Gene Discovery Gives Clues to Crohn's Disease, Colitis, University College London Study

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Action Points

  • Explain that mutation in genes encoding proteins that are involved in the interleukin-10 signaling pathways are tied to severe inflammatory bowel disease.
  • Note that the mutations identified in the study are rare and recessive, and probably don’t contribute to less severe forms of the disease.

Genetic mutations in interleukin-10 receptors may be responsible for inflammatory bowel disease in patients who inherit the disorder, researchers said.

In an analysis of two children who had early onset of the disease and their families, the researchers found mutations in genes encoding the IL10R proteins, which make up interleukin-10 receptors, according to Erik-Oliver Glocker, MD, of University College London, and colleagues.

“The presence of severe inflammatory bowel disease is the most prominent phenotype in patients with IL10R1 or IL10R2 deficiency,” the researchers reported the Nov. 5 issue of the New England Journal of Medicine.

“We therefore infer that a lack of interleukin-10 signaling is the principal malfunction and is a likely cause of inflammatory bowel disease in patients with IL10R2 deficiency.”

In an accompanying editorial, Brian Kelsall, MD, of the National Institute of Allergy and Infectious Diseases, called the study the “first substantial support for a functional role for the immunosuppressive cytokine interleukin-10 in the pathogenesis of inflammatory bowel disease.”

According to the authors, the molecular cause of inflammatory bowel disease is largely unknown. But previous animal studies have shown that mice deficient in interleukin-10 or one of its receptors have severe enterocolitis.

Interleukin-10 restricts excessive immune responses and limits the secretion of proinflammatory cytokines, such as interleukin-12 and tumor necrosis factor-alpha (TNF-alpha), the researchers said.

So in their study, they examined the families of two unrelated children who have a severe form of Crohn’s disease that occurs in the first year of life. A total of 15 persons were assessed, including siblings.

Investigators analyzed the genomes of each family, performing gene-specific and protein-specific assays to determine the functional effects of the mutations on interleukin-10 signaling.

In four of nine patients with early-onset colitis, the researchers found three distinct homozygous mutations in genes IL10RA, IL10RB — which encode the IL10R1 and IL10R2 proteins, respectively — and ultimately make up the interleukin-10 receptor.

These mutations abrogate interleukin-10-induced signaling, the researchers said.

They also found increased secretion of tumor necrosis factor (TNF) alpha and other proinflammatory cytokines in patients deficient in IL10R proteins.

“We have shown that loss-of-function mutations in either IL10RA or IL10RB can be found in children with severe, early-onset enterocolitis,” they added.

The findings “are consistent with the idea that a lack of negative-feedback signaling mediated by interleukin-10 perturbs homeostasis of the intestinal immune system.”

They speculated that in the absence of any interleukin-10 mediated anti-inflammatory response, the presence of intestinal bacteria may lead to activation of a quick immune response, “resulting in a hyperinflammatory response with associated tissue damage.”

Meanwhile, with conventional therapy unsuccessful in the two young patients, the researchers attempted an allogenic stem-cell transplantation, which was successful.

Kelsall cautioned, however, that past trials of recombinant interleukin-10 in inflammatory bowel disease patients have been largely disappointing.

“Although interleukin-10 had an acceptable side-effect profile, systemic treatment with the drug did not prevent the recurrence of Crohn’s disease in patients after surgical resection,” he said, “and induced only modest responses in patients with corticosteroid-refractory Crohn’s disease and in those with mild-to-moderate ulcerative colitis.”

Kelsall also noted that the mutations identified in the study are rare and recessive, and probably don’t contribute to less severe forms of the disease.

He did, however, say that the study should “spur new energy to fuel the search for genetic and functional contributions by interleukin-10 and its receptors and their related signaling pathways in understanding the pathogenesis of inflammatory bowel disease and to re-evaluate therapeutic strategies.”

The study was supported by grants from the European Commission Marie Curie Excellence Program, the German Federal Ministry of Education and Research, the Intramural Research Program of the National Institutes of Health, and by fellowships from Deutsche Jose Carreras Leukamie-Stiftung and Else-Kroner-Fresenius-Stiftung.

A co-author reported financial relationships with Viamet, Cytokine PharmaSciences, and UCB.

Kelsall reported no conflicts of interest.

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