Characterization of cereal toxicity for celiac disease patients based on protein homology in grains 1 1The authors thank Drs. R. R. P. de Vries and R. Offringa for critical reading of the manuscript, A. de Ru for mass spectrometric analysis, and W. Benckhuijsen for peptide synthesis.

Vader, L. Willemijn; Stepniak, Dariusz; Bunnik, Evelien M.; Kooy, Yvonne; Haan, Willeke de; Drijfhout, Jan W.; Veelen, Peter A. van; Koning, Frits

doi:10.1016/s0016-5085(03)01204-6

Cited by 210 publications

(45 citation statements)

References 24 publications

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“…Notably however, introduction of a second deamidation site (e.g. Q10EQ17E (14) or Q10EQ24E (15)) significantly enhances affinity relative to Q10E (11), suggesting that a second acidic residue C-terminal to the core DQ2-αII epitope is important for the optimal immunological properties of the 33-mer. This is also supported by the observation that the doubly deamidated analogue Q17EQ24E (16) approximates the 33-mer binding characteristics.…”

Section: Sar Analysis Of the Binding Of The 33-mer Peptide To Hla-dq2mentioning

confidence: 99%

“…Finally, and perhaps most importantly, among HLA mediated diseases, Celiac Sprue is unique in that an environmental trigger (dietary gluten) has been identified and extensively dissected at an immunological level (4,5). In turn, these studies have led to the identification of proteolytically resistant gluten peptides that are generated by physiological processes and are efficiently presented to disease associated T cells in a DQ2 restricted fashion (12)(13)(14)(15). Thus, if these naturally occurring T cell stimulatory agents can be transformed into inhibitors of DQ2 mediated antigen presentation, they can be considered as appropriate medicinal leads for Celiac Sprue.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of HLA-DQ2-Mediated Antigen Presentation by Analogues of a High Affinity 33-Residue Peptide from α2-Gliadin

et al. 2006

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Human leukocyte antigen DQ2 is a class II major histocompatibility complex protein that plays a critical role in the pathogenesis of Celiac Sprue by binding to epitopes derived from dietary gluten and triggering the inflammatory response of disease-specific T cells. Inhibition of DQ2 mediated antigen presentation in the small intestinal mucosa of Celiac Sprue patients therefore represents a potentially attractive mode of therapy for this widespread but unmet medical need. Starting from a pro-inflammatory, proteolytically resistant, 33-residue peptide, LQLQPFPQPELPYPQPELPYPQPELPYPQPQPF, we embarked upon a systematic effort to dissect the relationships between peptide structure and DQ2 affinity, and to translate these insights into prototypical DQ2 blocking agents. Three structural determinants within the first 20 residues of this 33-mer peptide, including a PQPELPYPQ epitope, its N-terminal flanking sequence and a downstream Glu residue, were found to be important for DQ2 binding. Guided by the X-ray crystal structure of DQ2, the L11 and L18 residues in the truncated 20-mer analogue were replaced with sterically bulky groups so as to retain high DQ2 affinity but abrogate T cell recognition. A dimeric ligand, synthesized by regiospecific coupling of the 20-mer peptide with a bifunctional linker, was identified as an especially potent DQ2 binding agent. Two such ligands were able to attenuate the proliferation of disease-specific T cell lines in response to gluten antigens, and therefore represent prototypical examples of pharmacologically suitable DQ2 blocking agents for the potential treatment of Celiac Sprue.

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Section: Sar Analysis Of the Binding Of The 33-mer Peptide To Hla-dq2mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of HLA-DQ2-Mediated Antigen Presentation by Analogues of a High Affinity 33-Residue Peptide from α2-Gliadin

et al. 2006

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“…Oats include many varieties, naked and husked seeds, containing various amino acid sequences [23] and showing different immunoreactivities to anti-gliadin polyclonal antibodies [24]. We have previously reported that the prolamin avenins (the proteins corresponding to wheat gliadin) from different oat cultivars display different immunostimulatory activities on celiac lymphocytes from peripheral blood [25].…”

