TISSUE TRANSGLUTAMINASE SELECTIVELY MODIFIES GLIADIN PEPTIDES THAT ARE RECOGNIZED BY GUT-DERIVED T-CELLS IN CELIAC-DISEASE

The action of tissue Transglutaminase(1) (TGase) on specific protein-b ound glutamine residues plays a critical role in numerous biological p rocesses(2-5). Here we provide evidence for a new role of this enzyme in the common, HLA-DQ2 (and DQ8) associated(6) enteropathy, celiac dis ease (CD). The intestinal inflammation in CD is precipitated by exposu re to wheat gliadin in the diet(7) and is associated with increased mu cosal activity of TGase(8). This enzyme has also been identified as th e main target for CD-associated anti-endomysium autoantibodies(9), and is known to accept gliadin as one of its few substrates(10). We have examined the possibility that TGase could be involved in modulating th e 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(7,11,12). We found a specifi c ef feet of TGase on T-cell recognition of gliadin. This effect was l imited 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 cell s. Generation of epitopes by enzymatic modification is a new mechanism that may be relevant for breaking of tolerance and initiation of auto immune disease.