Primary immunodeficiency to pneumococcal infection due to a defect in toll-like receptor signaling
Primary immunodeficiency to pneumococcal infection due to a defect in toll-like receptor signaling
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DOI：
10.1016/j.jpeds.2003.10.034
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发表时间：
2004-04-01
影响因子：
5.1
通讯作者：
Speert, DP
中科院分区：
文献类型：
--
作者：
Currie, AJ;Davidson, DJ;Speert, DP
目的人Toll样受体（TLR）在体内启动保护性免疫应答中的作用尚不清楚。我们研究了TLR信号在防御感染的作用，在一个3岁的男孩与一个严重的缺陷，导致复发性肺炎链球菌bacteremia.Methods经典的免疫缺陷被排除后，病人的单核细胞，巨噬细胞和树突状细胞（DC）进行了研究。TLR信号反应的范围TLR和白细胞介素-1受体（IL-1 R）特异性激动剂进行了研究前和转录后通过测量NF-κ B易位和细胞因子mRNA和蛋白质expression.Results患者的单核细胞因子的生产在响应范围内的微生物来源的TLR激动剂和重组IL-1 β或IL-18的深刻缺陷。脂多糖（LPS）诱导的NF-κ B p50和p6 s的易位和LPS诱导的细胞因子mRNA转录的动力学是正常的，除了IL-6和IL-12 p40，这是转录不良。尽管缺乏反应TLR激动剂的患者的DC和B细胞，CD 40 L的反应是normal.Conclusions我们描述了一个病人缺乏TLR介导的细胞因子的生产与完整的白细胞介素受体相关激酶（IRAK）-4的表达，NF-κ B易位，并增强感染的易感性。这位病人证明，TLR信号，在完整的抗体反应的存在下，可能是一个非冗余的防御化脓性感染的要求。
Objective The role of human Toll-like receptors (TLRs) in initiating protective immune responses in vivo is not well understood. We investigated the role of TLR signaling in defense against infection in a 3-year-old boy with a severe defect resulting in recurrent Streptococcus pneumoniae bacteremia.Methods After classic immunodeficiencies were ruled out, the patient's mononuclear cells, macrophages, and dendritic cells (DCs) were studied. TLR signaling responses to a range of TLR- and interleukin-1 receptor (IL-1R)-specific agonists were investigated pre- and posttranscriptionally by measuring NF-KB translocation and cytokine mRNA and protein expression.Results The patient's monocytic cells were profoundly deficient in cytokine production in response to a range of microbial-derived TLR agonists and to recombinant IL-1beta or IL-18. Lipopolysaccharide (LPS)-induced translocation of NF-KB p50 and p6s and the kinetics of LPS-induced cytokine mRNA transcription were normal except for IL-6 and IL-12p40, which were poorly transcribed. Despite deficient responses to TLR agonists by the patient's DCs and B cells, CD40L responses were normal.Conclusions We describe a patient with deficient TLR-mediated cytokine production with intact interleukin receptor-associated kinase (IRAK)-4 expression, NF-KB translocation, and enhanced susceptibility to infection. This patient demonstrates that TLR signaling, in the presence of intact antibody responses, may be a nonredundant requirement for defense against pyogenic infections.