T-Cell Response to Gluten in Patients With HLA-DQ2.2 Reveals Requirement of Peptide-MHC Stability in Celiac Disease

Bodd, Michael; Kim, Chu‐Young; Lundin, Knut E.A.; Sollid, Ludvig M.

doi:10.1053/j.gastro.2011.11.021

Cited by 87 publications

(84 citation statements)

References 28 publications

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“…We have previously found that the DQ2.2-glut-L1 epitope binds stably to DQ2.2 as tested in a T cell assay (7). We wanted to test whether this was the case for the two novel DQ2.2 epitopes as well.…”

Section: Identification Of Novel T Cell Epitopes Among Dq22-enrichedmentioning

confidence: 98%

“…T cell lines (TCL) were generated from intestinal biopsies (7,25) that were obtained from CD patients: CD555 (DQA1*02:01/DQB*02, DQA1*03:02/DQB*03:03), CD594 (DQA1*02/DQB1*02), CD627 (DQA1*02:01/DQB1*02:02, DQA1*03:02/DQB1*05:03), and CD1005 (DQA1*02:01/DQB02:02, DQA1*01:01/05:01). TCLs were subsequently tested in proliferative T cell assays.…”

Section: T Cell Testingmentioning

confidence: 99%

“…One potential avenue could be to harness the disease-associated MHC molecules themselves and use them as affinity matrix to identify disease-relevant T cell epitopes. CD offers an opportunity to explore this approach, as distinct epitopes of the causative Ag gluten are recognized by lesion-resident CD4 + T cells in the context of disease-associated HLA-DQ molecules (7,8). Given the extreme complexity of gluten, the model of CD would not be much different from a situation when mixtures of multiple Ags would be used.…”

mentioning

confidence: 99%

“…The gluten T cell epitopes presented by DQ2.5 are fairly well characterized (12). Less is known about the gluten epitopes presented by DQ8 or DQ2.2, and only one DQ2.2 T cell epitope is known (7,12). Typically the gluten peptides that are recognized by T cells of CD patients are posttranslationally modified (13,14).…”

mentioning

confidence: 99%

“…Of 86 DQ2.2-binding gluten peptides, four core sequences were found to dominate. One of these core sequences is a previously known epitope (7). Two of the other core sequences were found to represent novel T cell epitopes by testing T cells of the intestinal CD lesions.…”

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confidence: 99%

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HLA-DQ Molecules as Affinity Matrix for Identification of Gluten T Cell Epitopes

Dørum

Bodd

Fallang

et al. 2014

The Journal of Immunology

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Even though MHC class II is a dominant susceptibility factor for many diseases, culprit T cell epitopes presented by disease-associated MHC molecules remain largely elusive. T cells of celiac disease lesions recognize cereal gluten epitopes presented by the disease-associated HLA molecules DQ2.5, DQ2.2, or DQ8. Employing celiac disease and complex gluten Ag digests as a model, we tested the feasibility of using DQ2.5 and DQ2.2 as an affinity matrix for identification of disease-relevant T cell epitopes. Known gluten T cell epitope peptides were enriched by DQ2.5, whereas a different set of peptides was enriched by DQ2.2. Of 86 DQ2.2-enriched peptides, four core sequences dominated. One of these core sequences is a previously known epitope and two others are novel epitopes. The study provides insight into the selection of gluten epitopes by DQ2.2. Furthermore, the approach presented is relevant for epitope identification in other MHC class II–associated disorders.

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Section: Identification Of Novel T Cell Epitopes Among Dq22-enrichedmentioning

confidence: 98%

Section: T Cell Testingmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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HLA-DQ Molecules as Affinity Matrix for Identification of Gluten T Cell Epitopes

Dørum

Bodd

Fallang

et al. 2014

The Journal of Immunology

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Direct cloning and tetramer staining to measure the frequency of intestinal gluten‐reactive T cells in celiac disease