Section: Introductionmentioning

confidence: 99%

Diversity of oat varieties in eliciting the early inflammatory events in celiac disease

et al. 2013

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Purpose Celiac disease (CD) is an autoimmune enteropathy, triggered by dietary gluten. The only treatment is a strict gluten-free diet. Oats are included in the list of gluten-free ingredients by European Regulation, but the safety of oats in CD is still a matter of debate. The present study examined the capability of different oat cultivars of activating the gliadin-induced transglutaminase-2 (TG2)-dependent events in some in vitro models of CD. In addition, we compared this capability with the electrophoresis pattern of peptic–tryptic digests of the proteins of the oat cultivars.MethodsK562(S) cells agglutination, transepithelial electrical resistance of T84-cell monolayers, intracellular levels of TG2 and phosphorylated form of protein 42–44 in T84 cells were the early gliadin-dependent events studied.ResultsThe results showed that the Nave oat cultivar elicited these events, whereas Irina and Potenza varieties did not. The ability of a cultivar to activate the above-described events was associated with the electrophoretic pattern of oat proteins and their reactivity to anti-gliadin antibodies.ConclusionWe found significant differences among oat cultivars in eliciting the TG2-mediated events of CD inflammation. Therefore, the safety of an oat cultivar in CD might be screened in vitro by means of biochemical and biological assays, before starting a clinical trial to definitely assess its safety.

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“…Gluten includes 2 major protein types, the gliadins and glutenins, both of which contain disease-activating peptides [2]. The closely related proteins in barley and rye that activate CeD are the hordeins and secalins, respectively [6]. Wheat, rye, and barley have a common ancestral origin in the grass family.…”

Section: Gastrointestinal Diseases Where Nutritional Factors Are Causalmentioning

confidence: 99%

Nutritional Influences in Selected Gastrointestinal Diseases

Lakatos

Kiss

Miheller

2011

Dig Dis

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Nutritional factors, as sources of luminal antigens, have been thought to be important factors in the immunopathogenesis of numerous gastrointestinal diseases. In some diseases, the role of the nutritional component is causal in the susceptible host. Such diseases include celiac disease, a common heritable chronic inflammatory condition of the small intestine induced by dietary wheat, rye and barley, in susceptible individuals. Specific HLA-DQ2 and HLA-DQ8 risk alleles are necessary, but not sufficient, for disease development. The well-defined role of HLA-DQ heterodimers encoded by these alleles is to present cereal peptides to CD4+ T cells, activating an inflammatory immune response in the intestine. Genome-wide association studies have been performed which identified the IL2-IL21 risk locus and other genes with immune functions and key roles in thymic T-cell selection. Another example for this group is Wilson’s disease, an autosomal recessive disorder of copper metabolism caused by mutation of the ATP7B gene, resulting in a defect of biliary copper excretion and toxic accumulation in the body, especially in the liver, brain and cornea, resulting in hepatic and/or neurological symptoms. In other diseases, however, the association is less well established. In such endeavor, epidemiological observations may become a valuable part of the overall investigations aimed at identifying dietary factors, which are involved in the initiation and perpetuation of the specific disease. As an example, relationships between nutrition and colorectal cancer have been hypothesized early on (e.g. folate, calcium, vitamin D, red meat). Similarly, intake of certain diet constituents like fat, refined sugar, fruits, vegetables and fiber was reported to be associated with the expression of inflammatory bowel diseases. In addition, in children with active Crohn’s disease, enteral nutrition was found to be equally effective as corticosteroids in induction of remission, with mucosal healing induced by downregulation of mucosal pro-inflammatory cytokine profiles in both the ileum and the colon after enteral nutrition. However, the particular effect of the consumption of each type of food remains questionable in most cases, at least in part because of insufficient data and serious methodological limitations (e.g. recall bias, heterogeneity between collected data, lack of correction for covariates, difficulties in double blinding).

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Characterization of cereal toxicity for celiac disease patients based on protein homology in grains 1 1The authors thank Drs. R. R. P. de Vries and R. Offringa for critical reading of the manuscript, A. de Ru for mass spectrometric analysis, and W. Benckhuijsen for peptide synthesis.

Cited by 210 publications

References 24 publications

Inhibition of HLA-DQ2-Mediated Antigen Presentation by Analogues of a High Affinity 33-Residue Peptide from α2-Gliadin

Inhibition of HLA-DQ2-Mediated Antigen Presentation by Analogues of a High Affinity 33-Residue Peptide from α2-Gliadin

Diversity of oat varieties in eliciting the early inflammatory events in celiac disease

Nutritional Influences in Selected Gastrointestinal Diseases

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