A Universal Approach to Eliminate Antigenic Properties of Alpha-Gliadin Peptides in Celiac Disease

Celiac disease is caused by an uncontrolled immune response to gluten, a heterogeneous mixture of wheat storage proteins, including the α-gliadins. It has been shown that α-gliadins harbor several major epitopes involved in the disease pathogenesis. A major step towards elimination of gluten toxicity for celiac disease patients would thus be the elimination of such epitopes from α-gliadins. We have analyzed over 3,000 expressed α-gliadin sequences from 11 bread wheat cultivars to determine whether they encode for peptides potentially involved in celiac disease. All identified epitope variants were synthesized as peptides and tested for binding to the disease-associated HLA-DQ2 and HLA-DQ8 molecules and for recognition by patient-derived α-gliadin specific T cell clones. Several specific naturally occurring amino acid substitutions were identified for each of the α-gliadin derived peptides involved in celiac disease that eliminate the antigenic properties of the epitope variants. Finally, we provide proof of principle at the peptide level that through the systematic introduction of such naturally occurring variations α-gliadins genes can be generated that no longer encode antigenic peptides. This forms a crucial step in the development of strategies to modify gluten genes in wheat so that it becomes safe for celiac disease patients. It also provides the information to design and introduce safe gluten genes in other cereals, which would exhibit improved quality while remaining safe for consumption by celiac disease patients

Multidisciplinary Approaches to Allergies

XXII, 480 p. 50 illus.online resource

The frequencies and weightings of HLA- DQ2 and HLA-DQ8 antigens in the Chinese population.

<p>A: HLA-DQ2; B: HLA-DQ8. Antigen frequency  =  sum of each individual antigen/n, where n  =  total number of subjects. Abbreviations: CI, confidence interval. The data sources are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081151#pone.0081151.s002" target="_blank">Table S2</a>.</p

The frequencies and weightings of HLA-DQ2.5 and HLA-DQ8 haplotypes in the Chinese population.

<p>A: HLA-DQ2.5; B: HLA-DQ8. Abbreviations: CI, confidence interval. The data sources are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081151#pone.0081151.s001" target="_blank">Table S1</a>.</p

Characteristics of included studies about CD cases diagnosed by biopsy and a GFD.

<p>+ positive; -negative</p><p>Abbreviations: NA, Not available in the content of the study; CD, celiac disease; RCD, refractory celiac disease; GFD, gluten-free diet;</p><p>IgA AGA: IgA anti-gliadin antibodies; IgG AGA: IgG anti-gliadin antibodies; IgA EMA: IgA anti-endomysial antibodies; IgG EMA: IgG anti-endomysial antibodies; IgA ARA: IgA anti-reticulin antibodies; IgG ARA: IgG anti-reticulin antibodies; IgA tTGs: IgA anti-tissue transglutaminase; IgG tTGs: IgG anti-tissue transglutaminase.</p><p>Three out of four original papers were on screening CD in at-risk groups in China, chronic diarrhea patients <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081151#pone.0081151-Jiang1" target="_blank">[22]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081151#pone.0081151-Wang1" target="_blank">[24]</a>, diarrhea-predominant irritable bowel syndrome, and insulin-dependent diabetes mellitus <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081151#pone.0081151-Wu1" target="_blank">[25]</a>. In the table, we only show the characteristics of suspected CD patients in these at-risk groups. Another original paper <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081151#pone.0081151-Freeman1" target="_blank">[19]</a> was about CD in Asian-Canadian adults, one out of 14 adult CD cases was born in Northern China in 1924 and then emigrated from China to Canada in 1973. Sun F <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081151#pone.0081151-Sun1" target="_blank">[26]</a> reported two CD cases, but one case was of European descent.</p