Projects per year
Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) all nestle within the umbrella term of autoimmune liver disease, in which the end result is immune-mediated hepatocellular or hepatobiliary injury. All three conditions are associated with gut inflammation; PSC and AIH being strongly linked to inflammatory bowel disease (IBD) and PBC to coeliac disease. This clinical observation has stimulated several intriguing pathogenic concepts in which gut commensals, pathogens and intestinal antigens are all implicated in causing liver injury. Th17-cells have also been linked to AIH, PBC and more recently PSC. Given that the intestine is a key regulator of immunopathogenic Th17 responses, this may underpin a common disease mechanism and open up novel treatment avenues based on rational targeting of immune pathways. Moreover, the discovery of long-lived mucosal memory T-cells being recruited to the liver in response to aberrantly expressed endothelial-cell adhesion molecules and chemokines, which are normally 'gut-restricted,' could plausibly explain why these diseases are associated with site-restricted tissue distributions and pave the way for therapeutic strategies based on modulating tissue specific lymphocyte homing. That particular gene-polymorphisms have been found which confer combined PSC/IBD susceptibility underscores the fundamental role of mucosal immunogenicity in disease pathogenesis. Mucosal lymphocytes may also play a pivotal role in graft versus host disease affecting the liver, and there is increasing evidence to support dysregulated mucosal immunity as being responsible for the hepatic manifestations of gluten-sensitive enteropathy, graft versus host disease, as wells as the pancreatobiliary manifestations of IgG4-related disease.
Bibliographical noteCopyright © 2013 Elsevier Ltd. All rights reserved.
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- 1 Finished
Adams, D. & Wakelam, M.
15/01/04 → 31/03/07
Project: Research Councils