title: Specificity of tissue transglutaminase explains cereal toxicity in celiac disease.
abstract: Celiac disease is caused by a selective lack of T cell tolerance for gluten. It is known that the enzyme tissue transglutaminase (tTG) is involved in the generation of T cell stimulatory gluten peptides through deamidation of glutamine, the most abundant amino acid in gluten. Only particular glutamine residues, however, are modified by tTG. Here we provide evidence that the spacing between glutamine and proline, the second most abundant amino acid in gluten, plays an essential role in the specificity of deamidation. On the basis of this, algorithms were designed and used to successfully predict novel T cell stimulatory peptides in gluten. Strikingly, these algorithms identified many similar peptides in the gluten-like hordeins from barley and secalins from rye but not in the avenins from oats. The avenins contain significantly lower percentages of proline residues, which offers a likely explanation for the lack of toxicity of oats. Thus, the unique amino acid composition of gluten and related proteins in barley and rye favors the generation of toxic T cell stimulatory gluten peptides by tTG. This provides a rationale for the observation that celiac disease patients are intolerant to these cereal proteins but not to other common food proteins.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, 2300 RC Leiden, Netherlands.
authors.forename: L Willemijn
authors.initials: LW
authors.lastname: Vader
authors.forename: Arnoud
authors.initials: A
authors.lastname: de Ru
authors.forename: Yvonne
authors.initials: Y
authors.lastname: van der Wal
authors.forename: Yvonne M C
authors.initials: YM
authors.lastname: Kooy
authors.forename: Willemien
authors.initials: W
authors.lastname: Benckhuijsen
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Mearin
authors.forename: Jan Wouter
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Peter
authors.initials: P
authors.lastname: van Veelen
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000201:enzymology / Q000209:etiology*; D002460:Cell Line; D002523:Edible Grain / Q000276:immunology*; D005903:Gliadin / Q000276:immunology; D005983:Glutens / Q000737:chemistry / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D011503:Transglutaminases / Q000502:physiology*
chemical_list: D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D005983:Glutens; D005903:Gliadin; D011503:Transglutaminases