Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome.
Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome.
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DOI：
10.1084/jem.20082767
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发表时间：
2009-06-08
期刊：
影响因子：
--
通讯作者：
Karasuyama H
中科院分区：
文献类型：
--
作者：
Minegishi Y;Saito M;Nagasawa M;Takada H;Hara T;Tsuchiya S;Agematsu K;Yamada M;Kawamura N;Ariga T;Tsuge I;Karasuyama H
高IgE综合征（HIES）是一种原发性免疫缺陷，其特征在于特应性表现和对细胞外病原体（通常为金黄色葡萄球菌）感染的易感性，这些病原体优先影响皮肤和肺。先前的研究报道了HIES患者中由亚型STAT 3突变引起的辅助性T细胞17（Th 17）分化缺陷。然而，全身性Th 17缺陷和皮肤/肺限制性对葡萄球菌感染的易感性之间的明显矛盾仍然令人困惑。我们提出了一个可能的分子解释这一神秘的矛盾。HIES T细胞显示Th 17细胞因子的产生受损，但经典促炎细胞因子（包括白细胞介素1β）的产生正常。正常人角质形成细胞和支气管上皮细胞的抗葡萄球菌因子，包括嗜中性粒细胞招募趋化因子和抗菌肽的生产，深深依赖于Th 17细胞因子和经典的促炎细胞因子的协同作用。相比之下，其他类型的细胞有效地刺激与经典的促炎细胞因子单独产生这样的因素。因此，角质形成细胞和支气管上皮细胞，不像其他细胞类型，未能产生抗葡萄球菌因子响应HIES T细胞衍生的细胞因子。这些结果似乎至少部分解释了为什么HIES患者会发生局限于皮肤和肺部的复发性葡萄球菌感染，而非嗜中性粒细胞缺乏患者的全身感染。
Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular pathogens, typically Staphylococcus aureus, which preferentially affect the skin and lung. Previous studies reported the defective differentiation of T helper 17 (Th17) cells in HIES patients caused by hypomorphic STAT3 mutations. However, the apparent contradiction between the systemic Th17 deficiency and the skin/lung-restricted susceptibility to staphylococcal infections remains puzzling. We present a possible molecular explanation for this enigmatic contradiction. HIES T cells showed impaired production of Th17 cytokines but normal production of classical proinflammatory cytokines including interleukin 1β. Normal human keratinocytes and bronchial epithelial cells were deeply dependent on the synergistic action of Th17 cytokines and classical proinflammatory cytokines for their production of antistaphylococcal factors, including neutrophil-recruiting chemokines and antimicrobial peptides. In contrast, other cell types were efficiently stimulated with the classical proinflammatory cytokines alone to produce such factors. Accordingly, keratinocytes and bronchial epithelial cells, unlike other cell types, failed to produce antistaphylococcal factors in response to HIES T cell–derived cytokines. These results appear to explain, at least in part, why HIES patients suffer from recurrent staphylococcal infections confined to the skin and lung in contrast to more systemic infections in neutrophil-deficient patients.
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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：
6.4
作者：
Huang, WT;Na, L;Schwarzenberger, P
通讯作者：
Schwarzenberger, P
影响因子：
64.8
作者：
Minegishi, Yoshiyuki;Saito, Masako;Karasuyama, Hajime
通讯作者：
Karasuyama, Hajime
影响因子：
4.4
作者：
Chung, DR;Kasper, DL;Tzianabos, AO
通讯作者：
Tzianabos, AO
影响因子：
4.8
作者：
Lien, E;Sellati, TJ;Golenbock, DT
通讯作者：
Golenbock, DT