STAT3 mutations in the hyper-IgE syndrome
STAT3 mutations in the hyper-IgE syndrome
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DOI：
10.1056/nejmoa073687
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发表时间：
2007-10-18
影响因子：
158.5
通讯作者：
Grimbacher, Bodo
中科院分区：
文献类型：
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作者：
Holland, Steven M.;Deleo, Frank R.;Grimbacher, Bodo
背景高IgE综合征（hyper-IgE syndrome，又称Job's syndrome）是一种罕见的免疫和结缔组织疾病，以皮炎、疖肿、囊肿形成性肺炎、血清IgE水平升高、乳牙列滞留和骨骼异常为特征。遗传为常染色体显性遗传;方法我们收集了高IgE综合征患者及其家族的纵向临床资料，并测定了刺激白细胞分泌的细胞因子水平以及静息和刺激细胞中的基因表达。这些数据牵连的信号转导子和转录激活子3基因（STAT 3）作为候选基因，我们然后sequenced.ResultsWe发现增加水平的促炎基因转录在未受刺激的外周血中性粒细胞和单核细胞的高IgE综合征的患者，与对照细胞的水平相比。在体外培养的单核细胞从患者刺激脂多糖，有或没有干扰素-（γ），有较高的肿瘤坏死因子（α）水平比同样处理的细胞从未受影响的人（P=0.003）。相比之下，高IgE综合征患者的细胞在白细胞介素-6的存在下产生较低水平的单核细胞趋化蛋白1（P=0.03），表明白细胞介素-6通过其下游介质（其中之一是STAT 3）信号传导的缺陷。我们在50例家族性和散发性高IgE综合征病例中发现了STAT 3的错义突变和单密码子框内缺失。18个离散的突变，其中5个是热点，预测直接影响的DNA结合和SRC同源2（SH 2）domains.ConclusionsSTAT3突变的基础散发和显性形式的高IgE综合征，免疫缺陷综合征，涉及先天免疫反应增加，经常性感染，和复杂的躯体功能。
BackgroundThe hyper-IgE syndrome (or Job's syndrome) is a rare disorder of immunity and connective tissue characterized by dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and bone abnormalities. Inheritance is autosomal dominant; sporadic cases are also found.MethodsWe collected longitudinal clinical data on patients with the hyper-IgE syndrome and their families and assayed the levels of cytokines secreted by stimulated leukocytes and the gene expression in resting and stimulated cells. These data implicated the signal transducer and activator of transcription 3 gene (STAT3) as a candidate gene, which we then sequenced.ResultsWe found increased levels of proinflammatory gene transcripts in unstimulated peripheral-blood neutrophils and mononuclear cells from patients with the hyper-IgE syndrome, as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide, with or without interferon-(gamma), had higher tumor necrosis factor (alpha) levels than did identically treated cells from unaffected persons (P=0.003). In contrast, the cells from patients with the hyper-IgE syndrome generated lower levels of monocyte chemoattractant protein 1 in response to the presence of interleukin-6 (P=0.03), suggesting a defect in interleukin-6 signaling through its downstream mediators, one of which is STAT3. We identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of the hyper-IgE syndrome. Eighteen discrete mutations, five of which were hot spots, were predicted to directly affect the DNA-binding and SRC homology 2 (SH2) domains.ConclusionsMutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features.