Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.
Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.
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DOI：
10.1016/j.jaci.2009.10.059
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发表时间：
2010-02
影响因子：
14.2
通讯作者：
Grimbacher, Bodo
中科院分区：
文献类型：
--
作者：
Woellner, Cristina;Gertz, E. Michael;Schaeffer, Alejandro A.;Lagos, Macarena;Perro, Mario;Glocker, Erik-Oliver;Pietrogrande, Maria C.;Cossu, Fausto;Franco, Josee L.;Matamoros, Nuria;Pietrucha, Barbara;Heropolitanska-Pliszka, Edyta;Yeganeh, Mehdi;Moin, Mostafa;Espanol, Teresa;Ehl, Stephan;Gennery, Andrew R.;Abinun, Mario;Breborowicz, Anna;Niehues, Tim;Kilic, Sara Sebnem;Junker, Anne;Turvey, Stuart E.;Plebani, Alessandro;Sanchez, Berta;Garty, Ben-Zion;Pignata, Claudio;Cancrini, Caterina;Litzman, Jiri;Sanal, Oezden;Baumann, Ulrich;Bacchetta, Rosa;Hsu, Amy P.;Davis, Joie N.;Hammarstroem, Lennart;Davies, E. Graham;Eren, Efrem;Arkwright, Peter D.;Moilanen, Jukka S.;Viemann, Dorothee;Khan, Sujoy;Laszlo Marodi;Cant, Andrew J.;Freeman, Alexandra F.;Puck, Jennifer M.;Holland, Steven M.;Grimbacher, Bodo
高IgE综合征（hyper-IgE syndrome，HIES）是一种原发性免疫缺陷病，其特征是肺部和皮肤感染、血清IgE升高以及软组织受累。最近，HIES与STAT3的杂合显性负突变和Th17细胞的严重减少有关。确定HIES患者的基因型和表型之间是否存在相关性，并建立区分STAT3突变型和野生型患者的诊断标准。我们收集了100名临床上高度怀疑患有HIES且血清IgE> 1000 IU/mL的患者的临床数据，测定了Th17细胞数量，并对STAT3进行了测序。通过使用机器学习方法探索诊断标准，以确定哪些特征最能预测STAT3突变。在64例患者中，我们发现了31种不同的STAT3突变，其中18种是新的。这些突变包括剪接位点和先前涉及的DNA结合和SH2结构域之外的突变。五个临床特征的组合预测了STAT3突变，准确率为85%。在携带STAT3突变的患者中，Th17细胞显著减少，而13名没有突变的患者中有10名具有低（<1%）Th17细胞，但产生IFN-γ的CD4 + T细胞明显减少。我们提出了以下STAT3缺陷型HIES的诊断指南：可能：IgE> 1000 IU/mL加上基于复发性肺炎、新生儿皮疹、病理性骨折、特征性面部和高腭的临床特征加权评分> 30。很可能：以上加上缺乏Th17细胞或明确的HIES家族史。突变型：以上加上STAT3中的显性负杂合突变。
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 tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in STAT3 and severe reductions of Th17 cells. To determine whether there is a correlation between the genotype and phenotype of HIES patients and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients. We collected clinical data, determined Th17 cell numbers, and sequenced STAT3 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation. In 64 patients we identified 31 different STAT3 mutations, 18 of which are novel. These included mutations at splice sites and outside the previously implicated DNA-binding and SH2 domains. A combination of five clinical features predicted STAT3 mutations with 85% accuracy. Th17 cells were profoundly reduced in patients harboring STAT3 mutations, while 10 out of 13 patients without mutations had low (<1%) Th17 cells but were distinct markedly reduced IFN-γ producing CD4+ T cells. We propose the following diagnostic guidelines for STAT3-deficient HIES: Possible: IgE >1000 IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: Above plus lack of Th17 cells or a family history for definitive HIES. Definitive: Above plus a dominant-negative heterozygous mutation in STAT3.
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DOI：
10.1084/jem.20080218
发表时间：
2008-07-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ma CS;Chew GY;Simpson N;Priyadarshi A;Wong M;Grimbacher B;Fulcher DA;Tangye SG;Cook MC
通讯作者：
Cook MC
影响因子：
15.9
作者：
Levy, DE;Lee, CK
通讯作者：
Lee, CK
影响因子：
--
作者：
Moin, Mostafa;Farhoudi, Abolhassan;Aghamohammadi, Asghar
通讯作者：
Aghamohammadi, Asghar
影响因子：
158.5
作者：
Grimbacher, B;Holland, SM;Puck, JM
通讯作者：
Puck, JM
影响因子：
6.4
作者：
Huang, WT;Na, L;Schwarzenberger, P
通讯作者：
Schwarzenberger, P