title: A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects.
abstract: The multifunctional, protein cross-linking transglutaminase 2 (TG2) is the main autoantigen in celiac disease, an autoimmune disorder with defined etiology. Glutamine-rich gliadin peptides from ingested cereals, after their deamidation by TG2, induce T-lymphocyte activation accompanied by autoantibody production against TG2 in 1-2% of the population. The pathogenic role and exact binding properties of these antibodies to TG2 are still unclear. Here we show that antibodies from different celiac patients target the same conformational TG2 epitope formed by spatially close amino acids of adjacent domains. Glu153 and 154 on the first alpha-helix of the core domain and Arg19 on first alpha-helix of the N-terminal domain determine the celiac epitope that is accessible both in the closed and open conformation of TG2 and dependent on the relative position of these helices. Met659 on the C-terminal domain also can cooperate in antibody binding. This composite epitope is disease-specific, recognized by antibodies derived from celiac tissues and associated with biological effects when passively transferred from celiac mothers into their newborns. These findings suggest that celiac antibodies are produced in a surface-specific way for which certain homology of the central glutamic acid residues of the TG2 epitope with deamidated gliadin peptides could be a structural basis. Monoclonal mouse antibodies with partially overlapping epitope specificity released celiac antibodies from patient tissues and antagonized their harmful effects in cell culture experiments. Such antibodies or similar specific competitors will be useful in further functional studies and in exploring whether interference with celiac antibody actions leads to therapeutic benefits.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Nagyerdei krt 98, Debrecen H-4032, Hungary.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Simon-Vecsei
authors.forename: Róbert
authors.initials: R
authors.lastname: Király
authors.forename: Péter
authors.initials: P
authors.lastname: Bagossi
authors.forename: Boglárka
authors.initials: B
authors.lastname: Tóth
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dahlbom
authors.forename: Sergio
authors.initials: S
authors.lastname: Caja
authors.forename: Éva
authors.initials: É
authors.lastname: Csosz
authors.forename: Katri
authors.initials: K
authors.lastname: Lindfors
authors.forename: Daniele
authors.initials: D
authors.lastname: Sblattero
authors.forename: Éva
authors.initials: É
authors.lastname: Nemes
authors.forename: Markku
authors.initials: M
authors.lastname: Mäki
authors.forename: László
authors.initials: L
authors.lastname: Fésüs
authors.forename: Ilma R
authors.initials: IR
authors.lastname: Korponay-Szabó
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D002446:Celiac Disease / Q000276:immunology*; D002478:Cells, Cultured; D003461:Crystallography; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005903:Gliadin / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation; D051379:Mice; D008958:Models, Molecular; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013601:T-Lymphocytes / Q000276:immunology; D011503:Transglutaminases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D005903:Gliadin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins