Mitochondrial DNA An Endogenous Trigger for Immune Paralysis
Mitochondrial DNA An Endogenous Trigger for Immune Paralysis
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DOI：
10.1097/aln.0000000000001008
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发表时间：
2016-04-01
期刊：
影响因子：
8.8
通讯作者：
Limmer, Andreas
中科院分区：
文献类型：
--
作者：
Schaefer, Simon T.;Franken, Lars;Limmer, Andreas
背景：即使没有初始感染源，危重患者患败血症的风险也很高，但其败血症易感性增加的分子机制（包括免疫系统受到抑制）仍不清楚。尽管微生物和病原体相关分子模式被认为是脓毒症和脓毒症免疫抑制的诱导剂，但内源性 Toll 样受体 (TLR) 配体（例如线粒体 DNA (mtDNA)）在改变免疫反应中的作用尚不清楚。方法：线粒体 DNA 血清中线粒体基因 D-Loop 和 D-Loop 的浓度 对 165 名脓毒症患者和 50 名健康志愿者的腺苷三磷酸酶 6 进行了测定（定量聚合酶链反应）。此外，在野生型和 TLR9 敲除小鼠中分析了细胞毒性 T 细胞活性，先注射/未注射线粒体 DNA，然后注射表达卵清蛋白的腺病毒载体。 结果：脓毒症患者的线粒体 DNA 血清浓度增加（腺苷三磷酸酶 6 倍、123 倍；D 环 76 倍、P < 0.0001）与志愿者相比。此外，单次mtDNA注射在野生型中引起了对适应性T细胞毒性的深刻的、TLR9依赖性的免疫抑制，但在TLR9敲除小鼠中则不然，并引发了各种免疫抑制机制，包括脾微结构的破坏、交叉呈递树突状细胞的缺失以及程序性细胞死亡配体1和1的上调。 吲哚胺2,3-双加氧酶。小鼠中的一些发现在脓毒症患者中得到了反映，mtDNA 浓度与 30 天死亡率增加相关。结论：这项研究的结果表明，mtDNA（一种内源性危险相关分子模式）是一种迄今为止未知的脓毒症免疫麻痹诱导剂，也是危重患者初始炎症和随后的免疫抑制之间可能存在的联系。
Background: Critically ill patients are at high risk to suffer from sepsis, even in the absence of an initial infectious source, but the molecular mechanisms for their increased sepsis susceptibility, including a suppressed immune system, remain unclear. Although microbes and pathogen-associated molecular pattern are accepted inducers of sepsis and septic immunosuppression, the role of endogenous Toll-like receptor (TLR) ligands, such as mitochondrial DNA (mtDNA), in altering the immune response is unknown.Methods: Mitochondrial DNA serum concentrations of the mitochondrial genes D-Loop and adenosine triphosphatase 6 were determined (quantitative polymerase chain reaction) in 165 septic patients and 50 healthy volunteers. Furthermore, cytotoxic T-cell activity was analyzed in wild-type and TLR9 knockout mice, with/without previous mtDNA administration, followed by injection of an ovalbumin-expressing adenoviral vector.Results: Mitochondrial DNA serum concentrations were increased in septic patients (adenosine triphosphatase 6, 123-fold; D-Loop, 76-fold, P < 0.0001) compared with volunteers. Furthermore, a single mtDNA injection caused profound, TLR9-dependent immunosuppression of adaptive T-cell cytotoxicity in wild-type but not in TLR9 knockout mice and evoked various immunosuppressive mechanisms including the destruction of the splenic microstructure, deletion of cross-presenting dendritic cells, and up-regulation of programmed cell death ligand 1 and indoleamine 2,3-dioxygenase. Several of these findings in mice were mirrored in septic patients, and mtDNA concentrations were associated with an increased 30-day mortality.Conclusions: The findings of this study imply that mtDNA, an endogenous danger associated molecular pattern, is a hitherto unknown inducer of septic immunoparalysis and one possible link between initial inflammation and subsequent immunosuppression in critically ill patients.