Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
J Transl Med. 2010 Jan 27;8:6. doi: 10.1186/1479-5876-8-6.
Activation of Toll-like receptors (TLRs) is widely accepted as an essential event for defence against infection. Many TLRs utilize a common signalling pathway that relies on activation of the kinase IRAK4 and the transcription factor NFkappaB for the rapid expression of immunity genes.
21 K DNA microarray technology was used to evaluate LPS-induced (TLR4) gene responses in blood monocytes from a child with an IRAK4-deficiency. In vitro responsiveness to LPS was confirmed by real-time PCR and ELISA and compared to the clinical predisposition of the child and IRAK4-deficient mice to Gram negative infection.
We demonstrated that the vast majority of LPS-responsive genes in IRAK4-deficient monocytes were greatly suppressed, an observation that is consistent with the described role for IRAK4 as an essential component of TLR4 signalling. The severely impaired response to LPS, however, is inconsistent with a remarkably low incidence of Gram negative infections observed in this child and other children with IRAK4-deficiency. This unpredicted clinical phenotype was validated by demonstrating that IRAK4-deficient mice had a similar resistance to infection with Gram negative S. typhimurium as wildtype mice. A number of immunity genes, such as chemokines, were expressed at normal levels in human IRAK4-deficient monocytes, indicating that particular IRAK4-independent elements within the repertoire of TLR4-induced responses are expressed.
Sufficient defence to Gram negative immunity does not require IRAK4 or a robust, 'classic' inflammatory and immune response.
Toll 样受体 (TLRs) 的激活被广泛认为是对抗感染的必要事件。许多 TLR 利用一种共同的信号通路，该通路依赖于 IRAK4 激酶的激活和转录因子 NFkappaB，以快速表达免疫基因。
使用 21 K DNA 微阵列技术评估 IRAK4 缺陷儿童血液单核细胞中 LPS 诱导（TLR4）基因反应。通过实时 PCR 和 ELISA 确认对 LPS 的体外反应性，并与儿童和 IRAK4 缺陷小鼠对革兰氏阴性感染的临床易感性进行比较。
我们证明 IRAK4 缺陷单核细胞中绝大多数 LPS 反应基因受到极大抑制，这一观察结果与 IRAK4 作为 TLR4 信号的必需组成部分的描述作用一致。然而，对 LPS 的反应严重受损与该儿童和其他 IRAK4 缺陷儿童观察到的革兰氏阴性感染发生率极低不一致。通过证明 IRAK4 缺陷小鼠对革兰氏阴性 S. typhimurium 的感染具有与野生型小鼠相似的抵抗力，验证了这种出乎意料的临床表型。一些免疫基因，如趋化因子，在人类 IRAK4 缺陷单核细胞中以正常水平表达，表明 TLR4 诱导反应的特定 IRAK4 非依赖性元件被表达。
革兰氏阴性免疫防御不需要 IRAK4 或强大的“经典”炎症和免疫反应。
