TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus.
TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus.
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DOI：
10.4049/jimmunol.0902592
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发表时间：
2010-02-15
期刊：
影响因子：
--
通讯作者：
Shlomchik MJ
中科院分区：
文献类型：
--
作者：
Nickerson KM;Christensen SR;Shupe J;Kashgarian M;Kim D;Elkon K;Shlomchik MJ
系统性红斑狼疮的特征是产生抗核酸相关抗原的自身抗体。我们先前发现，抗Sm抗体需要TLR7，抗染色质自身抗体需要TLR9。然而，尽管TLR7缺乏改善了疾病，但TLR9缺乏加剧了疾病。尽管这一发现的机制和临床意义，它还没有被阐明。在这项研究中，我们研究了TLR7、TLR9、TLR7和TLR9或MyD88基因缺陷的MRL/LPR狼疮易感小鼠，以测试TLR7和TLR9是独立发挥作用，还是相互调节。我们发现，受TLR9调控的疾病(因此在没有TLR9的情况下更严重)依赖于TLR7的表现。此外，尽管TLR7和TLR9在不同的自身抗体亚群上平行作用，TLR9也抑制TLR7依赖的RNA相关自身抗体的产生，这表明先前未知的自身抗体产生的交叉调节。通过比较缺乏TLR7和/或TLR9的小鼠和缺乏MyD88的小鼠的疾病，我们还识别了具有TLR和MyD88独立成分的疾病的某些方面。这些结果为TLR9如何调节和TLR7如何增强疾病提供了新的模型，并提供了对自身免疫性疾病的一些方面的洞察，这些方面受TLR信号的影响，以及不受TLR信号的影响。
Systemic lupus erythematosus is characterized by the production of autoantibodies against nucleic acid-associated Ags. We previously found that Tlr7 was required for anti-Sm and Tlr9 for anti-chromatin autoantibodies. Yet, although Tlr7 deficiency ameliorated disease, Tlr9 deficiency exacerbated it. Despite the mechanistic and clinical implications of this finding, it has yet to be elucidated. In this study, we characterize MRL/lpr lupus-prone mice genetically deficient in Tlr7, Tlr9, both Tlr7 and Tlr9, or Myd88 to test whether Tlr7 and Tlr9 function independently or instead regulate each other. We find that disease that is regulated by Tlr9 (and hence is worse in its absence) depends on Tlr7 for its manifestation. In addition, although Tlr7 and Tlr9 act in parallel pathways on different subsets of autoantibodies, Tlr9 also suppresses the production of Tlr7-dependent RNA-associated autoantibodies, suggesting previously unrecognized cross-regulation of autoantibody production as well. By comparing disease in mice deficient for Tlr7 and/or Tlr9 to those lacking Myd88, we also identify aspects of disease that have Tlr- and Myd88-independent components. These results suggest new models for how Tlr9 regulates and Tlr7 enhances disease and provide insight into aspects of autoimmune disease that are, and are not, influenced by TLR signals.
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影响因子：
32.4
作者：
Herlands, Robin A.;Christensen, Sean R.;Sweet, Rebecca A.;Hershberg, Uri;Shlomchik, Mark J.
通讯作者：
Shlomchik, Mark J.
影响因子：
30.5
作者：
Buerckstuemmer, Tilmann;Baumann, Christoph;Superti-Furga, Giulio
通讯作者：
Superti-Furga, Giulio
影响因子：
32.4
作者：
Berland, Robert;Fernandez, Luis;Imanishi-Kari, Thereza
通讯作者：
Imanishi-Kari, Thereza
影响因子：
4.4
作者：
Cocca, BA;Cline, AM;Radic, MZ
通讯作者：
Radic, MZ
Toll样受体9控制鼠狼疮中的抗DNA自身抗体产生。
DOI：
10.1084/jem.20050338
发表时间：
2005-07-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Christensen SR;Kashgarian M;Alexopoulou L;Flavell RA;Akira S;Shlomchik MJ
通讯作者：
Shlomchik MJ