A u-secalin contained decamer shows a celiac disease prevention activity (original) (raw)
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A ω-secalin contained decamer shows a celiac disease prevention activity
Journal of Cereal Science, 2012
Celiac disease (CD) is an autoimmune permanent enteropathy that is triggered in susceptible individuals after the ingestion of gluten, a storage protein fraction presents in wheat, rye and barley endosperm. Specific gluten peptides can bind to HLA-DQ2/8 and induce lamina propria CD4 þ T cell responses causing damage of the small intestine mucosa. Recent studies suggested that beside immunodominant and toxic epitopes, wheat gluten also contains epitopes capable of preventing the mucosal response in vitro. Among them, a decapeptide (QQPQDAVQPF) from wheat was reported to have an antagonist effect on the agglutination of K562(S) cells and celiac T-cell activation, although the corresponding nucleotidic sequence remained unknown. This study was therefore designed to clone the sequence encoding the protein carrying the decapetide with CD protective properties. A u-secalin gene encoding containing the decapeptide QQPQRPQQPF was isolated. Although the decapeptide was not identical to the one previously described, QQPQRPQQPF showed the same capability to prevent K562(S) cell agglutination and celiac mucosa immune activation induced by toxic gliadins. The u-secalin gene was found in wheat carrying the wheaterye chromosomal translocations 1BL.1RS. The identification of this immunomodulatory gliadin sequence, naturally occurring in cultivars of wheat toxic for celiac patients, might offer new therapeutic strategies for CD.
A Universal Approach to Eliminate Antigenic Properties of Alpha-Gliadin Peptides in Celiac Disease
PLoS ONE, 2010
Celiac disease is caused by an uncontrolled immune response to gluten, a heterogeneous mixture of wheat storage proteins, including the a-gliadins. It has been shown that a-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 a-gliadins. We have analyzed over 3,000 expressed a-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 a-gliadin specific T cell clones. Several specific naturally occurring amino acid substitutions were identified for each of the a-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 a-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.
Journal of Agricultural Science and Technology, 2020
Among gliadins, α-gliadins are important active proteins in triggering celiac disease in human beings owing to the presence of toxic epitopes. A set of 177 α-gliadin gene sequences and the corresponding proteins were analyzed. Twenty accessions of hexaploids including 1, 14, and 5, respectively representing A, B, and D, with no intact CD-epitopes in α-gliadins, were identified. Twenty-two and 13 conserved motifs in non-repetitive domains NR1 and NR2, respectively, of α-gliadins differentiated all the amino acid sequences encoded by A genome of both diploids and hexaploids. Most of the amino acid sequences encoded by D genome (70 of 75 in hexaploids and 13 of 16 in diploids) could be identified by 22 amino acid motif. Large variations and lesser number of intact CDepitopes was observed for α-gliadins belonging to B genome. As compared to diploids, repeat length of polyglutamine repetitive domain QII of B genome was lower in hexaploids indicating loss of Q residues during evolution of...
Toxic, Immunostimulatory and Antagonist Gluten Peptides in Celiac Disease
Current Medicinal Chemistry, 2009
Celiac disease (CD) is an increasingly diagnosed, permanent autoimmune enteropathy, triggered, in susceptible individuals, by the ingestion of gluten, the alcohol -soluble protein fraction of some cereals, such as wheat, rye and barley. The main protein of wheat gluten is called gliadin, the similar proteins of rye and barley are secalin and hordein, respectively. Approximately 96% of CD patients express the HLA molecule DQ2, while the remainder mostly express the less common haplotype DQ8, reflecting the pivotal role of these molecules in the pathogenesis of CD. Because of their aminoacid sequence and tri-dimensional structure, gluten peptides selectively bind to these HLA alleles present on the surface of antigen presenting cells and then they are presented to the T lymphocytes in intestinal mucosa, thus starting the inflammatory immune response. CD is defined by the characteristic histological changes of small bowel mucosa: villous atrophy, crypts hyperplasia and T cells infiltration of the lamina propria, along with the increase of the number of intraepithelial lymphocytes. The withdrawal of the gluten-containing food from the diet determines a complete recovery of the intestinal mucosa, whereas the reintroduction causes a relapse of the disease.
