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Genome-wide analysis of B and T cell gene expression during a six-week gluten challenge in patients with celiac disease

ABSTRACT: Dietary gluten proteins (prolamins) from wheat, rye, and barley are the driving forces behind celiac disease, an organ-specific autoimmune disorder that targets both the small intestine and organs outside the gut. In the small intestine, gluten induces inflammation and a typical morphological change of villous atrophy and crypt hyperplasia. Gut lesions improve and heal when gluten is excluded from the diet and the disease relapses when patients consume gluten. Oral immune tolerance towards gluten may be kept for years or decades before breaking tolerance in genetically susceptible individuals. Celiac disease provides a unique opportunity to study autoimmunity and the transition in immune cells as gluten breaks oral tolerance. Seventy-three celiac disease patients on a long-term gluten-free diet ingested a known amount of gluten daily for six weeks. A peripheral blood sample and intestinal biopsies were taken before and six weeks after initiating the gluten challenge. Biopsy results were reported on a continuous numeric scale that measured the villus height to crypt depth ratio to quantify gluten-induced gut mucosal injury. Pooled B and T cells were isolated from whole blood, and RNA was analyzed by DNA microarray looking for changes in peripheral B- and T-cell gene expression that correlated with changes in villus height to crypt depth, as patients maintained or broke oral tolerance in the face of a gluten challenge.

ORGANISM(S): Homo sapiens

PROVIDER: GSE87629 | GEO | 2017/01/27

SECONDARY ACCESSION(S): PRJNA345434

REPOSITORIES: GEO

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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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Genome-wide analysis of B and T cell gene expression during a six-week gluten challenge in patients with celiac disease

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