Serodiagnostic Assays for Celiac Disease Based on the Open or Closed Conformation of the Autoantigen, Transglutaminase 2 Katri Lindfors & Outi Koskinen & Kalle Kurppa & Kaija Laurila & Pekka Collin & Katri Haimila & Jukka Partanen & Päivi Saavalainen & Markku Mäki & Katri Kaukinen Received: 14 January 2011 /Accepted: 21 February 2011 /Published online: 9 March 2011 # Springer Science+Business Media, LLC 2011 Abstract The autoantigen of celiac disease, transglutaminase 2 (TG2), adopts an open conformation during enzymatic activation. We studied diagnostic accuracy of serodiagnostic assays using TG2 in its open and closed conformation as antigens in patients with diagnostic difficulties. The open TG2 antibody (TG2ab) test identified 93% of untreated celiac patients in contrast to 44%, 27%, and 68% detected by closed and conventional TG2ab and endomysial antibody (EmA) tests, respectively. The assay was able to detect 60% of non- responding celiac patients seronegative for conventional TG2ab and EmA. The titers of the openTG2abs were higher than those of the closed TG2abs. The serological test utilizing TG2 in an open conformation was more accurate than the other assays in finding active celiac disease even in patients having negative or borderline conventional celiac autoanti- bodies and in revealing poor dietary response non-invasively. It thus offers a promising tool in the diagnostics and follow-up of celiac disease. Keywords Celiac disease . gluten . transglutaminase 2 . open conformation . diagnostic accuracy Introduction In a subgroup of genetically predisposed individuals carrying the human leukocyte antigen (HLA) DQ2 and DQ8 mole- cules, the ingestion of wheat-, rye-, and barley-derived gluten prolamins causes an abnormal immune reaction called celiac disease. This disorder is characterized by small-bowel mucosal villous atrophy, crypt hyperplasia, and the presence of serum immunoglobulin class A endomysial autoantibodies targeted against a multifunctional protein, transglutaminase 2 (TG2) [1]. It is widely accepted that TG2 is the major, if not sole, autoantigen in celiac disease and plays a central role in the disease pathogenesis [2]. The celiac disease autoantigen TG2 is a ubiquitously expressed protein found in different cellular compartments and with a multitude of functions. In the cytosol, TG2 functions mainly as a G-protein and in the cell surface as a co-receptor involved in adhesion [3]. In the extracellular environment, it acts as an enzyme promoting the cross- linking of extracellular matrix proteins by catalyzing the transamidation of glutamine residues to lysine, resulting in proteolytically resistant ε-(γ-glutamyl)lysine isopeptide bonds [3]. Extracellular TG2 is catalytically inactive under normal physiological conditions [4] but upon enzymatic activation, for instance in response to tissue injury, TG2 is K. Lindfors : O. Koskinen : K. Kurppa : K. Laurila : M. Mäki Pediatric Research Center, University of Tampere and Tampere University Hospital, Tampere, Finland P. Collin : K. Kaukinen Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland P. Collin : K. Kaukinen (*) School of Medicine, University of Tampere, Finn-Medi 3, FIN-33014, Tampere, Finland e-mail: katri.kaukinen@uta.fi K. Haimila : J. Partanen Finnish Red Cross Blood Service, Helsinki, Finland P. Saavalainen Department of Medical Genetics and Research Program for Molecular Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland J Clin Immunol (2011) 31:436–442 DOI 10.1007/s10875-011-9514-x