A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy.
A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy.
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DOI：
10.1126/scitranslmed.3007410
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发表时间：
2014-01-08
影响因子：
17.1
通讯作者：
Benson M
中科院分区：
文献类型：
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作者：
Bruhn S;Fang Y;Barrenäs F;Gustafsson M;Zhang H;Konstantinell A;Krönke A;Sönnichsen B;Bresnick A;Dulyaninova N;Wang H;Zhao Y;Klingelhöfer J;Ambartsumian N;Beck MK;Nestor C;Bona E;Xiang Z;Benson M
在常见疾病中，诊断标记和治疗候选基因的鉴定由于涉及数千个基因而变得复杂。我们假设与过敏症关键基因IL 13共调控的基因将形成一个模块，有助于识别候选基因。我们通过小干扰RNA介导的敲低25个假定的IL 13调节转录因子，然后进行表达谱分析，确定了T辅助细胞2（TH2）细胞模块。该模块包含候选基因，其诊断潜力得到了临床研究的支持。人类TH2细胞以及小鼠过敏模型的功能研究表明，缺失其中一个基因S100A4，导致过敏症状减少，包括TH2细胞活化、体液免疫和效应细胞浸润。树突状细胞需要S100A4来激活T细胞。用抗S100A4抗体治疗导致小鼠模型中的过敏症状减少，以及过敏患者的过敏原攻击T细胞减少。这一策略，这可能是普遍适用于复杂的疾病，确定和验证了一个重要的诊断和治疗过敏症的候选基因。
The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (TH2) cell module by small interfering RNA–mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.