IMMUNOLOGICAL DETECTION OF TISSUE TRANSGLUTAMINASE AUTOANTIBODIES IN COELIAC DISEASE
Satu SulkanenKaija LaurilaK‐L KolhoAnnikki SarnestoT. HalttunenIlma R. Korponay–SzabóErkki SavilahtiPekka CollinMarkku Mäki
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Tissue transglutaminase
So far the reliability of the anti-tissue transglutaminase (anti-tTG) test for the diagnosis of coeliac disease has mostly been evaluated using slightly different enzyme-linked immunosorbent assays (ELISAs) in selected and usually small groups of patients. The aims of this study were: (1) to evaluate the reliability of the IgA anti-tTG antibodies for the diagnosis of coeliac disease; and (2) to define the sensitivity and specificity of a commercially available kit for the anti-tTG antibodies' quantitative determination.Each centre in this international multi-centre study collected sera from three groups of subjects: coeliac disease patients at the onset of (1) or on a gluten-free diet for at least 12 months (2); disease and healthy controls (3).The anti-tTG antibodies were determined in duplicate using an ELISA-based commercially available kit (Eu-tTG Eurospital, Trieste, Italy).The following overall cases and controls have been enrolled: (1) 399 subjects with active coeliac disease; (2) 351 treated coeliac disease cases; (3) 432 controls. The centralized re-testing was performed on: (1) group a: 176 patients with active coeliac disease (mean anti-tTG, 21 arbitrary units [AU]); (2) group b: 172 treated coeliac disease cases (mean anti-tTG, 5 AU); (3) group c: 206 controls (mean anti-tTG, 3 AU). In active coeliacs, the anti-tTG antibodies showed a significant progressive decrease with age, while in controls an opposite trend was found. In active coeliac disease patients, the anti-tTG antibodies were significantly higher in coeliacs with a grade III enteropathy than in those showing a grade II lesion. In treated coeliacs, the mean anti-tTG values were significantly lower in patients strictly adhering to a gluten-free diet than in those reporting dietary transgressions. The sensitivity and the specificity of the Eu-tTG assay were 90% and 96%, respectively.The results of this study show that the commercially available test for the anti-tTG antibodies' determination is a reproducible and valuable tool for the diagnosis and follow up of coeliac disease.
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Celiac disease (CD) is an intestinal malabsorption characterized by intolerance to cereal proteins accompanied by immunological responses to dietary gliadins and tissue transglutaminase, an autoantigen located in the endomysium. Tissue transglutaminase belongs to the family of enzymes that catalyze protein cross-linking reactions and is constitutively expressed in many tissues as well as being activated during apoptosis. The role of gliadins in eliciting the immune response in CD and how transglutaminase is linked to the primary reaction are still unclear. In this work, we report the production and analysis of six phage Ab libraries from the peripheral and intestinal lymphocytes of three CD patients. We were able to isolate Abs to transglutaminase from all intestinal lymphocytes libraries but not from those obtained from peripheral lymphocytes. This is in contrast to Abs against gliadin, which could be obtained from all libraries, indicating that the humoral response against transglutaminase occurs at the local level, whereas that against gliadin occurs both peripherally and centrally. Abs from all three patients recognized the same transglutaminase epitopes with a bias toward the use of the V(H)5 Ab variable region family. The possible role of these anti-transglutaminase Abs in the onset of CD and associated autoimmune pathologies is discussed.
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Tissue transglutaminase is the major autoantigen recognized in the sera of coeliac patients. An enzyme-linked immune-adsorbed assay based on tissue transglutaminase was recently used to measure serum tissue transglutaminase immunoglobulins A for coeliac disease diagnosis.To determine the sensitivity, the specificity, the positive and negative predictive values of an immunoenzymatic assay based on guinea pig tissue transglutaminase, to compare antititransglutaminase immunoenzymatic assay to the antiendomysium immunofluorescent assay, and to define a cost-effective sequence to execute serum antibody determination in coeliac patients.We assessed for coeliac disease antibodies 91 pediatric patients with symptoms suggestive of coeliac disease, and 23 patients with coeliac disease on a gluten-free diet as controls.Antitransglutaminase immunoglobulins A showed 93.1% sensitivity, 93.6% specificity, 87.1% positive and 96.7% negative predictive values. Antitransglutaminase immunoglobulins A were significantly higher in antiendomysium positive subjects. Correlation between antitransglutaminase immunoglobulins A and antigliadin immunoglobulins A was not significant.Our results show that antitransglutaminase immunoenzymatic assay represents a cost-effective strategy for patients' serological evaluation and it could substitute EMA determination, which could be considered a second level evaluation.
