Toxic, Immunostimulatory and Antagonist Gluten Peptides in Celiac Disease (original) (raw)
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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...
Background: Celiac disease (CD) is a Th1-driven autoimmune permanententeropathythatistriggeredbydietarygluten.Molecules abletoshifttheimmuneresponsefromaTh1-toaTh2-typeresponse have been suggested as therapeutic agents for Th1 autoimmune diseases. Objective: We sought to investigate the possibility that a decapep- tide from durum wheat (p10mer, QQPQDAVQPF), which was pre- viouslyshowntopreventtheactivationofceliacperipherallympho- cytes, may promote a shift from a Th1- to a Th2-type immune response in gluten-specific intestinal T cells of CD patients. Design: Intestinal T lymphocyte lines derived from 8 children with CD were incubated with gliadin peptides both alone and simulta- neously with p10mer. Cell proliferation and the production of interferon- and interleukin-10 by these T cells were measured. Results:The incubation of celiac intestinal T cells with deamidated gliadinpeptidesresultedinasignificant(P0.008)increaseincell proliferationandinterferon-release,whereasthesimultaneo...
Journal of Agricultural and Food Chemistry, 2013
Tissue transglutaminase (TG2) plays a central role in celiac disease (CD) pathogenesis by strongly enhancing the immunogenicity of gluten, the CD-triggering antigen. By deamidating specific glutamine (Q) residues, TG2 favors the binding of gluten peptides to DQ2/8 molecules and, subsequently, their recognition by cognate T cells. Six peptides were previously identified within wheat gliadin whole extracts by tagging the TG2-susceptible Q residues with monodansylcadaverine (MDC) and nanospray tandem mass spectrometry (nanoESI-MS/MS). The immunogenicity of these peptides was next tested in gliadinspecific T-cell lines established from CD intestinal mucosa. Four peptides, corresponding to known epitopes of αand γ-gliadins, induced cell proliferation and interferon (IFN)-γ production. Interestingly, one of the two non-T-cell stimulatory peptides corresponded to the 31−49 α-gliadin peptide implicated in the innate immune activation in CD mucosa. This study describes a strategy for identifying immunogenic gluten peptides potentially relevant for CD pathogenesis in protein extracts from wheat and other edible cereals.
Fine specificity of monoclonal antibodies against celiac disease-inducing peptides in the gluteome
The American journal of clinical nutrition, 2008
In celiac disease patients, peptides derived from dietary gluten are recognized by HLA-DQ2-restricted CD4(+) T cells, which results in inflammation. Such immune-stimulatory peptides are found in both gliadins and glutenins. Monoclonal antibodies (mAbs) against these peptides can be used to screen food for the presence of such peptides. We aimed to determine the specificity of 5 mAbs raised against T cell stimulatory peptides found in alpha- and gamma-gliadins and in low- and high-molecular-weight glutenins and to compare it with the specificity of patient-derived T cells. The reactivity of the mAbs with gluten peptides, enzymatic gluten digests, and intact gluten proteins was determined and compared with that of gluten-specific T cells by using a combination of immunologic and biochemical techniques. Furthermore, the reactivity of the mAbs with gluten homologues in barley, rye, and oat was determined. The specificity of the mAbs largely overlaps with that of gluten-specific T cells....
A u-secalin contained decamer shows a celiac disease prevention activity
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.
Analytical and functional approaches to assess the immunogenicity of gluten proteins
Frontiers in Nutrition
Gluten proteins are the causative agents of celiac disease (CD), a lifelong and worldwide spread food intolerance, characterized by an autoimmune enteropathy. Gluten is a complex mixture of high homologous water-insoluble proteins, characterized by a high content of glutamine and proline amino acids that confers a marked resistance to degradation by gastrointestinal proteases. As a consequence of that, large peptides are released in the gut lumen with the potential to activate inflammatory T cells, in CD predisposed individuals. To date, several strategies aimed to detoxify gluten proteins or to develop immunomodulatory drugs to recover immune tolerance to gluten are under investigation. This review overviews the state of art of both analytical and functional methods currently used to assess the immunogenicity potential of gluten proteins from different cereal sources, including native raw seed flours and complex food products, as well as drug-treated samples. The analytical design ...
