Hoarau Cyrille, Gérard Bénédicte, Lescanne Emmanuel, Henry Dominique, François Stéphanie, Lacapère Jean-Jacques, El Benna Jamel, Dang Pham My-Chan, Grandchamp Bernard, Lebranchu Yvon, Gougerot-Pocidalo Marie-Anne, Elbim Carole
Unité de Formation et de Recherche de Médecine, Cellules Dendritiques et Greffes, Université François Rabelais, Tours, France.
J Immunol. 2007 Oct 1;179(7):4754-65. doi: 10.4049/jimmunol.179.7.4754.
Polymorphonuclear neutrophils (PMN) play a key role in innate immunity. Their activation and survival are tightly regulated by microbial products via pattern recognition receptors such as TLRs, which mediate recruitment of the IL-1R-associated kinase (IRAK) complex. We describe a new inherited IRAK-4 deficiency in a child with recurrent pyogenic bacterial infections. Analysis of the IRAK4 gene showed compound heterozygosity with two mutations: a missense mutation in the death domain of the protein (pArg12Cys) associated in cis-with a predicted benign variant (pArg391His); and a splice site mutation in intron 7 that led to the skipping of exon 7. A nontruncated IRAK-4 protein was detected by Western blotting. The patient's functional deficiency of IRAK-4 protein was confirmed by the absence of IRAK-1 phosphorylation after stimulation with all TLR agonists tested. The patient's PMNs showed strongly impaired responses (L-selectin and CD11b expression, oxidative burst, cytokine production, cell survival) to TLR agonists which engage TLR1/2, TLR2/6, TLR4, and TLR7/8; in contrast, the patient's PMN responses to CpG-DNA (TLR9) were normal, except for cytokine production. The surprisingly normal effect of CpG-DNA on PMN functions and apoptosis disappeared after pretreatment with PI3K inhibitors. Together, these results suggest the existence of an IRAK-4-independent TLR9-induced transduction pathway leading to PI3K activation. This alternative pathway may play a key role in PMN control of infections by microorganisms other than pyogenic bacteria in inherited IRAK-4 deficiency.
多形核中性粒细胞（PMN）在固有免疫中起关键作用。它们的激活和存活通过模式识别受体（如Toll样受体（TLR））受微生物产物的严格调控，这些受体介导白细胞介素-1受体相关激酶（IRAK）复合物的募集。我们描述了一名患有复发性化脓性细菌感染儿童的一种新的遗传性IRAK-4缺陷。对IRAK4基因的分析显示为复合杂合性，存在两个突变：蛋白质死亡结构域中的错义突变（p.Arg12Cys），与一个预测的良性变异（p.Arg391His）顺式相关；以及内含子7中的剪接位点突变，导致外显子7跳跃。通过蛋白质印迹法检测到一种非截短的IRAK-4蛋白。在用所有测试的TLR激动剂刺激后，未检测到IRAK-1磷酸化，证实了患者IRAK-4蛋白的功能缺陷。患者的PMN对参与TLR1/2、TLR2/6、TLR4和TLR7/8的TLR激动剂表现出强烈受损的反应（L-选择素和CD11b表达、氧化爆发、细胞因子产生、细胞存活）；相比之下，患者的PMN对CpG-DNA（TLR9）的反应正常，但细胞因子产生除外。在用PI3K抑制剂预处理后，CpG-DNA对PMN功能和凋亡的惊人正常作用消失。总之，这些结果表明存在一条不依赖IRAK-4的TLR9诱导的转导途径，导致PI3K激活。这条替代途径可能在遗传性IRAK-4缺陷中PMN对除化脓性细菌以外的微生物感染的控制中起关键作用。
