Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease.
Molberg O. Mcadam SN. Korner R. Quarsten H. Kristiansen C. Madsen L. Fugger L. Scott H. Noren O. Roepstorff P. Lundin KE. Sjostrom H. Sollid LM.
Institute of Transplantation Immunology, Rikshospitalet, University of Oslo, Norway.
The action of tissue Transglutaminase (TGase) on specific protein-bound glutamine residues plays a critical role in numerous biological processes. Here we provide evidence for a new role of this enzyme in the common, HLA-DQ2 (and DQ8) associated enteropathy, celiac disease (CD). The intestinal inflammation in CD is precipitated by exposure to wheat gliadin in the diet and is associated with increased mucosal activity of TGase. This enzyme has also been identified as the main target for CD-associated anti-endomysium autoantibodies, and is known to accept gliadin as one of its few substrates. We have examined the possibility that TGase could be involved in modulating the reactivity of gliadin specific T cells. This could establish a link between previous reports of the role of TGase in CD and the prevailing view of CD as a T-cell mediated disorder. We found a specific effect of TGase on T-cell recognition of gliadin. This effect was limited to gliadin-specific T cells isolated from intestinal CD lesions. We demonstrate that TGase mediates its effect through an ordered and specific deamidation of gliadins. This deamidation creates an epitope that binds efficiently to DQ2 and is recognized by gut-derived T cells. Generation of epitopes by enzymatic modification is a new mechanism that may be relevant for breaking of tolerance and initiation of autoimmune disease.
Hepatic failure and liver cell damage in acute Wilsons disease involve CD95 (APO-1/Fas) mediated apoptosis.
Strand S. Hofmann WJ. Grambihler A. Hug H. Volkmann M. Otto G. Wesch H. Mariani SM. Hack V. Stremmel W. Krammer PH. Galle PR.
University Hospital, Department of Gastroenterology, Heidelberg, FRG.
Wilson's disease can result in fulminant liver failure due to hepatic copper overload. The CD95 system mediates apoptosis and has been demonstrated to be involved in liver disease. In this study CD95 mediated apoptosis was investigated in patients with fulminant hepatic failure in the course of Wilson's disease and in an in vitro model of copper treated human hepatoma cells. In patients, hepatic expression of CD95 and CD95L mRNA and apoptosis were detected. Copper overload in vitro resulted in hepatocytic apoptosis which could be reduced with a neutralizing anti-CD95L antibody. Copper treatment of hepatocytes results in activation of the CD95 system and induction of apoptosis which is operative during the course of hepatic failure in acute Wilson's disease.