Inflammatory Bowel Disease and Mutations Affecting the Interleukin-10 Receptor

作者：Erik‐Oliver Glocker, Daniel Kotlarz, Kaan Boztuǧ, E. Michael Gertz, Alejandro A. Schäffer, Fatih Noyan, Mario Perro, Jana Diestelhorst, Anna Allroth, Dhaarini Murugan, Nadine Hätscher, Dietmar Pfeifer, Karl‐Walter Sykora, Martin G. Sauer, Hans Kreipe, Martin Lacher, R. Nustede, Cristina Woellner, Ulrich Baumann, Ulrich Salzer, Sibylle Koletzko, Neil Shah, Anthony W. Segal, Axel Sauerbrey, Stephan Buderus, Scott B. Snapper, Bodo Grimbacher, Christoph Klein · 发表于：New England Journal of Medicine · 年份：2009 · DOI：10.1056/nejmoa0907206 · 被引用次数：1455 · 研究领域：Inflammatory Bowel Disease、T-cell and B-cell Immunology、Immunodeficiency and Autoimmune Disorders

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 pati...