A Decapeptide from Durum Wheat Prevents Celiac Peripheral Blood Lymphocytes from Activation by Gliadin Peptides

Abstract

ABSTRACT:Identifying antagonist peptides able to inhibit the abnormal immune response triggered by gliadin peptides in celiac disease (CD) is an alternative therapeutic strategy for CD. The aim of this study was to evaluate the antagonist effect of 10mer, a decapeptide (sequence QQPQDAVQPF) from alcohol-soluble protein fraction of durum wheat, assessing its ability to prevent celiac peripheral blood lymphocytes from activation by gliadin peptides. Peripheral blood mononuclear cells (PBMC) were obtained from DQ2-positive untreated coeliac children and from healthy controls and incubated with the peptic-tryptic digest of bread wheat gliadin (GLP) and peptide 62-75 from ␣-gliadin both alone and with 10mer simultaneously. PBMC proliferation, release of pro-inflammatory Th1 cytokines interferon-␥ and tumor necrosis factor-␣, release of immunoregulatory cytokine IL-10, and analysis of CD25 expression as indexes of lymphocytes activation were carried out. Enhanced lymphocytes activation was seen after exposure to GLP and p62-75, whereas the simultaneous incubation with 10mer inhibits the lymphocytes response. These data indicate that a peptide naturally occurring in durum wheat exerts in vitro an antagonist effect against gliadin toxicity and could have a protective effect in CD disease. C D is an increasingly diagnosed auto-immune enteropathy (prevalence 1:150), driven by an abnormal T-cell response to wheat gluten-derived peptides and strongly associated with HLA-DQ2, which is present in more than 90% of CD patients (1-3). So far, the only effective treatment is the withdrawal of the gluten-containing cereals from the diet (4). Complying with a gluten-free diet is difficult because of the diffusion of the cereals-based foods and it affects patients' quality of life; therefore, new treatments are being actively searched.An alternative therapeutic possibility may be to identify modified gliadin (a gluten fraction) peptides that are not toxic and are also able to inhibit the pathogenic immune response. In fact, some single amino acid substitutions at critical position of T-cell epitopes convert highly toxic peptides in ligand antagonists, as tested both in animal and ex vivo models (5,6). It has been reported that some peptides obtained by amino acid modifications of peptide 57-73 from ␣-gliadin abolish the production of interferon (IFN)-␥ by celiac PBMC incubated with the p57-73 itself (7).This therapeutic strategy could also rely upon ligand antagonists naturally occurring in some grains, such as a decapeptide (10mer) identified in the peptic-tryptic digest of the alcoholsoluble protein fraction of durum wheat (GLP) (8). This molecule, whose sequence is QQPQDAVQPF, named in previous studies "1157" after its molecular weight, has been demonstrated to protect some cellular lines from gliadin toxicity (8,9).Although in CD pathogenesis the central role is played by gluten-specific HLA DQ2/DQ8 restricted CD4ϩ intestinal T cells, recent studies indicate that the peripheral blood lymphocytes from celiac patients could be as ...

Modulatory Effect of Gliadin Peptide 10-mer on Epithelial Intestinal CACO-2 Cell Inflammatory Response

“…In this study, we investigated the ability to modulate the epithelial intestinal early response in celiac disease by a decapeptide (p10-mer, QQPQDAVQPF), already described to prevent activation of celiac peripheral lymphocytes by gliadin peptides and to down-regulate the adaptive immune response towards wheat prolamins [15].…”

“…We described p10-mer, a decapeptide (sequence QQPQDAVQPF) [13] that prevents the activation of peripheral celiac lymphocytes by gliadin peptides [14] and promotes a shift from a Th1-type response toward a Th2-type response in celiac disease [15]. In the present study we evaluated "in vitro" the modulating effect of p10-mer on gliadin-triggered intestinal epithelial cell inflammation.…”

Gliadin Peptides Induce Tissue Transglutaminase Activation and ER-Stress through Ca2+ Mobilization in Caco-2 Cells

“…In some experiments, we used N-terminal-biotin-labeled p31–43 and p57–68. Three synthetic peptide were used as irrelevant control peptides: QQPQDAVQPF from durum wheat (pCTR) [19]; PLIRPLLARPAK, which represents the 537–548 region of the human thyroid peroxidase (pHTP) [2]; LPQFEEIRNLALQTLPAM, which represents the C-terminal sequence of A-gliadin (p229–246) [20].…”

Runs of Homozygosity in sub-Saharan African populations provide insights into a complex demographic and health history

“…Other genes related to trypanosomiasis infection and kidney disease, like APOL1 90 , or to different forms of hypertension, like ATP1A1 2 , AQP2 2 and CSK 2,91 were found in ROHi in different regions from SSA. As was shown in Table 6 within RHZ haplotypes it is also possible to find multiple protein coding genes related to diverse biological functions like immune response ( HLA complex or IRF gene family), cellular cycle ( ANP32A 92; 93 ), chromosomal aberrations (like different members of the GOLGA gene family 94 ) cancer ( NOX5 95 ), brain development ( KIAA0513 96 ) and olfactory receptors ( OR gene family) among others. These heterozygous regions might represent haplotypes enriched for variants that have a negative impact on fitness in homozygosity, or regions that harbor loci with heterozygote advantage (overdominance) under any form of balancing selection.…”