Gastroenterology

Gastroenterology

Volume 122, Issue 7, June 2002, Pages 1729-1737
Gastroenterology

Clinical Research
The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides,☆☆

https://doi.org/10.1053/gast.2002.33606Get rights and content

Abstract

Background & Aims: Gluten (GLU)-specific T-cell responses in HLA-DQ2 positive adult celiac disease (CD) patients are directed to an immunodominant α-gliadin (GLIA) peptide that requires deamidation for T-cell recognition. The aim of the current study was to determine which GLU peptide(s) are involved early in disease. Methods: We have characterized the GLU-specific T-cell response in HLA-DQ2 positive children with recent onset CD. Results: We found that 50% of these patients do not respond to the α-GLIA peptide but to a diverse set of GLIA and glutenin (GLT) peptides, including 6 novel epitopes. Moreover, individual patients respond to distinct (combinations of) GLU peptides. T-cell cross-reactivity toward homologous GLIA and GLT peptides was observed, which might play a role in the initial spreading of the GLU-specific T-cell response. Although all pediatric patients displayed deamidation-dependent responses, deamidation-independent responses were found in the majority of patients as well. Finally, T-cell responses to 3 of these novel GLU peptides were found in adult CD patients. Conclusions: The diversity of the GLU-specific T-cell response is far greater than was previously appreciated. Both adult and young CD patients can respond to a diverse repertoire of GLU peptides. The observation that T-cell responses to 3 of the novel peptides are independent of deamidation indicates that T-cell responses can be initiated toward native GLU peptides. The possibility that deamidation drives the GLU response toward immunodominant T-cell stimulatory peptides after disease initiation is discussed.

GASTROENTEROLOGY 2002;122:1729-1737

Section snippets

Children with CD

Twenty-six white CD patients were included in the present study. Their age at diagnosis (first small bowel biopsy) was between 1 and 12 years old (average age 4.0 years ± 2.5; 1 year old, 4 patients; 2 years old, 3 patients; 3 years old, 9 patients; 4 years old, 6 patients; 6 years old, 2 patients; 9 years old, 1 patient; 12 years old, 1 patient). In addition, biopsies of 4 adult CD patients were obtained. Only DQ2 (DQA1*0501/DQB1*02) positive patients with a confirmed diagnosis of CD have been

Establishment of GLU-specific T-cell lines from pediatric CD patients

T-cell biopsies were collected from young patients that were suspected of CD as indicated by typical clinical symptoms and/or a positive anti-endomysium test. Individual biopsies were cultured with either a trypsin/pepsin digest of GLU (termed GLU hereafter) or the same preparation that had additionally been treated with tTG (termed tTG-GLU hereafter). After 5 days, IL-2 was added and cultures that showed evidence of T-cell proliferation were expanded and tested for specificity in a

Discussion

It is generally accepted that CD is caused by uncontrolled T-cell responses to GLU peptides that are presented by HLA-DQ2 and/or -DQ8 molecules. In recent years, 5 GLU peptides have been identified that stimulate TCCs derived from small intestinal biopsies of CD patients.12, 13, 15, 16, 18 An important breakthrough has been the demonstration that deamidation of the GLU peptides by the enzyme tTG is either required for, or enhances, T-cell recognition of 4 of these peptides.12, 13, 14, 15, 16, 17

Acknowledgements

The authors thank Drs. C. Csizmadia and J. Schweizer for generous help in obtaining patient samples and Drs. B.O. Roep and R.R.P. de Vries for critically reading the manuscript.

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Address requests for reprints to: Frits Koning, Ph.D., Department of Immunohematology and Blood Transfusion, E3-Q, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. e-mail: [email protected]; fax: (31) 71-5216751.

☆☆

Supported by the European Community project no. BMH CT-98, a grant from the Dutch Digestive Disease Foundation (WS 98-24) and the University of Leiden.

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