British Journal of Nutrition, 2020
The only generally accepted treatment of coeliac disease (CD) is a lifelong gluten-free diet. Wheat gluten proteins include gliadins, low and high molecular weight glutenins. However, we have found significant structural variations within these protein families among different cultivars. To determine which structural motifs might be less toxic than others, we assessed five variants of α-gliadin immunodominant CD-toxic peptides synthesised as 16mers in CD T cell stimulation assays with gluten-sensitive T cell lines generated from duodenal biopsies from CD-affected individuals. The peptides harboured the overlapping T cell epitopes DQ 2.5-glia-α-2 and naturally occurring variants that differed in certain amino acids (AA). The results revealed that introduction of two selected AA substitutions in α-gliadin peptides reduced immunogenicity. A peptide with three AA substitutions involving two glutamic acids (E) and one glutamine residue (G) revealed the peptide was negative in 5:5 samples...
Journal of Chromatography B, 2007
Current knowledge indicates that both innate and adaptive immune responses are involved in Celiac disease (CD) driven by different gliadin peptides. By studying a representative recombinant ␣-gliadin form, a further 25-mer peptide resistant to gastric, pancreatic, and human intestinal brush-border membrane enzymes was detected. This peptide latter encompasses the sequence 31-43 known to elicit the innate immune response in CD. The resistance of 25-mer, as well as that of the already described 33-mer related to the CD adaptive immune response, was confirmed on a standard flour wheat sample representative of the most widespread European varieties.
The Plant journal : for cell and molecular biology, 2015
The gluten proteins from wheat, barley and rye are responsible both for celiac disease (CD) and for non-celiac gluten sensitivity, two pathologies affecting up to 6-8% of the human population worldwide. The wheat α-gliadin proteins contain three major CD immunogenic peptides: the p31-43, which induces the innate immune response; the 33-mer, formed by six overlapping copies of three highly stimulatory epitopes; and an additional DQ2.5-glia-α3 epitope which partially overlaps with the 33-mer. NGS and Sanger sequencing of α-gliadin genes from diploid and polyploid wheat provided six types of α-gliadins (named 1 to 6) with strong differences in their frequencies in diploid and polyploid wheat, and in the presence and abundance of these CD immunogenic peptides. Immunogenic variants of the p31-43 peptide were found in most of the α-gliadins. Variants of the DQ2.5-glia-α3 epitope were associated with specific types of α-gliadins. Remarkably, only Type 1 α-gliadins contained 33-mer epitopes...
Frontiers in Nutrition, 2020
Recent studies suggested that gliadin proteins from the ancient diploid einkorn wheat Triticum monococcum retained a reduced number of immunogenic peptides for celiac disease patients because of a high in vitro digestibility with respect to hexaploid common wheat. In this study, we compared the immunological properties of gliadins from two Triticum monococcum cultivars (Hammurabi and Norberto-ID331) with those of a Triticum durum cultivar (Adamello). Gliadins were digested by mimicking the in vitro gastrointestinal digestion process that includes the brush border membrane peptidases. Competitive ELISA, based on R5 monoclonal antibody, showed that gastrointestinal digestion reduced the immunogenicity of Triticum monococcum gliadins; conversely, the immunogenic potential of Triticum durum gliadins remained almost unchanged by the in vitro digestion. The immune stimulatory activity was also evaluated by detecting the IFN-γ production in gliadin-reactive T-cell lines obtained from the small intestinal mucosa of HLA-DQ2+ celiac disease patients. Interestingly, gastrointestinal digestion markedly reduced the capability of Triticum monococcum gliadins (p < 0.05) of both cultivars to activate T cells, while it slightly affected the activity of Triticum durum. In conclusion, our results showed that Triticum durum was almost unaffected by the in vitro gastrointestinal digestion, while Triticum monococcum had a marked sensibility to digestion, thus determining a lower toxicity for celiac disease patients.
American Journal of Clinical Nutrition
Celiac disease (CD) is a Th1-driven autoimmune permanent enteropathy that is triggered by dietary gluten. Molecules able to shift the immune response from a Th1- to a Th2-type response have been suggested as therapeutic agents for Th1 autoimmune diseases. We sought to investigate the possibility that a decapeptide from durum wheat (p10mer, QQPQDAVQPF), which was previously shown to prevent the activation of celiac peripheral lymphocytes, may promote a shift from a Th1- to a Th2-type immune response in gluten-specific intestinal T cells of CD patients. Intestinal T lymphocyte lines derived from 8 children with CD were incubated with gliadin peptides both alone and simultaneously with p10mer. Cell proliferation and the production of interferon-gamma and interleukin-10 by these T cells were measured. The incubation of celiac intestinal T cells with deamidated gliadin peptides resulted in a significant (P < 0.008) increase in cell proliferation and interferon-gamma release, whereas t...