Al Khatib Shadi, Keles Sevgi, Garcia-Lloret Maria, Karakoc-Aydiner Elif, Reisli Ismail, Artac Hasibe, Camcioglu Yildiz, Cokugras Haluk, Somer Ayper, Kutukculer Necil, Yilmaz Mustafa, Ikinciogullari Aydan, Yegin Olcay, Yüksek Mutlu, Genel Ferah, Kucukosmanoglu Ercan, Baki Ali, Bahceciler Nerin N, Rambhatla Anupama, Nickerson Derek W, McGhee Sean, Barlan Isil B, Chatila Talal
Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, Calif 90095-1752, USA.
J Allergy Clin Immunol. 2009 Aug;124(2):342-8, 348.e1-5. doi: 10.1016/j.jaci.2009.05.004. Epub 2009 Jul 3.
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 and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 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 IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively.
Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES 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 T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.
高免疫球蛋白E综合征（HIES）的特征为脓肿、湿疹、反复感染、骨骼和结缔组织异常、血清免疫球蛋白E升高以及炎症反应减弱。它以常染色体显性和常染色体隐性形式存在，表现出共同和独特的临床特征。大多数常染色体显性HIES患者在信号转导和转录激活因子（STAT）-3中存在杂合突变，且辅助性T细胞（TH）17分化受损。
阐明不同形式HIES的潜在机制。
对25名被诊断为HIES的土耳其儿童进行队列研究，通过DNA测序检测STAT3突变。用抗磷酸化（p）STAT3和-pSTAT1抗体进行细胞内染色，评估白细胞介素（IL）-6和IL-21对STAT3的激活以及干扰素-α对STAT1的激活。分别通过测量IL-17和干扰素-γ的产生来评估TH17和TH1细胞分化。
6名受试者存在影响DNA结合、Src同源2和反式激活结构域的STAT3突变，其中包括3个新发现的突变。HIES患者中，有STAT3突变的受试者（而非无突变的受试者）在细胞因子刺激后STAT3磷酸化水平降低，而pSTAT1激活未受影响。两组患者的TH17反应均受损，但STAT3突变消除了TH17分化的早期步骤，而STAT3正常的HIES患者的缺陷影响了更下游的步骤。
在这组土耳其HIES儿童中，大多数患者的STAT3正常，这表明疾病发病机制中存在其他靶点。无论STAT3突变状态如何，TH17反应受损都很明显，这表明不同遗传形式的HIES具有共同的功能结果。
