Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease

Molberg, Øyvind; McAdam, Stephen N.; Körner, Roman; Quarsten, Hanne; Kristiansen, Christel; Madsen, Lars Siim; Fugger, Lars; Scott, Helge; Norén, Ove; Roepstorff, Peter; Lundin, Knut E.A.; Sjöström, Hans; Sollid, Ludvig M.

doi:10.1038/nm0698-713

Cited by 1,061 publications

(785 citation statements)

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“…Moreover, tTG selectively deamidates gliadin peptides, leading to a strongly enhanced T-cell-stimulatory activity. 13 Epidemiological studies, performed by accurate serological screening in the general population, have radically changed our knowledge about CD prevalence, showing that the disease occurs worldwide much more frequently than previously thought (Table 1). [14][15][16][17][18][19][20][21] The highest reported prevalence is in Europe: 1 in 99 in Finland, 1 in 122 in Northern Ireland and 1 in 175 people in Italy.…”

Section: Introductionmentioning

confidence: 99%

Celiac disease: diagnostic criteria in progress

2011

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Until a few years ago, celiac disease (CD) was thought to be a rare food intolerance that was confined to childhood and characterized by severe malabsorption and flat intestinal mucosa. Currently, CD is regarded as an autoimmune disorder that is common in the general population (affecting 1 in 100 individuals), with possible onset at any age and with many possible presentations. The identification of CD is challenging because it can begin not only with diarrhea and weight loss but also with atypical gastrointestinal (constipation and recurrent abdominal pain) and extra-intestinal symptoms (anemia, raised transaminases, osteoporosis, recurrent miscarriages, aphthous stomatitis and associated autoimmune disorders), or it could be completely symptomless. Over the last 20 years, the diagnostic accuracy of serology for CD has progressively increased with the development of highly reliable tests, such as the detection of IgA tissue transglutaminase and antiendomysial and IgG antideamidated gliadin peptide antibodies. The routine use of antibody markers has allowed researchers to discover a very high number of 'borderline' cases, characterized by positive serology and mild intestinal lesions or normal small intestine architecture, which can be classified as potential CD. Therefore, it is evident that the 'old celiac disease' with flat mucosa is only a part of the spectrum of CD. It is possible that serology could identify CD in its early stages, before the appearance of severe intestinal damage. In cases with a positive serology but with mild or absent intestinal lesions, the detection of HLA-DQ2 and HLA-DQ8 can help reinforce or exclude the diagnosis of gluten sensitivity.

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Section: Introductionmentioning

confidence: 99%

Celiac disease: diagnostic criteria in progress

2011

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“…These complexes are recognized by gluten-specific T cells isolated from small intestinal tissue of coeliac disease patients. 7,8 Most of the DQ2-negative patients express the HLA-DQ8 molecule, which is also capable of binding gluten-derived peptides with subsequent activation of gluten-specific T cells. 7 The heterodimeric DQ2 protein is encoded by the HLA-DQA1*05 and HLA-DQB1*02 alleles, in either the cis or the trans configuration.…”

Section: Introductionmentioning

confidence: 99%

Defining the contribution of the HLA region to cis DQ2-positive coeliac disease patients

et al. 2004

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The major genetic susceptibility to coeliac disease is contributed by the human leukocyte antigen (HLA) region. The primary association is with the HLA-DQ2 molecule, encoded by the DQA1*05 and DQB1*02 alleles, which is expressed by over 90% of patients. The aim of our study was to perform an extensive scan of the entire HLA region to determine whether there is evidence for the presence of additional HLA susceptibility genes for coeliac disease in the Dutch population, acting independently of DQ2. In all, 16 microsatellite markers and the DQA1 and DQB1 genes were genotyped in simplex cis DQ2-positive coeliac disease families and cis DQ2-positive control families. Allele frequencies of markers on phase-known DQ2-positive haplotypes transmitted to patients were compared to a combined group of DQ2-positive nontransmitted and control haplotypes, thereby controlling for the DQ2 contribution. No significant differences at any of the marker loci were detected, suggesting that DQ2 is the major HLA risk factor for coeliac disease. Individuals homozygous for DQ2 or heterozygous for DQA1*05-DQB1*02/DQA1*0201-DQB1*02 were found to be at five-fold increased risk for development of coeliac disease (Po10 À8 ). This risk seems to be conferred by the presence of a second DQB1*02 allele next to one DQA1*05-DQB1*02 haplotype, independently of the second DQA1 allele.

