Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 361, Issue 21, Pages 2033-2045Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa0907206
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Funding
- European Commission Marie Curie Excellence program [MEXT-CT-2006-042316]
- Deutsche Forschungsgemeinschaft [SFB621]
- German Federal Ministry of Education and Research (PID-NET)
- Intramural Research Program of the National Institutes of Health
- Deutsche Jose Carreras Leukmie-Stiftung
- Else-Krner-Fresenius-Stiftung
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BACKGROUND The molecular cause of inflammatory bowel disease is largely unknown. METHODS We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease. We screened six additional patients with early-onset colitis for mutations in two candidate genes and carried out functional assays in patients' peripheral-blood mononuclear cells. We performed an allogeneic hematopoietic stem-cell transplantation in one patient. RESULTS In four of nine patients with early-onset colitis, we identified three distinct homozygous mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a heterotetramer to make up the interleukin-10 receptor. The mutations abrogate interleukin-10-induced signaling, as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10. Consistent with this observation was the increased secretion of tumor necrosis factor alpha and other proinflammatory cytokines from peripheral-blood mononuclear cells from patients who were deficient in IL10R subunit proteins, suggesting that interleukin-10-dependent negative feedback regulation is disrupted in these cells. The allogeneic stem-cell transplantation performed in one patient was successful. CONCLUSIONS Mutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis, involving hyperinflammatory immune responses in the intestine. Allogeneic stem-cell transplantation resulted in disease remission in one patient.
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