over the last nine years we have answered the first two questions and thus the hypothesis is still valid.4 When lymphocytes are activated by dendritic cells (DC) in gut-associated lymphoid tissues (GALT) they are not only programmed to respond to antigen but are also imprinted with a homing phenotype which directs their subsequent trafficking back to the gut.5 After antigen has been cleared, a population of long-lived memory cells remain that retain gut tropism and thereby provide immune surveillance against the same pathogen entering the gut in the future. The molecular basis of this tissuespecific homing has recently been elucidated. Lymphocytes are recruited into tissues from the blood by sequential interactions with adhesion molecules and chemotactic cytokines called chemokines presented on the endothelium lining the vessels in the target tissue. Adhesion molecules allow lymphocytes with an appropriate receptor to recognise and bind the endothelium and chemokines can then direct migration through the endothelium CURRENT KEY DEVELOPMENTS Roger Williams