背景:高IgE综合征(HIES)是一种原发性免疫缺陷,其特征是肺部和皮肤感染,血清IgE升高,以及软组织和骨组织的受累。最近,HIES与信号转导和转录激活因子3(STAT3)中的杂合显性阴性突变和T(H)17细胞的严重减少有关。
目的:确定HIES患者的基因型与表型之间是否存在相关性,并建立诊断标准以区分STAT3突变和STAT3野生型患者。
方法:我们收集了临床数据,确定T(H)17个细胞数,并对100例临床怀疑为HIES且血清IgE>1000IU/mL的患者进行了STAT3测序。我们通过使用机器学习方法来探索诊断标准,以确定哪些特征最好地预测STAT3突变。
结果:在64例患者中,我们鉴定了31种不同的STAT3突变,其中18个是小说。这些包括在剪接位点和先前涉及的DNA结合和Src同源2结构域外部的突变。5种临床特征的组合预测STAT3突变的准确率为85%。T(H)17细胞在携带STAT3突变的患者中显著减少,13例无突变患者中有10例的T(H)17细胞较低(<1%),但其差异在于产生IFN-γ的CD4(+)T细胞显著减少.
结论:我们提出以下STAT3缺陷型HIES的诊断指南。可能:IgE>1000IU/mL加上基于复发性肺炎的临床特征加权评分>30,新生皮疹,病理性骨折,特征性的面孔,和高口感。可能:这些特征加上缺乏T(H)17细胞或明确的HIES家族史。明确的:这些特征加上STAT3中的显性阴性杂合突变。
BACKGROUND: The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells.
OBJECTIVE: To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients.
METHODS: We collected clinical data, determined T(H)17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation.
RESULTS: In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T(H)17 cells but were distinct by markedly reduced IFN-gamma-producing CD4(+)T cells.
CONCLUSIONS: We propose the following diagnostic
guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.