Gastroenterology

Gastroenterology

Volume 123, Issue 3, September 2002, Pages 803-809
Gastroenterology

Basic–Alimentary Tract
Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues,☆☆,

https://doi.org/10.1053/gast.2002.35381Get rights and content

Abstract

Background & Aims: Celiac disease is a gluten-induced enteropathy that shows a strong association with HLA-DQ2 and -DQ8. Gluten-specific T cells, invariably restricted by DQ2 or DQ8, can be isolated from celiac lesions. Such gut-derived T cells have a preference for recognition of gluten that has been specifically deamidated by tissue transglutaminase. Only a few gliadin T-cell epitopes have been identified by earlier work. The aim of this study was to perform a systematic characterization of DQ2-restricted T-cell epitopes in α- and γ-gliadins. Methods: Epitopes were identified by mass spectrometry analysis of peptide fragments of recombinant gliadins and by use of synthetic peptides. Results: We identified several new γ-gliadin epitopes and an additional α-gliadin epitope. Interestingly, these and the previously identified epitopes are not randomly scattered across the gliadins but cluster in regions of the proteins with high content of proline residues. Conclusions: Several DQ2-restricted T-cell epitopes exist in gliadin that are located in regions rich in proline. This likely reflects epitope selection at the levels of digestive and antigen-presenting cell processing, transglutaminase-mediated deamidation, and/or peptide binding to DQ2.

GASTROENTEROLOGY 2002;123:803-809

Section snippets

Subjects

Nine Norwegian adult patients with celiac disease were included in the study, which was approved by the regional ethical committee. Patients CD411 and CD467 were untreated, whereas patients CD370, CD380, CD423, CD429, CD430, CD432, and CD450 were on a gluten-free diet. All subjects expressed the disease-associated DQ2 molecule encoded by DQA1*05/DQB1*02 alleles.

Amplification, cloning, and production of recombinant gliadins

By polymerase chain reaction amplification of genomic DNA isolated from the wheat strain Mjølner using γ-gliadin specific primers,11 a

Identification of 3 new DQ2-restricted T-cell epitopes in a recombinant γ-gliadin

Five individual recombinant γ-gliadins, which all contained the previously identified DQ2-γ-I and DQ2-γ-II epitopes (Table 1), were expressed in E. coli. To identify new epitopes present in the recombinant γ-gliadins, we chose a T-cell line (TCL) from patient CD411 (TCL 411E) that responded to all the tTG-treated recombinant gliadin proteins (γ-1 to γ-5) but not to the DQ2-γ-I and DQ2-γ-II epitopes. TCCs made from this TCL were used to identify positive fractions following purification of a

Discussion

An understanding of which T-cell epitopes are recognized in celiac disease and the processes leading to their selection should identify potential therapeutic targets for this disease and shed light onto the mechanisms responsible for the observed associations between HLA and disease. We previously identified 2 overlapping DQ2-restricted intestinal T-cell epitopes in α-gliadin that both contain multiple proline residues, and both require deamidation by tTG.7 Although these 2 α-gliadin epitopes

Acknowledgements

The authors thank Marie Kongshaug Johannesen, Eva Boretti, and Nicole Sessler for excellent technical assistance as well as the patients with celiac disease who donated biological material for this study.

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    Address requests for reprints to: Ludvig M. Sollid, M.D., Institute of Immunology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway. e-mail: [email protected]; fax: (47) 230 73822.

    ☆☆

    Supported by research grants from the Research Council of Norway, the European Commission (BMH4-CT98-3087, QLRT-2000-00657, QLGA-CT-2000-51218), the Norwegian Foundation for Health and Rehabilitation, and the Deutsche Forschungsgemeinschaft (SFB 510, project D4).

    H.A.-H. and S.N.M. contributed equally to this study.

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