Diversity in oat potential immunogenicity: basis for the selection of oat varieties with no toxicity in coeliac disease

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Abstract

Background and aims

Coeliac disease (CD) is triggered by an abnormal reaction to gluten. Peptides resulting from partially digested gluten of wheat, barley or rye cause inflammation of the small intestinal mucosa. Previous contradictory studies suggest that oats may trigger the abnormal immunological response in patients with CD. Monoclonal antibodies (moAbs) against the main immunotoxic 33-mer peptide (A1 and G12) react strongly against wheat, barley and rye but have less reactivity against oats. The stated aim of this study is to test whether this observed reactivity could be related to the potential toxicity of oats for patients with CD.

Methods

In the present study, different oat varieties, controlled for their purity and by their distinct protein pattern, were used to examine differences in moAb G12 recognition by ELISA and western blot. Immunogenicity of oat varieties was determined by 33-mer concentration, T cell proliferation and interferon γ production.

Results

Three groups of oat cultivars reacting differently against moAb G12 could be distinguished: a group with considerable affinity, a group showing slight reactivity and a third with no detectable reactivity. The immunogenicity of the three types of oats as well as that of a positive and negative control was determined with isolated peripheral blood mononuclear T cells from patients with CD by measurement of cell proliferation and interferon γ release. A direct correlation of the reactivity with G12 and the immunogenicity of the different prolamins was observed.

Conclusions

The results showed that the reactivity of the moAb G12 is proportional to the potential immunotoxicity of the cereal cultivar. These differences may explain the different clinical responses observed in patients suffering from CD and open up a means to identify immunologically safe oat cultivars, which could be used to enrich a gluten-free diet.

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Most cited references 16

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Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue.

Lu Shan, Shuo-Wang Qiao, Helene Arentz-Hansen … (2015)

Dietary gluten proteins from wheat, rye, and barley are the primary triggers for the immuno-pathogenesis of Celiac Sprue, a widespread immune disease of the small intestine. Recent molecular and structural analyses of representative gluten proteins, most notably alpha- and gamma-gliadin proteins from wheat, have improved our understanding of these pathogenic mechanisms. In particular, based on the properties of a 33-mer peptide, generated from alpha-gliadin under physiological conditions, a link between digestive resistance and inflammatory character of gluten has been proposed. Here, we report three lines of investigation in support of this hypothesis. First, biochemical and immunological analysis of deletion mutants of alpha-2 gliadin confirmed that the DQ2 restricted T cell response to the alpha-2 gliadin are directed toward the epitopes clustered within the 33-mer. Second, proteolytic analysis of a representative gamma-gliadin led to the identification of another multivalent 26-mer peptide that was also resistant to further gastric, pancreatic and intestinal brush border degradation, and was a good substrate of human transglutaminase 2 (TG2). Analogous to the 33-mer, the synthetic 26-mer peptide displayed markedly enhanced T cell antigenicity compared to monovalent control peptides. Finally, in silico analysis of the gluten proteome led to the identification of at least 60 putative peptides that share the common characteristics of the 33-mer and the 26-mer peptides. Together, these results highlight the pivotal role of physiologically generated, proteolytically stable, TG2-reactive, multivalent peptides in the immune response to dietary gluten in Celiac Sprue patients. Prolyl endopeptidase treatment was shown to abolish the antigenicity of both the 33-mer and the 26-mer peptides, and was also predicted to have comparable effects on other proline-rich putatively immunotoxic peptides identified from other polypeptides within the gluten proteome.

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A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease.

Carlo Catassi, Carmela Cinzia D’Agate, Temístocles Ítalo de Santana … (2006)