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To evaluate whether anti-endomysial and anti-transglutaminase antibodies are relevant important markers of coeliac disease in an historical group of patient sera.Sera from 196 children suspected to suffer from coeliac disease were analysed for these antibodies.A total of 233 serum samples were obtained simultaneously with a biopsy. Coeliac disease was confirmed in 37 (19%) patients. Antibodies against guinea pig transglutaminase were determined by enzyme-linked immunosorbent assay (ELISA); endomysial antibodies were determined by immunofluorescence.In 17 samples, immunoglobulin A (IgA) anti-transglutaminase levels were increased; 16 of these came from coeliac patients. High levels correlated with high prediagnostic or challenge-related gluten intake. The additional anti-transglutaminase-positive patient was assumed to suffer from sequelae to gastroenteritis.Raised IgA anti-transglutaminase levels were correlated with presence of coeliac disease. Negative tests were seen in some coeliac patients when on a gluten-containing diet. The IgA anti-transglutaminase test using guinea pig antigen was less sensitive than anti-endomysial antibodies but rather specific for active coeliac disease. In our study, anti-endomysial antibodies were more specific than anti-transglutaminase antibodies for active coeliac disease.
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In view of the high diagnostic accuracy of immunoglobulin-A-tissue transglutaminase antibodies for detecting coeliac disease, we have explored whether a small bowel biopsy is always required to establish the diagnosis.To define the transglutaminase antibody level giving a positive predictive value for coeliac disease of 100% and to subsequently assess the proportion of new diagnoses of coeliac disease having such a result.The Celikey kit (Phadia GmbH, Frieburg, Germany) was used to measure transglutaminase antibody levels.All patients with transglutaminase antibody levels >30 U/mL, i.e. 10 x upper limit of normal in 2002/2003 had characteristic small bowel mucosal lesions. In a subsequent audit, 58% of 112 new diagnoses of coeliac disease in 2004/2005 had levels above this cut-off value.We have shown that a transglutaminase antibody level can be defined which gives a positive predictive value of 100% for coeliac disease. From published data, these observations can be extended to most second-generation transglutaminase antibody kits. Our data provide further evidence that diagnostic guidelines could be modified so that small bowel biopsy is no longer regarded as mandatory in patients with such high transglutaminase antibody levels. This will avoid an invasive procedure and lead to a more rapid diagnosis and earlier treatment for over half of the new patients with coeliac disease.
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This study was done to evaluate the diagnostic utility of antibodies against deamidated gliadin peptides compared to traditional markers for coeliac disease.To evaluate diagnostic utility of antibodies against deamidated gliadin peptide (DGP).Sera from 176 adults, referred for endoscopy without previous analysis of antibodies against tissue transglutaminase (tTG) or endomysium (EmA), were retrospectively analysed by ELISAs detecting IgA/IgG antibodies against DGP or a mixture of DGP and tTG, and compared with IgA-tTG and EmA. Seventy-nine individuals were diagnosed with coeliac disease.Receiver operating characteristic analyses verified the manufacturers' cut-off limits except for IgA/IgG-DGP/tTG. In sera without IgA deficiency, the sensitivity was higher for IgA/IgG-DGP (0.85-0.87) compared with IgA-tTg (0.76) and EmA (0.61). All tests showed high specificity (0.95-1.00). Eighteen coeliac disease-sera were negative regarding IgA-tTG, nine of which were positive for IgA/IgG-DGP. Sera from coeliac disease-patients >70 years were more often negative for IgA-tTG (50%) and IgA/IgG-DGP (36%) than younger patients (15% and 8% respectively) (P < 0.01). Three of the four IgA-deficient patients were positive in the IgA/IgG-DGP assay.In this study of patients unselected regarding IgA-tTg/EmA, thus unbiased in this respect, IgA/IgG-DGP identified adult coeliac disease patients negative for antibodies against endomysium and tissue transglutaminase. Serology is often negative in elderly patients with coeliac disease; a small bowel biopsy should therefore be performed generously before coeliac disease is excluded.
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