IRAK-4 mutation (Q293X):: Rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells
IRAK-4 mutation (Q293X):: Rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells
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DOI：
10.4049/jimmunol.177.11.8202
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发表时间：
2006-12-01
影响因子：
4.4
通讯作者：
Speert, David P.
中科院分区：
文献类型：
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作者：
Davidson, Donald J.;Currie, Andrew J.;Speert, David P.
先天性免疫缺陷最近被报道是由于Q293 X IRAK-4突变导致TLR/IL-1 R信号传导缺陷。在这项研究中，我们报告了一种快速等位基因特异性检测这种突变的方法，并证明了细胞类型特异性和配体特异性缺陷的IL-1 R相关激酶（IRAK）4缺陷的细胞反应，表明这种蛋白质在人PBMC和原代真皮成纤维细胞和LPS，IL-1 β和TNF-α信号的差异作用。我们证明转录和转录后缺陷，尽管NF-κ B信号和完整的MyD 88独立的信号，并提出功能失调的复合物1（IRAK 1/TRAF 6/TAK 1）信号，作为IRAK-4缺陷的结果，产生特定的MAPK激活缺陷，可能支持该患者的先天性免疫缺陷。这些研究证明了研究携带临床相关突变的原代人类细胞的重要性;它们强调了先天免疫信号传导的复杂性，并阐明了IRAK-4的新作用以及辅助促炎信号传导对正常人类先天免疫应答和免疫缺陷的根本重要性。
Innate immunodeficiency has recently been reported as resulting from the Q293X IRAK-4 mutation with consequent defective TLR/IL-1R signaling. In this study we report a method for the rapid allele-specific detection of this mutation and demonstrate both cell type specificity and ligand specificity in defective IL-1R-associated kinase (IRAK) 4-deficient cellular responses, indicating differential roles for this protein in human PBMCs and primary dermal fibroblasts and in LPS, IL-1 beta, and TNF-alpha signaling. We demonstrate transcriptional and post-transcriptional defects despite NF-kappa B signaling and intact MyD88-independent signaling and propose that dysfunctional complex 1 (IRAK1/TRAF6/TAK1) signaling, as a consequence of IRAK-4 deficiency, generates specific defects in MAPK activation that could underpin this patient's innate immunodeficiency. These studies demonstrate the importance of studying primary human cells bearing a clinically relevant mutation; they underscore the complexity of innate immune signaling and illuminate novel roles for IRAK-4 and the fundamental importance of accessory proinflammatory signaling to normal human innate immune responses and, inummodeficiencies.