Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.
Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.
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DOI：
10.1016/j.jaci.2009.05.004
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发表时间：
2009-08
影响因子：
14.2
通讯作者：
Chatila, Talal
中科院分区：
文献类型：
--
作者：
Al Khatib, Shadi;Keles, Sevgi;Garcia-Lioret, Maria;Koc-Aydiner, Elif Kara;Reisli, Ismail;Artac, Hasibe;Camcioglu, Yildiz;Cokugras, Haluk;Somer, Ayper;Kutukculer, Necil;Yilmaz, Mustafa;Ikinciogullari, Aydan;Yegin, Olcay;Yuksek, Mutlu;Genel, Ferah;Kucukosmanoglu, Ercan;Baki, Ali;Bahceciler, Nerin N.;Rambhatla, Anupama;Nickerson, Derek W.;McGhee, Sean;Barlan, Isil B.;Chatila, Talal
高IgE综合征(HIEs)的特征是脓肿、湿疹、反复感染、骨骼和结缔组织异常、血清IgE升高和炎症反应减弱。它以常染色体显性(AD)和隐性(AR)形式存在，表现出共同和不同的临床特征。大多数AD-HIEs患者存在信号转导和转录激活因子3(STAT3)杂合突变和Th17分化障碍。以阐明不同形式的HIE的潜在机制。通过DNA测序，对25名被诊断为HIE的土耳其儿童进行了STAT3突变检查。用抗p(P)STAT3和pSTAT1抗体进行细胞内染色，检测IL-6和IL-21对STAT3的激活和干扰素α对STAT1的激活。通过检测IL-17和干扰素γ的产生来评估Th17和Th1细胞的分化。有6名受试者有影响DNA结合、SH2和反式激活结构域的STAT3突变，其中包括3个新的突变。突变阳性但非突变阴性的HIEs受试者在细胞因子刺激下STAT3的磷酸化程度降低，而pSTAT1的激活不受影响。两组患者都表现出Th17反应受损，但尽管STAT3突变破坏了Th17分化的早期步骤，但STAT3正常的HIE患者的缺陷(S)影响了更多的远端步骤。在这群患有HIE的土耳其儿童中，大多数人的STAT3正常，这与疾病的发病机制有关。无论STAT3突变状态如何，Th17反应受损都很明显，这表明不同的HIE基因形式共享共同的功能结果。
The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE and diminished inflammatory responses. It exists as autosomal dominant (AD) and recessive (AR) forms that manifest common and distinguishing clinical features. A majority of those with AD-HIES suffers from heterozygous mutations in Signal Transducer and Activator of Transcription 3 (STAT3) and impaired Th17 differentiation. To elucidate mechanisms underlying different forms of HIES. A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by interferon alpha (IFNα) was assessed by intracellular staining with anti-phospho (p)STAT3 and pSTAT1 antibodies. Th17 and Th1 cell differentiation was assessed by measuring the production of IL-17 and IFNγ, respectively. Six subjects had STAT3 mutations affecting the DNA binding, SH2 and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative HIES subjects exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, while pSTAT1 activation was unaffected. Both patient groups exhibited impaired Th17 responses, but whereas STAT3 mutations abrogated early steps in Th17 differentiation, the defect(s) in HIES patients with normal STAT3 affected more distal steps. In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired Th17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.
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影响因子：
30.5
作者：
Acosta-Rodriguez, Eva V.;Napolitani, Giorgio;Sallusto, Federica
通讯作者：
Sallusto, Federica
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
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：
158.5
作者：
Grimbacher, B;Holland, SM;Puck, JM
通讯作者：
Puck, JM