A collaborative study by an international group including researchers from the National Institutes of Health, Hannover Medical School, and University College London, has identified mutations in two genes, interleukin-10 receptor 1 (IL10R1) and interleukin-10 receptor 2 (IL10R2), that cause inflammatory bowel disease (IBD) in children. The discovery enabled researchers to bring about disease remission in one of the patient participants by allogeneic hematopoietic stem cell transplantation. The findings are published in the recent issue of The New England Journal of Medicine.

The research group carried out a genetic-linkage analysis and candidate-gene sequencing on samples obtained from two unrelated consanguineous families with IBD-affected children. The researchers also examined mutations in two candidate genes in an additional six patients who suffered from early-onset colitis, and performed functional assays using the patients’ peripheral blood mononuclear cells. Allogeneic hematopoietic stem-cell transplantation was then carried out in one study participant.

The study reported that four out of nine patients suffering from early-onset colitis carried three distinct homozygous mutations in IL10RA and IL10RB genes. The genes code for IL10R1 and IL10R2 proteins that function together to receive signals from the IL-10 receptor. Mutations in these genes were seen to disrupt the IL-10-induced signaling, which was demonstrated by poor phosphorylation of STAT3 (signal transducer and activator of transcription 3) on stimulation with IL-10. The disrupted signaling in turn resulted in hyperinflammatory immune responses in the gastrointestinal system of the affected patients.

Consistent with these findings, the increased secretion of tumor necrosis factor and other proinflammatory cytokines from peripheral-blood mononuclear cells were also noted in patients with deficiency of IL10R subunit proteins, suggesting the disruption of IL-10-dependent negative feedback regulation in the cells. Allogenic bone marrow transplantation performed in a patient who had previously not responded to other treatment approaches, brought about dramatic improvements and helped the person remain in remission from the disease for over a year.

Several evidences have also shown the involvement of IL-6 in the development and perpetuation of IBD. A study by Carey et al (Inflammatory Bowel Diseases, 2008) documented upregulation of proinflammatory IL-6:STAT3-dependent biological network in the pathogenesis of pediatric-onset IBD patients at the time of diagnosis and during therapy. The researchers noted an upregulation of the circulating IL-6 in the patients and also observed an increased STAT3 activation in the peripheral blood granulocytes, affected colon biopsies, and IL-6-stimulated CD3⁺/CD4⁺ lymphocytes of these patients. The findings suggested that targeting IL-6:STAT3 network could aid in reducing mucosal inflammation.

According to the Centers for Disease Control and Prevention (CDC), the overall economic burden of IBD in the United States amounts to more than $1.7 billion. The condition responds poorly to medical treatment and requires lifelong care.

The current findings, which claim to be the first of its kind in illustrating that a single genetic mutation is adequate to cause IBD, could aid researchers in designing therapeutic strategies for pediatric as well as adult IBD patients with disrupted IL-10 signaling.

References

1. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory Bowel Disease and Mutations Affecting the Interleukin-10 Receptor. N Engl J Med. 2009 Nov 19;361(21):2033-45.

2. Researchers Discover Mutations in Two Genes that Cause Early-Onset Inflammatory Bowel Disease. Press Release. National Institutes of Health. Last accessed November 19, 2009.

3. Carey R, Jurickova I, Ballard E, et al. Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease. Inflamm Bowel Dis. 2008 Apr;14(4):446-57.