Intestinal T-cell responses to high-molecular-weight glutenins in celiac disease

Molberg, Øyvind; Flaete, Nina Solheim; Jensen, Tore; Lundin, Knut E.A.; Arentz‐Hansen, Helene; Anderson, Olin D.; Uhlen, Anne Kjersti; Sollid, Ludvig M.

doi:10.1016/s0016-5085(03)00890-4

Cited by 128 publications

(87 citation statements)

References 24 publications

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“…However, SDS volumes of these five lines are still comparable with those of the medium-quality bread wheat. Glutenin proteins can also elicit T-cell responses in CD patients (11,34,35); however, their stimulatory capacity is far less than the gliadin proteins (11). The transgenic lines produced here will not be completely devoid of sequences stimulatory to T cells of CD patients, because they contain small amounts of gliadin proteins as well as glutenin proteins.…”

Section: Discussionmentioning

confidence: 96%

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Effective shutdown in the expression of celiac disease-related wheat gliadin T-cell epitopes by RNA interference

Gil-Humanes

Pistón

Tollefsen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

175

189

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Celiac disease (CD) is an enteropathy triggered by the ingestion of gluten proteins from wheat and similar proteins from barley and rye. The inflammatory reaction is controlled by T cells that recognize gluten peptides in the context of human leukocyte antigen (HLA) DQ2 or HLA-DQ8 molecules. The only available treatment for the disease is a lifelong gluten-exclusion diet. We have used RNAi to down-regulate the expression of gliadins in bread wheat. A set of hairpin constructs were designed and expressed in the endosperm of bread wheat. The expression of gliadins was strongly down-regulated in the transgenic lines. Total gluten protein was extracted from transgenic lines and tested for ability to stimulate four different T-cell clones derived from the intestinal lesion of CD patients and specific for the DQ2-α-II, DQ2-γ-VII, DQ8-α-I, and DQ8-γ-I epitopes. For five of the transgenic lines, there was a 1.5-2 log reduction in the amount of the DQ2-α-II and DQ2-γ-VII epitopes and at least 1 log reduction in the amount of the DQ8-α-I and DQ8-γ-I epitopes. Furthermore, transgenic lines were also tested with two T-cell lines that are reactive with ω-gliadin epitopes. The total gluten extracts were unable to elicit T-cell responses for three of the transgenic wheat lines, and there were reduced responses for six of the transgenic lines. This work shows that the down-regulation of gliadins by RNAi can be used to obtain wheat lines with very low levels of toxicity for CD patients.RNAi | post-transcriptional gene silencing | gluten intolerance | celiac sprue

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Section: Discussionmentioning

confidence: 96%

“…These epitopes are generally very rich in proline and glutamine residues (10). Although a number of epitopes are derived from glutenins (11), the majority of the epitopes reside in the gliadin fraction (10,12). Wheat gliadin genes occur in tightly linked clusters, termed blocks, located at complex loci on group 1 and 6 chromosomes.…”

mentioning

confidence: 99%

Effective shutdown in the expression of celiac disease-related wheat gliadin T-cell epitopes by RNA interference

Gil-Humanes

Pistón

Tollefsen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

175

189

View full text Add to dashboard Cite

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“…Separate, single biopsy specimens were challenged with chymotrypsin-treated gluten (0.2 mg/ml) or the overlapping M36999 ␥-gliadin peptides (10 M of each peptide) (14). T-cell cloning and T-cell proliferation assays were performed as described previously (14,15). T-cell reactivity was tested in 3-day proliferative restimulation assays by the incorporation of [ 3 H]thymidine during the final 24 h. T-cell lines that showed reactivity for TG2-treated gluten presented via DQ2.3 were isolated from five out of six DQ8/DQ2.5 heterozygote patients.…”

Section: Gluten-specific T-cells and T-cell Proliferation Assay-t-cellmentioning

confidence: 99%

Structural and Functional Studies of trans-Encoded HLA-DQ2.3 (DQA103:01/DQB102:01) Protein Molecule

Tollefsen

Hotta

Chen

et al. 2012

Journal of Biological Chemistry

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Background: trans-Encoded HLA-DQ molecules are biologically interesting, but no structures of such molecules exist. Results: X-ray crystal structure of the trans-encoded DQ2.3 (DQA1*03:01/DQB1*02:01) was determined. Structural data are presented together with functional T-cell data. Conclusion: DQ2.3 has preference for negative charged anchors at P1 and P4. Significance: This work helps to understand why DQ2.3 is associated with a particular risk for type 1 diabetes.

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“…Although the disease-activating proteins in these grains are widely termed "gluten" (and for simplicity are referred to here in quotation marks), strictly speaking, gluten only encompasses the diseaseactivating proteins in wheat. Gluten includes 2 major protein types, the gliadins and glutenins, both of which contain disease-activating peptides (7)(8)(9). The closely related proteins in barley and rye that activate CD are the hordeins and secalins, respectively (10)(11)(12).…”

Section: The Role Of Dietary Proteins In Disease Pathogenesis CD Is mentioning

confidence: 99%

Celiac disease: pathogenesis of a model immunogenetic disease

Kagnoff¹

2007

J. Clin. Invest.

333

238

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Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. Although celiac disease is predicted by screening studies to affect approximately 1% of the population of the United States and is seen both in children and in adults, 10%-15% or fewer of these individuals have been diagnosed and treated. This article focuses on the role of adaptive and innate immune mechanisms in the pathogenesis of celiac disease and how current concepts of immunopathogenesis might provide alternative approaches for treating celiac disease.

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Intestinal T-cell responses to high-molecular-weight glutenins in celiac disease

Cited by 128 publications

References 24 publications

Effective shutdown in the expression of celiac disease-related wheat gliadin T-cell epitopes by RNA interference

Effective shutdown in the expression of celiac disease-related wheat gliadin T-cell epitopes by RNA interference

Structural and Functional Studies of trans-Encoded HLA-DQ2.3 (DQA103:01/DQB102:01) Protein Molecule

Celiac disease: pathogenesis of a model immunogenetic disease

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Intestinal T-cell responses to high-molecular-weight glutenins in celiac disease

Cited by 128 publications

References 24 publications

Effective shutdown in the expression of celiac disease-related wheat gliadin T-cell epitopes by RNA interference

Effective shutdown in the expression of celiac disease-related wheat gliadin T-cell epitopes by RNA interference

Structural and Functional Studies of trans-Encoded HLA-DQ2.3 (DQA1*03:01/DQB1*02:01) Protein Molecule

Celiac disease: pathogenesis of a model immunogenetic disease

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Resources

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Structural and Functional Studies of trans-Encoded HLA-DQ2.3 (DQA103:01/DQB102:01) Protein Molecule