Patients on a gluten free diet showed IgA titres not distinguishable from the titres of healthy controls (data not shown). catalysed modifications were not restricted to single gliadin types and epitopes. Furthermore, haptenisation CHM 1 and long term immobilisation of gliadin peptides by tTG catalysed binding to abundant extracellular matrix proteins could be instrumental in the perpetuation of intestinal inflammation and some associated autoimmune diseases in coeliac disease. strong class=”kwd-title” Keywords: coeliac disease, collagens, tissue transglutaminase Several years ago gliadins were identified as the aetiological agent of coeliac disease.1,2 Gliadins are the alcohol soluble fraction of gluten, the storage proteins of wheat, which are characterised by a high content of glutamine and proline residues. Gliadins have been classified into the major fractions , , and gliadins, and subdivided into their subcomponents 1C11 1C6, 1C3, and 5.3,4 Gliadin toxicity was confirmed in several studies, with the main focus on the amino terminal region of A\gliadin, a major component of \gliadin.5,6,7,8,9 Later, short peptides from \ and \gliadins, which stimulate intestinal T cells from coeliac patients, were identified. The peptides bind to human leucocyte antigen (HLA)\DQ2 or \DQ8, a necessary precondition for the development of coeliac disease. Binding of these peptides to HLA\DQ2 or \DQ8 and the resultant T cell stimulation is potentiated when distinct glutamine residues are deamidated by tissue transglutaminase (tTG),10,11,12,13,14,15,16,17 the autoantigen in coeliac disease.18 tTG is an ubiquitous cellular enzyme that is upregulated CHM 1 in wound healing, angiogenesis, and Rabbit Polyclonal to SLC39A1 apoptosis where its main function is cross linking of proteins via creation of stable isopeptide bonds between a donor glutamine residue and an acceptor lysine residue.19 However, a low pH favours tTG catalysed deamidation of donor glutamines instead of its incorporation into an isopeptid bond. Of particular interest is the finding that the glutamine\rich gliadins are excellent donor substrates for the otherwise highly substrate specific tTG.20 The amino acid composition around glutamine residues was shown to be critical for the reactivity of tTG with the gliadin peptides as their positional change or substitution in these peptides can enhance or abolish HLA binding and T cell CHM 1 reactivity.13,14,17,21 Evidence for the involvement of all gliadins in the pathogenesis of coeliac disease has been derived from the presence of antibodies against \, \22,23 and \gliadins,24 and from the damaging potential of \gliadins.25,26 Recent reports described immune response to glutenins, which differ in structure from gliadins and which are insoluble in aqueous alcohol.27,28,29 The heterogeneity in the T cell stimulatory properties of various gliadin or glutenin peptides in childhood and adult patients gave rise to the hypothesis that the early immune response CHM 1 in coeliacs is directed towards several gliadin and glutenin peptides, while longstanding inflammation favours a few immunodominant gliadin peptides, preferentially deamidated by tTG and thus binding more tightly to HLA\DQ2 and \DQ8.28,29,30 To date, the catalytic activity of tTG for the different gliadins has not been compared. Furthermore, while tTG mediated deamidation of distinct peptides from \ and \gliadins was described in detail,10,11,12,13,14,15,16,17 no information on the nature of complexes between gliadins and tTG, and between gliadins and extracellular matrix components in the small intestine is available. Here we demonstrate that all investigated gliadins are good substrates for tTG. In addition, gliadin peptides can react with tTG, resulting in gliadin\tTG cross link and complex formation. Furthermore, tTG catalyses the binding of gliadin peptides to interstitial collagen types I, III, and VI, which suggests the generation of complex neoepitopes and long term immobilisation of pathogenic.