Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a toll-like receptor 9-dependent pathway
Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a toll-like receptor 9-dependent pathway
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DOI：
10.4049/jimmunol.172.8.4926
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发表时间：
2004-04-15
影响因子：
4.4
通讯作者：
Hasegawa, H
中科院分区：
文献类型：
--
作者：
Pichyangkul, S;Yongvanitchit, K;Hasegawa, H
恶性疟原虫严重感染的一个共同特征是促炎细胞因子的全身释放增加，这有助于疟疾的发病机制。使用人类血液，我们发现血液阶段树突状细胞或可溶性树突状细胞提取物激活浆细胞样树突状细胞（PDCs）上调CD 86表达并产生IFN-α。在疟疾感染的患者中也检测到IFN-α的产生，但循环PDC的水平显著降低，这可能是因为疟原虫刺激的CCR 7上调，这对PDC迁移至关重要。受试者刺激的PDCs引起T细胞应答较差，但促进γ δ T细胞增殖和IFN-γ产生。小鼠DCs可重复产生抗肿瘤免疫刺激作用，并需要Toll样受体9（TLR 9）-MyD 88信号通路。虽然已知的TLR 9配体是病原体DNA中的CpG基序，但可溶性的双链体提取物的活性远大于双链体DNA的活性，并且它是热不稳定的，并且可以用硫酸铵沉淀，不像细菌DNA的活性。这些结果表明，疟原虫提取物中含有一种新的和以前未知的TLR 9配体，并表明这种配体对PDCs的刺激作用可能在人类恶性疟疾的免疫调节和免疫发病机制中发挥关键作用。
A common feature of severe Plasmodium falciparum infection is the increased systemic release of proinflammatory cytokines that contributes to the pathogenesis of malaria. Using human blood, we found that blood stage schizonts or soluble schizont extracts activated plasmacytoid dendritic cells (PDCs) to up-regulate CD86 expression and produce IFN-alpha. IFN-alpha production was also detected in malaria-infected patients, but the levels of circulating PDCs were markedly reduced, possibly because of schizont-stimulated up-regulation of CCR7, which is critical for PDC migration. The schizont-stimulated PDCs elicited a poor T cell response, but promoted gammadelta T cell proliferation and IFN-gamma production. The schizont immune stimulatory effects could be reproduced using murine DCs and required the Toll-like receptor 9 (TLR9)-MyD88 signaling pathway. Although the only known TLR9 ligand is CpG motifs in pathogen DNA, the activity of the soluble schizont extract was far greater than that of schizont DNA, and it was heat labile and precipitable with ammonium sulfate, unlike the activity of bacterial DNA. These results demonstrate that schizont extracts contain a novel and previously unknown ligand for TLR9 and suggest that the stimulatory effects of this ligand on PDCs may play a key role in immunoregulation and immunopathogenesis of human falciparum malaria.