Ifih1 gene dose effect reveals MDA5-mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity.
Ifih1 gene dose effect reveals MDA5-mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity.
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DOI：
10.4049/jimmunol.1102705
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发表时间：
2012-02-01
期刊：
影响因子：
--
通讯作者：
Bolland S
中科院分区：
文献类型：
--
作者：
Crampton SP;Deane JA;Feigenbaum L;Bolland S
I型干扰素（IFN-I）通常在抗病毒反应中产生，但慢性高水平的IFN-I表达与自身免疫性疾病相关。多种病毒传感器在其反应中产生IFN-I，但除tlr外，尚不完全清楚哪些途径直接参与自发免疫病理的发展。为了进一步探索病毒途径诱导的IFN-I与自身免疫之间的联系，我们产生了一种新的转基因（Tg）小鼠系，其中含有Ifih1的多个拷贝，Ifih1是一种编码细胞质dsRNA传感器MDA5的基因，已被证实与糖尿病和狼疮有关。我们发现MDA5过表达导致慢性IFN-I状态，其特征是在缺乏CD8+或抗体反应的情况下，通过快速清除病毒来抵抗致命病毒感染。尽管每个免疫细胞群都有干扰素激活的迹象，但自发性MDA5激活本身并不足以引发自身免疫或炎症病理。当与FcγR2B缺乏狼疮易感背景相结合时，MDA5过表达确实加速了开关自身抗体的产生，加速了肾小球肾炎的发病率和早期死亡率。因此，MDA5 Tg小鼠提供的证据表明，慢性升高的IFN-I水平并不足以启动自身免疫或炎症，尽管它们可能加剧正在进行的自身免疫病理。
Type I interferons (IFN-I) are normally produced during antiviral responses, yet high levels of chronic IFN-I expression correlate with autoimmune disease. A variety of viral sensors generate IFN-I in their response, but other than TLRs it is not fully known which pathways are directly involved in the development of spontaneous immune pathologies. To further explore the link between IFN-I induced by viral pathways and autoimmunity, we generated a new transgenic (Tg) mouse line containing multiple copies of Ifih1, a gene encoding the cytoplasmic dsRNA sensor MDA5 with proven linkage to diabetes and lupus. We show that MDA5 overexpression led to a chronic IFN-I state characterized by resistance to a lethal viral infection through rapid clearance of virus in the absence of a CD8+ or antibody response. Spontaneous MDA5 activation was not sufficient to initiate autoimmune or inflammatory pathology by itself even though every immune cell population had signs of interferon activation. When combined with the lupus-susceptible background of the FcγR2B deficiency, MDA5 overexpression did accelerate the production of switched autoantibodies, the incidence of glomerulonephritis and early lethality. Thus, MDA5 Tg mice provide evidence that chronic elevated levels of IFN-I are not sufficient to initiate autoimmunity or inflammation although they might exacerbate an ongoing autoimmune pathology.
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