Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.
Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.
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DOI：
10.1056/nejmoa0907206
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发表时间：
2009-11-19
期刊：
影响因子：
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通讯作者：
Klein C
中科院分区：
文献类型：
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作者：
Glocker EO;Kotlarz D;Boztug K;Gertz EM;Schäffer AA;Noyan F;Perro M;Diestelhorst J;Allroth A;Murugan D;Hätscher N;Pfeifer D;Sykora KW;Sauer M;Kreipe H;Lacher M;Nustede R;Woellner C;Baumann U;Salzer U;Koletzko S;Shah N;Segal AW;Sauerbrey A;Buderus S;Snapper SB;Grimbacher B;Klein C
炎症性肠病的分子病因在很大程度上是未知的。我们对两个无血缘关系的家庭的样本进行了遗传连锁分析和候选基因测序，这些家庭的孩子都患有早发性炎症性肠病。我们对另外6名早发性结肠炎患者进行了两个候选基因的突变筛查，并对患者的外周血单核细胞进行了功能分析。我们在一名患者中进行了异基因造血干细胞移植。在9名早发性结肠炎患者中的4名患者中，我们发现了IL10RA和IL10RB基因的三个不同的纯合子突变，分别编码IL10R1和IL10R2蛋白，这两个蛋白形成了组成白细胞介素10受体的异源四聚体。这些突变消除了白介素10诱导的信号转导，表现为在白介素10刺激下STAT3(信号转导和转录激活子3)的磷酸化缺失。与此一致的是，IL10R亚单位蛋白缺陷患者的外周血单个核细胞分泌肿瘤坏死因子α和其他促炎细胞因子增加，这表明这些细胞中依赖白细胞介素10的“负反馈”调节被破坏。1例患者的异基因干细胞移植获得成功。在早发性小肠结肠炎患者中发现了编码IL10R亚单位蛋白的基因突变，涉及肠道的高炎性免疫反应。异基因干细胞移植导致一名患者病情缓解。
The molecular cause of inflammatory bowel disease is largely unknown. 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. 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. 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.