et al. 2013

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Knowledge of the frequency of disease-driving CD4 + T cells in lesions of chronic human inflammatory diseases is limited. In celiac disease (CD), intestinal gluten-reactive CD4+ T cells, which recognize gluten peptides only in the context of the disease-associated HLA-DQ molecules, are key pathogenic players. By cloning CD4 + T cells directly from intestinal biopsies of CD patients, we found that 0.5-1.8% of CD4 + T cells were gluten reactive. About half of the gluten-reactive T cells were specific for either the immunodominant DQ2.5-glia-α1a or DQ2.5-glia-α2 epitopes, suggesting that direct visualization of gluten-specific T cells could be possible. Assessed by flow cytometry, tetramer-positive T cells were present in 10/10 untreated CD patients with a frequency of 0.1-1.2% of CD4 + T cells. Gluten-specific T cells were also detectable in most treated CD patients (7/10). Moreover, the frequency of gluten-specific T cells correlated with the degree of histological damage in the gut mucosa as scored by Marsh-grading, and also with serum IgA anti-transglutaminase 2 antibody levels. Tetramer staining of gluten-reactive T cells in biopsy material is a useful tool for future studies of such cells in CD and could also potentially serve as a diagnostic supplement in selected cases. Keywords: Celiac disease r Frequency r Gluten-specific T cells r TetramerAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionCeliac disease (CD) is a chronic inflammatory disease of the small intestine triggered by gluten proteins from wheat, barley, and ryeCorrespondence: Dr. Melinda Ráki e-mail: melinda.raki@rr-research.no [1]. The only available treatment for CD is a lifelong gluten-free diet. CD is a multifactorial, polygenic disease, and the HLA locus is by far the single most important genetic risk factor [2]. The great majority of CD patients express the HLA class II molecule * These authors contributed equally to this work. Many of these T cells recognize either the α gliadin epitope DQ2.5-gliaα1a or DQ2.5-glia-α2 [9,10]. Importantly, deamidation of specific glutamine residues to glutamate by the enzyme transglutaminase 2 (TG2) increases the T-cell stimulatory capacity of most gluten epitopes [10][11][12]. CD provides a unique opportunity to study CD4 + T cells recognizing the disease-driving antigen (gluten) at the site of inflammation. The development of MHC-peptide multimers has greatly facilitated the detection of antigen-specific T cells [13]. Glutenspecific T cells can be visualized in the peripheral blood of CD patients undergoing a short gluten challenge by using DQ2.5-glia-α1a and DQ2.5-glia-α2 tetramers [14]. However, isolation of gluten-reactive T cells from the intestinal lesion still requires long term in vitro culturing. It is becoming increasingly evident that the phenotype of CD4 + T cells is plastic [15]. Studying freshly isolated T cells will therefore be important to accurately characterize these T cells.The frequency of antigen-specific CD4 +...

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Frequency of HLA‐DQ, susceptibility genotypes for celiac disease, in Brazilian newborns

Almeida

Gandolfi

Costa

et al. 2018

Molec Gen & Gen Med

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BackgroundThe frequency of HLA‐DQ2 and DQ8 predisposing genotypes for celiac disease (CD) has shown significant variation among different world regions and has not been previously determined among the highly interbred Brazilian population. The aim of this study was to investigate the frequency of these genotypes among Brazilian newborns (NB).MethodsWe typed DQA1*05 ‐ DQB1*02 (DQ2.5) and DQA1*03 ‐ DQB1*03:02 (DQ8) alleles in 329 NB using qPCR technique. Subsequently we confirmed our results by PCR‐SSP using a reference kit which further identified DQ2.2 (DQA1*02:01 ‐ DQB1*02).ResultsAmong the 329 NB, using qPCR technique: 5 (1.52%) carried both DQ2.5 and DQ8 variants; 58 (17.63%) carried only DQ2.5 (DQA1*05 and DQB1*02) and 47 (14.29%) carried only the DQ8 (DQA1*03 and DQB1*03:02) variant. The use of the PCR‐SSP method yielded further information; among the 329 samples: 34 (10.34%) tested positive for DQ2.2 and among the 47 previously DQ8 positives samples, we found 10 (3.04%) that also tested positives for DQ2.2.Conclusion43.7% of the analyzed individual tested positive for at least one of the CD predisposing HLA‐DQ genotypes in our group of Brazilian NB. The highest frequency was found for DQ2.5 positive subjects (17.6%) followed by DQ8 (11.3%); DQ2.2 (10.3%); DQ8 and DQ2.2 (3.0%); DQ2.5 and DQ8 (1.5%). We found no positive sample for DQ2.5 associated with DQ2.2.

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T-Cell Response to Gluten in Patients With HLA-DQ2.2 Reveals Requirement of Peptide-MHC Stability in Celiac Disease

Cited by 87 publications

References 28 publications

HLA-DQ Molecules as Affinity Matrix for Identification of Gluten T Cell Epitopes

HLA-DQ Molecules as Affinity Matrix for Identification of Gluten T Cell Epitopes

Direct cloning and tetramer staining to measure the frequency of intestinal gluten‐reactive T cells in celiac disease

Frequency of HLA‐DQ, susceptibility genotypes for celiac disease, in Brazilian newborns

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