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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
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.
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.
Source Information
The authors' affiliations are listed in the Appendix.
Drs. Glocker, Kotlarz, Boztug, Grimbacher, and Klein contributed equally to this article.
This article (10.1056/NEJMoa0907206) was published on November 4, 2009, at NEJM.org.
Address reprint requests to Dr. Klein at the Department of Pediatric Hematology/Oncology, Hannover Medical School, Carl-Neuberg-Straße, 1 D-30625, Hannover, Germany, or at klein.christoph{at}mh-hannover.de; or to Dr. Grimbacher at the Department of Immunology and Molecular Pathology, Royal Free Hospital and University College London, Pond St., London NW3 2QG, United Kingdom, or at b.grimbacher{at}ucl.ac.uk.
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