Treatment of celiac disease (CD) is based on the avoidance of gluten-containing food. However, it is not known whether trace amounts of gluten are harmful to treated patients. The objective was to establish the safety threshold of prolonged exposure to trace amounts of gluten (ie, contaminating gluten). This was a multicenter, double-blind, placebo-controlled, randomized trial in 49 adults with biopsy-proven CD who were being treated with a gluten-free diet (GFD) for > or =2 y. The background daily gluten intake was maintained at < 5 mg. After a baseline evaluation (t0), patients were assigned to ingest daily for 90 d a capsule containing 0, 10, or 50 mg gluten. Clinical, serologic, and histologic evaluations of the small intestine were performed at t0 and after the gluten microchallenge (t1). At t0, the median villous height/crypt depth (Vh/Cd) in the small-intestinal mucosa was significantly lower and the intraepithelial lymphocyte (IEL) count (x 100 enterocytes) significantly higher in the CD patients (Vh/Cd: 2.20; 95% CI: 2.11, 2.89; IEL: 27; 95% CI: 23, 34) than in 20 non-CD control subjects (Vh/Cd: 2.87; 95% CI: 2.50, 3.09; IEL: 22; 95% CI: 18, 24). One patient (challenged with 10 mg gluten) developed a clinical relapse. At t(1), the percentage change in Vh/Cd was 9% (95% CI: 3%, 15%) in the placebo group (n = 13), -1% (-18%, 68%) in the 10-mg group (n = 13), and -20% (-22%, -13%) in the 50-mg group (n = 13). No significant differences in the IEL count were found between the 3 groups. The ingestion of contaminating gluten should be kept lower than 50 mg/d in the treatment of CD.

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Toward the Assessment of Food Toxicity for Celiac Patients: Characterization of Monoclonal Antibodies to a Main Immunogenic Gluten Peptide

Belén Morón, Michael T Bethune, Isabel Comino … (2008)

Background and Aims Celiac disease is a permanent intolerance to gluten prolamins from wheat, barley, rye and, in some patients, oats. Partially digested gluten peptides produced in the digestive tract cause inflammation of the small intestine. High throughput, immune-based assays using monoclonal antibodies specific for these immunotoxic peptides would facilitate their detection in food and enable monitoring of their enzymatic detoxification. Two monoclonal antibodies, G12 and A1, were developed against a highly immunotoxic 33-mer peptide. The potential of each antibody for quantifying food toxicity for celiac patients was studied. Methods Epitope preferences of G12 and A1 antibodies were determined by ELISA with gluten-derived peptide variants of recombinant, synthetic or enzymatic origin. Results The recognition sequences of G12 and A1 antibodies were hexameric and heptameric epitopes, respectively. Although G12 affinity for the 33-mer was superior to A1, the sensitivity for gluten detection was higher for A1. This observation correlated to the higher number of A1 epitopes found in prolamins than G12 epitopes. Activation of T cell from gluten digested by glutenases decreased equivalently to the detection of intact peptides by A1 antibody. Peptide recognition of A1 included gliadin peptides involved in the both the adaptive and innate immunological response in celiac disease. Conclusions The sensitivity and epitope preferences of the A1 antibody resulted to be useful to detect gluten relevant peptides to infer the potential toxicity of food for celiac patients as well as to monitor peptide modifications by transglutaminase 2 or glutenases.

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Author and article information

Journal

Journal ID (nlm-ta): Gut

Journal ID (publisher-id): gut

Journal ID (hwp): gutjnl

Title: Gut

Publisher: BMJ Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0017-5749

ISSN (Electronic): 1468-3288

Publication date (Electronic): 12 February 2011

Publication date (Print): July 2011

Publication date PMC-release: 12 February 2011

Volume: 60

Issue: 7

Pages: 915-922

Affiliations

[1 ]Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain

[2 ]Centro Nacional de Biotecnología (CNB-CSIC), Departamento de Genética Molecular de Plantas, Cantoblanco, Madrid, Spain

[3 ]School of Applied Sciences, RMIT University, Melbourne, Australia

[4 ]Hospital Virgen de las Nieves, Granada, Spain

[5 ]Instituto de Agricultura Sostenible (CSIC), Alameda del Obispo, Córdoba, Spain

[6 ]Departamento de Biología Experimental, Campus Universitario Las Lagunillas, Jaén, Spain

[7 ]Biomedal, Sevilla, Spain

Author notes

Correspondence to Professor Carolina Sousa, Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad de Sevilla, C/Profesor García González, no. 2, Sevilla 41012, Spain; csoumar@ 123456us.es

Article

Publisher ID: gutjnl225268

DOI: 10.1136/gut.2010.225268

PMC ID: 3112367

PubMed ID: 21317420

SO-VID: 55b0bfb9-69fe-4554-a769-1a332682b02a

Copyright © © 2011, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

Diversity in oat potential immunogenicity: basis for the selection of oat varieties with no toxicity in coeliac disease

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Abstract

Background and aims

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Results

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Gamma Delta T cells

Most cited references 16

Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue.

A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease.

Toward the Assessment of Food Toxicity for Celiac Patients: Characterization of Monoclonal Antibodies to a Main Immunogenic Gluten Peptide

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