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Could the Dual Activation of IRF1 and IRF1-Regulated Genes Be a Key to Celiac Disease Symptoms?

A new study shows that activation of IRF1 and IRF1-regulated genes together, both directly and via the interleukin-18 dependent inflammasome, would greatly increase the severity of the inflammatory response.


Genes acting in concert could worsen celiac disease symptoms. Photo: CC--Glen Bowman

Celiac.com 10/18/2017 - Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten.

A team of researchers recently set out to clarify the role of small intestinal epithelial cells in the immunopathology of celiac disease, especially the influence of celiac disease-associated bacteria.

The research team included G Pietz, R De, M Hedberg, V Sjöberg, O Sandström, O Hernell, S Hammarström, and ML Hammarström. They are variously affiliated with the Department of Clinical Microbiology, Immunology, and the Department of Clinical Sciences and Pediatrics at Umeå University, in Umeå, Sweden.

The team collected duodenal biopsies from children with active celiac disease, treated celiac disease, and a group of clinical control subjects.

They then purified intestinal epithelial cells, and analyzed them for gene expression changes at the mRNA and protein levels.

To assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells, they used two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers.

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In patients with active celiac disease, intestinal epithelial cells significantly upregulated more than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1.

Of these genes, 70 percent were upregulated by interferon-γ via the IRF1 pathway. Notably, IRF1 was also upregulated by bacteria associated with celiac disease.

Intestinal epithelial cells also expressed the NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes.

Over-expression of IRF1 appears to be a key factor in the epithelial reaction in celiac disease. This may be inherent, but may also be due to presence of undesirable microbes that trigger or influence IRF1.

From this study, the researchers conclude that activation of IRF1 and IRF1-regulated genes together, both directly and via the interleukin-18 dependent inflammasome, would greatly increase the severity of the inflammatory response, and trigger the pathological gut response that is common in active celiac disease. Could this provide a key to unlocking the mysteries of celiac disease and its associated symptoms?

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