[HTML][HTML] Inflammatory bowel disease and mutations affecting the interleukin-10 receptor

EO Glocker, D Kotlarz, K Boztug… - … England Journal of …, 2009 - Mass Medical Soc
EO Glocker, D Kotlarz, K Boztug, EM Gertz, AA Schäffer, F Noyan, M Perro, J Diestelhorst…
New England Journal of Medicine, 2009Mass Medical Soc
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 …
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 α 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.
The New England Journal Of Medicine