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Causes and Treatment of Very-Early Onset IBD

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Many infants with inflammatory bowel disease (IBD) have genetic defects that disrupt IL-10 signaling, according to the August issue of Gastroenterology. However, these children can be successfully treated by allogeneic hematopoietic stem cell transplantation, researchers report.

IBD develops mostly in adolescents and young adults, but can occur in very young children, including infants. Infant and very-early onset IBD (diagnosed at <than 6 years of age) results in severe growth failure and extensive colonic inflammation with lack of small bowel disease.

Daniel Kotlarz and Christoph Klein became interested in the disorder when Klein was asked to see a 6-year old who developed very-early onset severe IBD when he was 3 months old. “Due to this disease, he was hospitalized almost all his life and none of the therapies… induced any sustained remission,” said Klein, who became inspired to investigate causes of this severe and unusual disorder. His interest led to a genetic analysis of 66 children with very-early onset IBD (see video).

Video abstract from Daniel Kotlarz and Christoph Klein

Of the children analyzed, 16 were found to have loss-of-function mutations in IL10 orIL10R genes. Most patients were born to consanguineous parents and had homozygous biallelic mutations (point mutations or deletions), but some patients also had compound heterozygous mutations.

Allogeneic hematopoietic stem cell transplantation was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. Experiments confirmed reconstitution of IL-10 signaling in cells from all patients who received the transplant.

The authors did not observe clear genotype−phenotype correlations: 2 siblings with the same homozygous IL10RB mutation had distinct level of disease severity, indicating that other factors contribute to disease progression. Furthermore, mutations in IL-10−related genes were found in only a third of the patients with onset in the first year of life; the authors propose that variants in genes such as XIAP or NCF1 (p47-phox) could be involved.

IL-10 is an anti-inflammatory and immunosuppressive cytokine that acts on different immune cells through a transmembrane heterotetrameric complex (IL-10R). IL-10 primarily affects hematopoietic and immune cells, so transplantation of allogeneic hematopoietic stem cells can cure disorders in this signaling pathway.

In an editorial that accompanied the article, Aleixo Muise et al. say that the findings indicate that infants with colitis and perianal disease should be screened for IL-10 signaling defects. However, it is not clear whether it is effective to screen older children with severe perianal disease who are refractory to treatment.

Kotlarz et al. hope that researchers will investigate whether IL-10 signaling is associated with other forms of IBD. Although they found that allogeneic hematopoietic stem cell transplantation could successfully treat patients with IL-10 signaling deficiencies, some cases of early-onset IBD might be caused by dysfunction of non-hematopoietic cells, so other therapeutic approaches are necessary.

Read the article online.
Kotlarz D, Beier R, Murugan D, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 2012;143:347–355.

Read the accompanying editorial:
Muise AM, Snapper SB, Kugathasan S. The age of gene discovery in very early onset inflammatory bowel disease. Gastroenterology 2012;143:285–288.

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Kristine Novak

Kristine Novak

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About The Author:

Dr. Kristine Novak

Dr. Kristine Novak

Dr. Kristine Novak is a science writer and editor based in San Francisco. She has extensive experience covering gastroenterology, hepatology, immunology, oncology, clinical, and biotechnology research discoveries.

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