The interplay between IL-15, gluten and HLA-DQ8 drives the development of coeliac disease in mice
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ABSTRACT:
PROVIDER: PRJNA556711 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9838870.fastq.gz | Fastqsanger.gz | |||
| SRR9838880.fastq.gz | Fastqsanger.gz | |||
| SRR9838890.fastq.gz | Fastqsanger.gz | |||
| SRR9838900.fastq.gz | Fastqsanger.gz | |||
| SRR9838910.fastq.gz | Fastqsanger.gz |
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Project description:Coeliac disease (CeD) is a complex, polygenic inflammatory enteropathy with autoimmune features caused by exposure to dietary gluten that occurs in a subset of genetically susceptible HLA-DQ8 and HLA-DQ2 individuals. Attempts to develop a pathophysiologically relevant animal model that develops villous atrophy (VA) have failed. The need to develop non-dietary treatments for this common disorder is now widely recognized, but it is hampered by the lack of a preclinical model. Furthermore, while human studies have led to major advances in our understanding of CeD pathogenesis, direct demonstration of the respective roles of disease-predisposing HLA molecules, and adaptive and innate immunity in the development of tissue damage is missing. To address these unmet needs, we engineered a mouse model that reproduces the dual overexpression of IL-15 in the gut epithelium and the lamina propria (Lp) characteristic of active CeD, expresses the predisposing HLA-DQ8 molecule, and develops VA upon gluten ingestion. We show that overexpression of IL-15 in both the epithelium and Lp is required for development of VA, demonstrating the location-dependent central role of IL-15 in CeD pathogenesis. Furthermore, our study reveals the critical role played by both CD4+ and cytotoxic CD8+ T cells in VA development. Finally, it establishes that HLA-DQ8 is central for tissue destruction, but dispensable for loss of oral tolerance to gluten. This mouse model, by reflecting the complex interplay between gluten, genetics and the IL-15-driven tissue inflammation found in CeD, represents a powerful preclinical model to test new therapeutics and study disease pathogenesis.
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Project description:Coeliac disease is a small intestinal disorder caused by an abarrent immune response towards dietary gluten due to activation of pro-inflammatory gluten specific CD4+ T cells. Histological evaluation and classification of gluten induced musosal changes is part of the diagnostic work up. of adults. The kinetics of mucosal recovery following commencesment of a gluten free diet (disease remission) and the degree of mucosal changes induced by gluten reintroduction (gluten challenge) varies between patients. Also, patients classified with similar clinical and histological disease remission, can develop different degree of mucosal damage following the same gluten challenge regime. This variation poses a challenge for the interpretation of gluten induced mucosal changes both in a diagnostic and clinical trial settings. In this study, we have analysed material from small intestinal biopsies collected from 19 treated coeliac disease patients before and after completion of a 14-day oral gluten challenge. These patients are part of a previoslpreviouslyu described study where all patients were in clinical and mucosal remission at baseline but only some patients developed histological changes in the mucosa in response to gluten. We have performed shotgun LC-MSMS analysis and label-free quantification of total gut tissue and from laser capture microdissected epithelial cell layer samples. We found that differences in tissue proteome expression could separate patients as responders and non-responders to the gluten challenge. Patients whoich responded strongly to gluten , had signs of gut inflammation already at baseline, supported by presence of low-level blood inflammatory parameters and a slight increase in numbers of gluten-specific CD4+ T cells at baseline. Our proteomics analysis demonstrated baseline differences in gut tissue state between patients that were not evident from routine clinical and histological evaluation. These baseline differences likely explains why some patients respond more strongly to gluten challenge than others.
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Project description:Rye, wheat and barley contain gluten, proteins that trigger immune-mediated inflammation of the small intestine in people with coeliac disease (CD). The only treatment for CD is a lifelong gluten-free diet. To be classified as gluten-free by the World Health Organisation the gluten content must be below 20 mg/kg, but Australia has a more rigorous standard of no detectable gluten and not made from wheat, barley, rye or oats. The purpose of this study was to devise an LC-MS/MS method to detect rye in food. An MS-based assay could overcome some of the limitations of current immunoassays, wherein antibodies often show cross-reactivity and lack specificity due to the diversity of gluten proteins in commercial food and the homology between rye and wheat gluten isoforms. Comprehensive proteomic analysis of 20 rye cultivars originating from 12 countries enabled the identification of a panel of candidate rye-specific peptide markers. The peptide markers were assessed in 16 cereal and pseudo-cereal grains, and in 10 breakfast cereals and 7 snacks foods. Spelt flour was contaminated with rye at a level of 2% and trace levels of rye were found in a breakfast cereal that based on its labelled ingredients should be gluten-free.
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Project description:Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes1,2. The need to develop non-dietary treatments is now widely recognized3, but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease4, the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies.
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Project description:Background. Assessment of non-HLA variants alongside standard HLA testing was previously shown to improve the identification of potential coeliac disease (CD) patients. We intended to identify new genetic variants associated with CD in the Polish population that would improve CD risk prediction when used alongside HLA haplotype analysis. Results. Association analysis using four HLA-tagging SNPs showed that, as was found in other populations, positive predicting genotypes (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, and HLA-DQ2.5/DQ8) were found at higher frequencies in CD patients than in healthy control individuals in the Polish population. Both CD-associated SNPs discovered by GWAS were found in the CD susceptibility region, confirming the previously-determined association of the major histocompatibility (MHC) region with CD pathogenesis. The two most significant SNPs from the GWAS were rs9272346 (HLA-dependent; localized within 1 Kb of DQA1) and rs3130484 (HLA-independent; mapped to MSH5). Specificity of CD prediction using the four HLA-tagging SNPs achieved 92.9%, but sensitivity was only 45.5%. However, when a testing combination of the HLA-tagging SNPs and the MSH5 SNP was used, specificity decreased to 80%, and sensitivity increased to 74%.
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