Della Mina Erika, Borghesi Alessandro, Zhou Hao, Bougarn Salim, Boughorbel Sabri, Israel Laura, Meloni Ilaria, Chrabieh Maya, Ling Yun, Itan Yuval, Renieri Alessandra, Mazzucchelli Iolanda, Basso Sabrina, Pavone Piero, Falsaperla Raffaele, Ciccone Roberto, Cerbo Rosa Maria, Stronati Mauro, Picard Capucine, Zuffardi Orsetta, Abel Laurent, Chaussabel Damien, Marr Nico, Li Xiaoxia, Casanova Jean-Laurent, Puel Anne
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.
Imagine Institute, Paris Descartes University, 75015 Paris, France.
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E514-E523. doi: 10.1073/pnas.1620139114. Epub 2017 Jan 9.
Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4- or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient's fibroblasts, which responded very poorly to all TLR2/6 (PAMCSK, LTA, FSL-1), TLR1/2 (PAMCSK), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient's peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.
Toll样受体（TLR）家族和白细胞介素-1受体（IL-1R）家族的大多数成员通过涉及髓样分化因子88（MyD88）衔接蛋白和白细胞介素-1受体相关激酶（IRAK）复合物的经典途径转导信号。该复合物包含四个分子，其中至少有两个（IRAK-1和IRAK-4）是活性激酶。在小鼠和人类中，IRAK-4或MyD88的缺陷会消除白细胞和成纤维细胞中大多数TLR（TLR3和某些TLR4除外）和IL-1R信号。在缺乏IRAK-1的小鼠中，TLR和IL-1R反应较弱但并未消除，而IRAK-1在人类中的作用仍不清楚。我们在此描述一名患有X连锁MECP2缺乏相关综合征的男孩，其因一个大的新发Xq28染色体缺失，该缺失同时涵盖了MECP2和IRAK1。与许多患有MECP2无效突变的男孩一样，这名儿童在7个月大时就很早夭折。与大多数IRAK-4或MyD88缺陷患者不同，他在短暂的生命中并未患侵袭性细菌疾病。患者的成纤维细胞中完全不存在IRAK-1蛋白，这些细胞对所有测试的TLR2/6（PAMCSK、LTA、FSL-1）、TLR1/2（PAMCSK）和TLR4（LPS、MPLA）激动剂反应非常差，但对IL-1β的反应几乎未受影响。相比之下，患者的外周血单核细胞对所有测试的TLR1/2、TLR2/6、TLR4、TLR7和TLR8（R848）激动剂以及IL-1β反应正常。这名儿童的死亡使得无法对遗传性IRAK-1缺乏的临床后果进行长期评估。然而，这些发现表明，人类IRAK-1在成纤维细胞中是TLR下游而非IL-1R下游所必需的，而在白细胞中它在TLR和IL-1R下游均起冗余作用。
