Celiac disease is a pathologic immune reaction to ingested gluten proteins of wheat,rye and barley.In subjects with genetic predisposition,gluten-derived gliadin peptides induce chronic intestinal inflammation,jejunal villous atrophy and a conditional autoimmune process which targets several organs,Transglutaminase 2 (TG2) is the main autoantigen in celiac disease that affects 1% of Caucasians.The autoantibodies,particularly those of IgA class,are currently central in the medical diagnostic workup and therapy monitoring of the disease.Their presence correlates with gluten consumption and disease activity,and they also were shown to bind to the patients own TG2 antigen within diseased tissues.We have observed that celiac autoantibodies typically bind to a discontinuous epitope formed on TG2 by spatially close amino acids of adjacent domains.Core domain and N-terminal domain amino acid side chains determine the celiac epitope which is accessible both in closed and open conformation of the protein.The epitope is unique for celiac disease,since TG2-specific antibodies from patients with other autoimmune diseases prefer dissimilar binding sites.This disease-specific epitope has been seen with serum,tissue-deposited and passively transferred antibodies causing biological effects in newborns.Monoclonal mouse antibodies with partially overlapping epitope specificity released celiac antibodies from patient tissues and did not cause similar biological effects as celiac antibodies in vitro.Such antibodies could be suitable for antibody-based immunotherapy of celiac disease.