Myeloid dendritic cells from B6.NZM Sle1/Sle2/Sle3 lupus-prone mice express an IFN signature that precedes disease onset.
Myeloid dendritic cells from B6.NZM Sle1/Sle2/Sle3 lupus-prone mice express an IFN signature that precedes disease onset.
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DOI：
10.4049/jimmunol.1101686
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发表时间：
2012-07-01
期刊：
影响因子：
--
通讯作者：
Gallucci S
中科院分区：
文献类型：
--
作者：
Sriram U;Varghese L;Bennett HL;Jog NR;Shivers DK;Ning Y;Behrens EM;Caricchio R;Gallucci S
系统性红斑狼疮（SLE）患者表现出I型干扰素（IFN）反应基因的过度表达，称为“干扰素特征”。我们发现B6.NZMSle1/Sle 2/Sle 3（Sle 1，2，3）狼疮易感小鼠与非自身免疫C57 BL/6小鼠相比也表达干扰素标签。在体外，来自Sle 1、2、3小鼠的髓样树突状细胞（mDC）（GM-CSF骨髓来源的BMDCs）组成性过表达IFN应答基因，如IFNb、Oas-3、Mx-1、ISG-15和CXCL 10，以及IFN信号通路的成员STAT 1、STAT 2和IRF 7。干扰素标签在来自年轻的自身免疫前小鼠和来自具有高滴度自身抗体的小鼠的Sle 1、2、3 BMDC中是相似的，这表明mDC中的干扰素标签先于疾病发作，并且其独立于自身抗体。Sle 1、2、3 BMDC对IFNa和TLR 7和TLR 9激动剂R848和CpG的刺激反应过度。我们提出，这种超应答是由干扰素标签诱导的，并且仅部分地促成了标签，因为抑制TLR 7和TLR 9的寡核苷酸仅部分地抑制了组成性干扰素标签，并且预暴露于IFNa在野生型BMDC中诱导了与Sle 1、2、3 BMDC相同的超应答。在体内，mDC和较小程度的T和B细胞从年轻的预患病的Sle 1，2，3小鼠也表达干扰素标签，虽然他们缺乏的强度，BMDC显示在体外。Sle 1，2，3浆细胞样DC在体外表达干扰素标签，但在体内不表达，表明mDC可能在疾病发作前更相关。我们建议Sle 1，2，3小鼠是研究干扰素信号在狼疮发病机制中的作用的有用工具。
Patients with systemic lupus erythematosus (SLE) show an over-expression of Type I Interferon (IFN) responsive genes called “Interferon Signature”. We found that the B6.NZMSle1/Sle2/Sle3 (Sle1,2,3) lupus-prone mice also express an Interferon Signature compared to non autoimmune C57BL/6 mice. In vitro, myeloid dendritic cells (mDCs)(GM-CSF bone marrow-derived BMDCs) from Sle1,2,3 mice constitutively over-expressed IFN responsive genes such as IFNb, Oas-3, Mx-1, ISG-15 and CXCL10, and the members of IFN signaling pathway STAT1, STAT2, and IRF7. The Interferon Signature was similar in Sle1,2,3 BMDCs from young, pre-autoimmune mice and from mice with high titers of autoantibodies, suggesting that the Interferon Signature in mDCs precedes disease onset and it is independent from the autoantibodies. Sle1,2,3 BMDCs hyper-responded to stimulation with IFNa and the TLR7 and TLR9 agonists R848 and CpGs. We propose that this hyper-response is induced by the Interferon Signature and only partially contributes to the Signature, since oligonucleotides inhibitory for TLR7 and TLR9 only partially suppressed the constitutive Interferon Signature and pre-exposure to IFNa induced the same hyper-response in wild type BMDCs than in Sle1,2,3 BMDCs. In vivo, mDCs and with lesser extent T and B cells from young pre-diseased Sle1,2,3 mice also expressed the Interferon Signature, although they lacked the strength that BMDCs showed in vitro. Sle1,2,3 plasmacytoid DCs expressed the Interferon Signature in vitro but not in vivo, suggesting that mDCs may be more relevant before disease onset. We propose that Sle1,2,3 mice are useful tools to study the role of the Interferon Signature in lupus pathogenesis.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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DOI：
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发表时间：
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期刊：
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影响因子：
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DOI：
10.1084/jem.174.5.1179
发表时间：
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期刊：
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