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“…19 The recent identification of tTG as the main autoantigen recognized by EMA 22 has lead to the development of various studies that suggest an important role for this enzyme in the etiopathogenesis of CD. 23,24 Several methods have been proposed for the detection of humoral anti-tTG immunoreactivity in CD. 20,[25][26][27] The most sensitive assays to detect tTG-Abs were those using human recombinant tTG in a fluid-phase radioimmunoassay (RIA) format.…”

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confidence: 99%

Tissue transglutaminase autoantibody detection in human saliva: a powerful method for celiac disease screening

Bonamico

Ferri

Nenna

et al. 2004

The Journal of Pediatrics

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Objective To test the possibility of detecting tissue transglutaminase autoantibodies (tTG-Abs) in saliva with a novel sensitive fluid-phase radioimmunoassay (RIA).Study design Paired saliva and serum samples from 39 patients with celiac disease (CD), at the first biopsy (Group 1: 28 females, mean age 11.5 ± 11.1 years); 32 controls with a normal duodenal mucosa (Group 2: 18 females, mean age 8.1 ± 3.6 years); and 32 healthy volunteers (Group 3: 21 females, mean age 31.7 ± 9.8 years) were studied for tTG-Ab presence. Limit of positivity for salivary assay was calculated according to the 99th percentiles of Group 2 control children and was expressed as an autoantibody (Ab) index.Results Salivary tTG-Abs were found in 97.4% of the patients with CD and in 100% of the corresponding serum samples. All Group 3 subjects were negative with both saliva and serum assays. A correlation between saliva and serum tTG-Ab titers was found (r = 0.826, P = .0014).Conclusions This study demonstrates that it is possible to detect salivary tTG-Abs in CD with a non-invasive, simple to perform, reproducible and sensitive method. (J Pediatr 2004;144:632-6) C eliac disease (CD) may appear in a classic presentation, with gastrointestinal complaints and growth failure or with extraintestinal manifestations and ''atypical forms'' 1 characterized by anemia and short stature, 2,3 or with a silent form, more frequent in first-degree relatives of patients with CD. 4 The prevalence of CD is increased in subjects with elevated aminotransferase levels, 5,6 autoimmune diseases, 7,8 and chromosomal aberrations. 9,10 Complications of long-standing CD may include osteopathy, 11 endocrinopathy, 12 infertility, low birth weight infants, 13,14 cancer, 15 and dilated cardiomyopathy and other forms of heart failure. 16 CD has a high prevalence in the general population (0.55% in Italy), often in an asymptomatic form. 17 To reduce the risks associated with prolonged gluten exposure, CD should be diagnosed early, on the basis of the result of one or more intestinal biopsies. 18 Patients with CD receiving a gluten-containing diet have increased levels of anti-gliadin (AGA), anti-endomysium (EMA), 19 and anti-tissue transglutaminase autoantibodies (anti-tTG-Ab). 20 Serum AGA have proved to be effective in the identification of children at risk for CD, but less so in adult screening. 21 EMA are more specific than AGA but are observer-dependent, and sometimes they are not found in children with CD younger than aged 2 years. 19 The recent identification of tTG as the main autoantigen recognized by EMA 22 has lead to the development of various studies that suggest an important role for this enzyme in the etiopathogenesis of CD. 23,24 Several methods have been proposed for the detection of humoral anti-tTG immunoreactivity in CD. 20,[25][26][27] The most sensitive assays to detect tTG-Abs were those using human recombinant tTG in a fluid-phase radioimmunoassay (RIA) format. 26,27 Attempts have been made in assaying CD-related Ab in saliva, [28][29][30][31][32][...

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Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease

Cited by 1,061 publications

References 30 publications

Celiac disease: diagnostic criteria in progress

Celiac disease: diagnostic criteria in progress

Defining the contribution of the HLA region to cis DQ2-positive coeliac disease patients

Tissue transglutaminase autoantibody detection in human saliva: a powerful method for celiac disease screening

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