title: Transglutaminase 2-specific autoantibodies in celiac disease target clustered, N-terminal epitopes not displayed on the surface of cells.
abstract: The gluten-sensitive enteropathy celiac disease is tightly associated with the production of autoantibodies specific for the enzyme transglutaminase 2 (TG2). The mechanisms underlying the activation of autoreactive B cells, however, are not well defined. To gain more insight into this autoimmune response we have characterized the binding of TG2 by a panel of human mAbs generated by expression cloning of Ig genes from single plasma cells of the celiac disease lesion. The Abs were highly specific to TG2 and bound preferentially to the open, Ca(2+)-activated enzyme conformation. Epitope mapping revealed that they recognize few distinct conformational epitopes that cluster in the N-terminal half of the enzyme. Two of the epitopes were overlapping with the fibronectin binding site in TG2, and none of the epitopes was accessible when TG2 was in a cell surface-bound form. Based on our findings, we propose that the autoantibodies are generated against the soluble, catalytically active enzyme, whereas Abs reactive with cell surface-associated TG2 are absent from the response due to negative selection of B cells recognizing membrane-bound self-Ag. The findings give insight into the mechanisms controlling the formation of anti-TG2 autoantibodies in celiac disease.
authors.affiliation: Centre for Immune Regulation, University of Oslo and Oslo University Hospital, N-0372 Oslo, Norway.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Iversen
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Niro
authors.forename: Jorunn
authors.initials: J
authors.lastname: Stamnaes
authors.forename: Knut E A
authors.initials: KE
authors.lastname: Lundin
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
authors.forename: Ludvig M
authors.initials: LM
authors.lastname: Sollid
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D002446:Celiac Disease / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000737:chemistry / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D018985:Epitopes, B-Lymphocyte; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins