Gliadin‐reactive T cells in Italian children from preventCD cohort at high risk of celiac disease

Camarca, Alessandra; Auricchio, Renata; Picascia, Stefania; Fierro, Olga; Maglio, Mariantonia; Miele, Erasmo; Malamisura, Basilio; Greco, Luigi; Troncone, Riccardo; Gianfrani, Carmen

doi:10.1111/pai.12720

Cited by 22 publications

(16 citation statements)

References 29 publications

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“…In this study, the ability of heterozygous DR5/DR7 B-LCLs, from both celiacs and healthy controls, to present gliadin peptides to CD4 + T cells was compared to DR1/DR3 B-LCLs, in the same experimental conditions. The antigen presenting function of DR5/DR7 and DR1/DR3 B-LCLs was assessed by dosing the IFN-γ production in a T cell line generated from small intestinal mucosa of a DR5/DR7 patient previously described 6 and highly reactive to the immunodominant gliadin peptide (DQ2.5-glia-α1,2, QLQPFPQPELPYPQPQP). DR5/DR7 B-LCL#23 (Table 1 ), carrying the DQ2.5 genes in trans configuration, displayed overlapping ability to stimulate cognate TCL with respect to DR1/DR3 B-LCL#5, as shown in dose curve response to DQ2.5-glia-α1,2 peptide (Fig.…”

Section: Resultsmentioning

confidence: 99%

Differential expression of predisposing HLA-DQ2.5 alleles in DR5/DR7 celiac disease patients affects the pathological immune response to gluten

Pisapia

Picascia

Farina

et al. 2020

Sci Rep

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The DR5-DQ7/DR7-DQ2 genotype is very frequent among patients affected by celiac disease (CD), in Europe. This genotype, associated to high risk of CD, carries the HLA-DQA1*05 and HLA-DQB1*02 predisposing alleles, in trans configuration. The alleles encode the DQ2.5 heterodimer responsible of gluten peptide presentation on the surface of antigen-presenting cells (APCs), and consequent pathogenic CD4+ T cell activation. We demonstrated that DR5/DR7 APCs induce an anti-gluten CD4+ T cell response, of comparable intensity to that observed with APCs carrying DR1/DR3 genotype, which risk alleles are in cis configuration. In addition, we showed that DR5/DR7 APCs from celiac patients stimulated an effector CD4+ T cell response higher with respect to that induced by DR5/DR7 APCs from healthy subjects. To explain these findings, we assessed the DQ2.5 RNA and protein quantity. We showed that the expression of DQA1*05 and DQB1*02 risk alleles is much higher than the expression of non-CD-associated alleles, in agreement with the previous results obtained with DR1/DR3 genotype. The differential expression of transcripts influences the quantity of DQα1*05 and DQβ1*02 chains and, as consequence, the cell surface density of DQ2.5 heterodimers. Moreover, both RNA and proteins, are more abundant in APCs from celiac patients than controls. Finally, to unravel the mechanism regulating the expression of predisposing DQA1*05 and DQB1*02 alleles, we quantified the new synthetized RNA and found that the differential expression is explained by their transcription rate. Our results confirmed that the strength of antigen-specific CD4+ T cell response is mainly determined by the amount of gluten in the diet and provided a new possible approach for a personalized diagnosis and for risk stratification.

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Section: Resultsmentioning

confidence: 99%

Differential expression of predisposing HLA-DQ2.5 alleles in DR5/DR7 celiac disease patients affects the pathological immune response to gluten

Pisapia

Picascia

Farina

et al. 2020

Sci Rep

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“…T cell lines (TCLs) highly reactive to wheat gliadin proteins were generated from jejunal biopsies of N = 3 HLA-DQ2.5 celiac patients, as previously reported ( 26 , 27 ). Briefly, mucosal cells were in vitro stimulated with an enzymatic (pepsin-chymotrypsin) digest of gliadin proteins (PC-gliadin) in complete medium (X-Vivo 15 medium supplemented with 5% AB-pooled human serum and antibiotics, all purchased by Lonza, Canberra Australia).…”

Section: Methodsmentioning

confidence: 99%

Immunogenic Potential of Beer Types Brewed With Hordeum and Triticum spp. Malt Disclosed by Proteomics

