title: Autoantibodies from patients with celiac disease inhibit transglutaminase 2 binding to heparin/heparan sulfate and interfere with intestinal epithelial cell adhesion.
abstract: Autoantibodies from patients with celiac disease (CD) can influence transglutaminase 2 (TG2) activity and its cellular functions, but the exact mechanisms have remained unknown. Our objective was to study whether autoantibodies could modulate TG2 binding to heparin/heparan sulfate (HS) and intestinal epithelial cell attachment to fibronectin-TG2 matrix. Anti-TG2 antibodies were purified by TG2 affinity chromatography from sera of patients with active CD. Serum and antibody effects on TG2 binding to heparin/HS, on transamidase activity of TG2, as well as on Caco-2 cell attachment to fibronectin-TG2 matrix were assessed using microplate assays. Both sera and purified anti-TG2 antibodies from CD patients with high anti-TG2 IgA levels reduced TG2 binding to heparin/HS as compared with those with low anti-TG2 IgA or controls. There was a negative correlation between anti-TG2 IgA levels and TG2 binding to heparin/HS. Treatment of fibronectin-TG2 coated wells with CD patients' sera or purified anti-TG2 antibodies reduced attachment of Caco-2 cells onto the plate as compared with the control samples. The effect of CD patients' antibodies on Caco-2 cell attachment to fibronectin-TG2 matrix occurred independently of the inhibition of cell adhesion by Arg-Gly-Asp sequence containing peptides. Anti-TG2 autoantibodies had no effect on transamidase activity of TG2 in vitro. We suggest that modulation of adhesion function of TG2 by autoantibodies from patients with CD could be related to the inhibition of TG2 binding to HS residues of cell surface proteoglycans and could have possible implications for CD pathogenesis.
authors.affiliation: Immunology Group, Department of General and Molecular Pathology, University of Tartu, Ravila 19, 50411, Tartu, Estonia. kaupo.teesalu@ut.ee
authors.forename: Kaupo
authors.initials: K
authors.lastname: Teesalu
authors.forename: Marina
authors.initials: M
authors.lastname: Panarina
authors.forename: Oivi
authors.initials: O
authors.lastname: Uibo
authors.forename: Raivo
authors.initials: R
authors.lastname: Uibo
authors.forename: Meeme
authors.initials: M
authors.lastname: Utt
mesh_terms: D001323:Autoantibodies / Q000276:immunology* / Q000302:isolation & purification; D015153:Blotting, Western; D018938:Caco-2 Cells; D002446:Celiac Disease / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology*; D002846:Chromatography, Affinity; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology*; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D019204:GTP-Binding Proteins; D006493:Heparin; D006497:Heparan Sulfate; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases