Defective IL10 Signaling Defi ning a Subgroup of Patients With Inflammatory Bowel Disease
Defective IL10 Signaling Defi ning a Subgroup of Patients With Inflammatory Bowel Disease
复制标题
DOI：
10.1038/ajg.2011.112
复制
发表时间：
2011-08-01
影响因子：
9.8
通讯作者：
Ruemmele, Frank M.
中科院分区：
文献类型：
--
作者：
Begue, Bernadette;Verdier, Julien;Ruemmele, Frank M.
目的：早发性炎症性肠病(EO-IBD)发生于出生第一年，可能反映了控制肠道稳态的关键机制(S)的遗传缺陷，最近对白介素10(IL10)的研究提出了这一点。因此，我们旨在进一步阐明IBD患者抗炎反应缺陷的假说。方法：分析75例IBD患儿(包括13例排除自身免疫性疾病或经典免疫缺陷的EO-IBD患儿)外周血单核细胞来源的树突状细胞(MoDC)或外周血细胞(PBMC)抑制致炎细胞因子产生的转化生长因子-β(TGF-β)和IL-10的能力。用流式细胞仪和免疫印迹法检测IL6、IL10、IL21、IL22对IL10受体A/-B表达、STAT3活化的影响。对IL10RA和B基因进行测序。在回肠/结肠组织培养中检测对IL22的反应。用Taqman实时定量聚合酶链式反应分析组织基因表达。结果：所有IBD患者对细菌基序的反应产生IL-10均正常。与我们最初的假设相反，在IBD或EO-IBD的儿童中，除了两名出生3个月时出现肉芽肿阳性结肠炎的婴儿外，没有观察到转化生长因子β和IL10的抗炎潜力缺陷：分别由于IL10R的α链(p.R262C)和β链(p.E141X)突变，没有观察到对IL10的继发性反应，尽管在这两个患者中都存在完全功能的JAK-STAT3途径。在分析肠道细菌清除调节时，我们发现缺乏IL10RB的患者上调保护性转录对IL22的反应存在缺陷，而所有其他EO-IBD患者，包括α链异常的患者，反应正常。结论：IL10信号受损是IBD患者的一个亚群特征，而包括EO形式在内的大多数严重IBD儿童正常产生IL10并对IL10做出反应。IL22信号的缺陷可能还会损害肠道上皮细胞的清除。我们的数据指出了IBD的复杂性，它代表了一组具有几种致病异常的不同疾病。
OBJECTIVES: Early onset inflammatory bowel diseases (EO-IBD) developing during the first year of life are likely to reflect inherited defects in key mechanism(s) controlling intestinal homeostasis, as recently suggested for interleukin 10 (IL10). Thus, we aimed to further elaborate the hypothesis of defective anti-inflammatory responses in patients with IBD.METHODS: The capacities of transforming growth factor beta (TGF beta) and IL10 to inhibit proinflammatory cytokine production by monocyte-derived dendritic cells (MoDC) or peripheral blood cells (PBMC) was analyzed in 75 children with IBD, including 13 infants with EO-IBD (in whom autoimmune diseases or classical immunodeficiencies were ruled out). IL10 receptor-A/-B expression, STAT3 activation in response to IL6, IL10, IL21, IL22 were analyzed by FACS and western blotting. IL10RA and B genes were sequenced. The response to IL22 was tested in ileal/colonic tissue cultures. Tissue gene expression was analyzed by Taqman real-time polymerase chain reaction.RESULTS: Production of IL10 in response to bacterial motifs was normal in all IBD patients. In contrast to our original hypothesis, no defect of the anti-inflammatory potential of TGF beta and IL10 was observed in children with IBD or EO-IBD except two infants who presented with granuloma-positive colitis at 3 months of life: no response to IL10 was observed secondary to mutations in the alpha (p.R262C) or beta (p.E141X) chain of IL10R, respectively, although a fully functional Jak-STAT3 pathway was present in both patients. When analyzing the regulation of intestinal bacterial clearance, we detected a defect in the patient with absent IL10 RB to upregulate protective transcripts in response to IL22, whereas all other EO-IBD patients, including the patient with an abnormal alpha chain, responded normally.CONCLUSIONS: Impaired IL10 signaling characterizes a subgroup of IBD patients, whereas the majority of children with severe IBD including EO forms normally produces and responds to IL10. Defective IL22 signaling may additionally impair intestinal epithelial clearance. Our data point out the complexity of IBD, which represent a group of distinct diseases with several pathogenetic abnormalities.