et al. 2020

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The protein/peptide composition of five beer kinds, including two experimental beer-like products brewed with einkorn ( Triticum monococcum ), a beer labeled as “gluten-free,” a traditional all-barley malt and a wheat ( T. aestivum ) containing beer, was characterized with HPLC-ESI MS/MS-based proteomics. To enlarge the characterization of the components, the polypeptides were fractionated according to their molecular size (cut-off 6 kDa). All the beer types contained a variety of polypeptides arising from all the gliadin subfamilies (α-/β-, γ-, and ω-gliadins) able to induce an immune response in celiac disease (CD) patients in addition to a panel of IgE-reactive food allergens. Wheat storage proteins were heavily hydrolyzed in the beer samples brewed with einkorn. The presence of gluten-like fragments, also including the 25-mer and 33-mer-like of α-gliadin, was confirmed in beer brewed with barley and wheat malt as well as in the gluten-free beer. Both CD-toxic and allergenic peptides of all beer samples were drastically degraded when subjected to a simulated gastroduodenal (GD) digestion. After in vitro digestion, the level of gluten-like peptides assayed with the G12 competitive ELISA, was below the threshold (20 ppm) for a food to be considered as “gluten-free.” A few gliadin-derived epitopes occurred in the digests of beers crafted with wheat or Norberto-ID331 line of einkorn. In contrast, digests of all barley malt and gluten-free beers did not contain detectable gluten-like epitopes, but only minor fragments of hordeins and IgE-reactive food allergens. All beer samples evoked a weak immune response on gliadin-reactive celiac T cells isolated from intestinal biopsies of celiac patients. Compared to undigested polypeptides, the response was markedly reduced by GD digestion. Although the consumption of a moderate amount of beer brewed with barley or einkorn could deliver a relatively low amount of CD-toxic epitopes, the findings of this study emphasize the urgent need of a reliable and accurate quantification of gluten epitopes in all types of beer, also including the gluten-free one, to compute realistically the contribution of beer to the overall gluten intake, which can be responsible of intestinal tissue damages in celiacs.

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“…Potential‐CD is a condition defined by the presence of HLA DQ2/DQ8 risk alleles, positive CD‐associated serological markers but a mucosa with normal architecture . Recent findings have demonstrated the presence in the gut of subjects with potential‐CD of inflammatory T cells reactive to gluten peptides , concomitantly with the existence of regulatory mechanisms that counteract the activation of inflammatory pathways destructive of mucosal epithelium. Interestingly, another study has instead reported the lack of NK‐mediated cytotoxic pattern in the gut of this peculiar group of patients .…”

Section: Introductionmentioning

confidence: 99%

The intestinal expansion of TCRγδ⁺ and disappearance of IL4⁺ T cells suggest their involvement in the evolution from potential to overt celiac disease

et al. 2019

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Celiac disease (CD) is characterized by a spectrum of intestinal inflammatory lesions.Most patients have villous atrophy (overt-CD), while others have a morphologically normal mucosa, despite the presence of CD-specific autoantibodies (potential-CD). As the mechanism responsible for villous atrophy is not completely elucidated, we investigated biomarkers specific for the different celiac lesions. Phenotype and cytokine production of intestinal mucosa cells were analyzed by flow cytometry in gut biopsies of children with overt-or potential-CD and in healthy controls. Density of TCRγδ + T cells was found markedly enhanced in intestinal mucosa of children with overt-CD compared to potential-CD or controls. By contrast, very few IL4 + T cells infiltrated the mucosa with villous atrophy compared to morphologically normal mucosa. IL4 + T cells were classical CD4 + T-helper cells (CD161 − ), producing or not IFN-γ, and negative for IL17A. Our study demonstrated that the transition to villous atrophy in CD patients is characterized by increased density of TCRγδ + T cells, and concomitant disappearance of IL4 + cells. These findings suggest that immunomodulatory mechanisms are active in potential-CD to counteract the inflammatory cascade responsible of villous atrophy. Further studies are required to validate the use of IL4 + and TCRγδ + T cells as biomarkers of the different CD forms.Keywords: Celiac disease r Cytokines r Flow cytometry r Intestinal TCRγδ + T cells r Mucosal immunology Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Gliadin‐reactive T cells in Italian children from preventCD cohort at high risk of celiac disease

Cited by 22 publications

References 29 publications

Differential expression of predisposing HLA-DQ2.5 alleles in DR5/DR7 celiac disease patients affects the pathological immune response to gluten

Differential expression of predisposing HLA-DQ2.5 alleles in DR5/DR7 celiac disease patients affects the pathological immune response to gluten

Immunogenic Potential of Beer Types Brewed With Hordeum and Triticum spp. Malt Disclosed by Proteomics

The intestinal expansion of TCRγδ⁺ and disappearance of IL4⁺ T cells suggest their involvement in the evolution from potential to overt celiac disease

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Gliadin‐reactive T cells in Italian children from preventCD cohort at high risk of celiac disease

Cited by 22 publications

References 29 publications

Differential expression of predisposing HLA-DQ2.5 alleles in DR5/DR7 celiac disease patients affects the pathological immune response to gluten

Differential expression of predisposing HLA-DQ2.5 alleles in DR5/DR7 celiac disease patients affects the pathological immune response to gluten

Immunogenic Potential of Beer Types Brewed With Hordeum and Triticum spp. Malt Disclosed by Proteomics

The intestinal expansion of TCRγδ+ and disappearance of IL4+ T cells suggest their involvement in the evolution from potential to overt celiac disease

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The intestinal expansion of TCRγδ⁺ and disappearance of IL4⁺ T cells suggest their involvement in the evolution from potential to overt celiac disease