The Journal of Immunology, 2009
The identification of gluten peptides eliciting intestinal T cell responses is crucial for the design of a peptide-based immunotherapy in celiac disease (CD). To date, several gluten peptides have been identified to be active in CD. In the present study, we investigated the recognition profile of gluten immunogenic peptides in adult HLA-DQ2 ؉ celiac patients. Polyclonal, gliadin-reactive T cell lines were generated from jejunal mucosa and assayed for both proliferation and IFN-␥ production in response to 21 peptides from wheat glutenins and ␣-, ␥-, and-gliadins. A magnitude analysis of the IFN-␥ responses was performed to assess the hierarchy of peptide potency. Remarkably, 12 of the 14 patients recognized a different array of peptides. All ␣-gliadin stimulatory peptides mapped the 57-89 N-terminal region, thus confirming the relevance of the known polyepitope 33-mer, although it was recognized by only 50% of the patients. By contrast, ␥-gliadin peptides were collectively recognized by the great majority (11 of 14, 78%) of CD volunteers. A 17-mer variant of 33-mer, QLQPFPQPQLPYPQPQP, containing only one copy of DQ2-␣-I and DQ2-␣-II epitopes, was as potent as 33-mer in stimulating intestinal T cell responses. A peptide from-gliadin, QPQQPFPQPQQPFPWQP, although structurally related to the ␣-gliadin 17-mer, is a distinct epitope and was active in 5 out of 14 patients. In conclusion, these results showed that there is a substantial heterogeneity in intestinal T cell responses to gluten and highlighted the relevance of ␥and-gliadin peptides for CD pathogenesis. Our findings indicated that ␣-gliadin (57-73), ␥-gliadin (139-153), and-gliadin (102-118) are the most active gluten peptides in DQ2 ؉ celiac patients.
ISRN Allergy, 2011
Intestinal T cells from gluten sensitivity/celiac disease patients respond to a heterogeneous array of peptides. Our study extended this heterogeneity to humoral immune response to various wheat proteins and peptides in patients with gluten sensitivity or Crohn's disease. IgG and IgA antibodies in sera from those patients and healthy control subjects were measured against an array of wheat antigens and peptides. In gluten-sensitive patients, IgG reacted most against transglutaminase, prodynorphin, wheat extract, and α-, γ-, and ω-gliadin; IgA reacted most against wheat then transglutaminase, glutenin, and other peptides. In the sera of Crohn's disease patients, IgG reacted most against wheat and wheat germ agglutinin then transglutaminase, prodynorphin, α-, and γ-gliadin; IgA reacted foremost against prodynorphin then transglutaminase and α-gliadin. These results showed a substantial heterogeneity in the magnitude of IgG and IgA response against various wheat antigens and peptides. Measurements of IgG and IgA antibodies against such an array of wheat peptides and antigens can enhance the sensitivity and specificity of serological assays for gluten sensitivity and celiac disease and may also detect silent celiac disease or its overlap with inflammatory bowel disease.
Coeliac disease: immunogenicity studies of barley hordein and rye secalin-derived peptides
International Journal of Experimental Pathology, 2016
Coeliac disease (CD) is an inflammatory disorder of the small intestine. It includes aberrant adaptive immunity with presentation of CD toxic gluten peptides by HLA-DQ2 or DQ8 molecules to gluten-sensitive T cells. A x-gliadin/C-hordein peptide (QPFPQPEQPFPW) and a rye-derived secalin peptide (QPFPQPQQPIPQ) were proposed to be toxic in CD, as they yielded positive responses when assessed with peripheral blood T-cell clones derived from individuals with CD. We sought to assess the immunogenicity of the candidate peptides using gluten-sensitive T-cell lines obtained from CD small intestinal biopsies. We also sought to investigate the potential cross-reactivity of wheat gluten-sensitive T-cell lines with peptic-tryptic digested barley hordein (PTH) and rye secalin (PTS). Synthesised candidate peptides were deamidated with tissue transglutaminase (tTG). Gluten-sensitive T-cell lines were generated by culturing small intestinal biopsies from CD patients with peptic-tryptic gluten (PTG), PTH or PTS, along with autologous PBMCs for antigen presentation. The stimulation indices were determined by measuring the relative cellular proliferation via incorporation of 3 H-thymidine. The majority of T-cell lines reacted to the peptides studied. There was also cross-reactivity between wheat gluten-sensitive T-cell lines and the hordein, gliadin and secalin peptides. PTH, PTS, barley hordein and rye secalin-derived CD antigen-sensitive T-cell lines showed positive stimulation with PTG. x-gliadin/C-hordein peptide and rye-derived peptide are immunogenic to gluten-sensitive T-cell lines and potentially present in wheat, rye and barley. Additional CD toxic peptides may be shared.