Abstract
Background & AimsCeliac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bacteria.MethodsDuodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells.ResultsMore than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells.ConclusionA key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease.
Highlights
Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy caused by permanent intolerance to the food antigen gliadin in wheat gluten and related prolamines in barley and rye [1,2]
Further analyzed results from genome-wide hybridization bead array for gene expression in intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs) are supplied in Supplementary file 1 (S1 File)
Raw data behind figures and tables from quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in the manuscript are supplied in Supplementary file 2 (S2 File)
Summary
Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy caused by permanent intolerance to the food antigen gliadin in wheat gluten and related prolamines in barley and rye [1,2]. In CD patients, intake of gluten causes an inflammatory lesion in the small intestine, characterized by villous atrophy and crypt hyperplasia and increased numbers of T lymphocytes both within the epithelium, so called intraepithelial lymphocytes (IELs), and the lamina propria. T lymphocytes play a central role in the pathogenesis of CD and gluten specific CD4 and CD8 expressing T lymphocytes have been isolated from the small intestinal mucosa of CD patients [12,13]. There are indications that an epithelial reaction plays a central role in initiating and maintaining CD, i.e. CD8+IELs constitute the major cellular source of IFN-γ, IL-17A, and IL-10 in the inflamed intestinal mucosa of biopsies collected at diagnosis [6,8,14]. We have previously demonstrated that there are bacteria adherent to the epithelium that are over-represented in CD patients, among these two new species that were isolated from small intestinal biopsies of CD patients [18,19,20,21], and that an IL-17A response is seen when biopsies of CD patients with inactive disease are challenged ex vivo with these CD-associated bacteria [8]
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