Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity
Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity
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DOI：
10.1073/pnas.1206923109
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发表时间：
2012-09-04
影响因子：
11.1
通讯作者：
Cao, Wei
中科院分区：
文献类型：
--
作者：
Di Domizio, Jeremy;Dorta-Estremera, Stephanie;Cao, Wei
系统性自身免疫的免疫病理生理发展涉及许多因素，通过复杂的机制，尚未完全理解。在系统性红斑狼疮中，由浆细胞样树突状细胞（pDC）产生的I型干扰素（IFN-I）通过其对免疫细胞的多效性作用来促进自身免疫。然而，宿主衍生的因子，使异常IFN-Ⅰ生产和初始免疫耐受性的崩溃在很大程度上是未知的。先前，我们发现淀粉样前体蛋白在核酸存在下形成淀粉样原纤维。在这里，我们报告说，含有核酸的淀粉样蛋白纤维可以有效地激活pDC，并使IFN-I的生产响应于自身的DNA，自身的RNA，和死细胞碎片。pDC可以摄取含DNA的淀粉样蛋白原纤维，其保留在早期内体中以激活TLR 9，导致高IFN α/β产生。在用含有DNA的淀粉样蛋白纤维处理的小鼠中，快速的IFN应答与pDC浸润和活化相关。用含DNA的淀粉样纤维免疫非自身免疫小鼠，诱导抗一组自身抗原的抗核血清学。小鼠表现出阳性蛋白尿，并在肾脏中沉积抗体。有趣的是，pDC耗竭阻碍了IFN-I应答并选择性地消除了自身抗体的产生。我们的研究揭示了含有核酸的淀粉样蛋白原纤维的先天免疫功能，并通过pDC-IFN轴提供了受损蛋白质稳态和自身免疫之间的潜在联系。
The immunopathophysiologic development of systemic autoimmunity involves numerous factors through complex mechanisms that are not fully understood. In systemic lupus erythematosus, type I IFN (IFN-I) produced by plasmacytoid dendritic cells (pDCs) critically promotes the autoimmunity through its pleiotropic effects on immune cells. However, the host-derived factors that enable abnormal IFN-I production and initial immune tolerance breakdown are largely unknown. Previously, we found that amyloid precursor proteins form amyloid fibrils in the presence of nucleic acids. Here we report that nucleic acid-containing amyloid fibrils can potently activate pDCs and enable IFN-I production in response to self-DNA, self-RNA, and dead cell debris. pDCs can take up DNA-containing amyloid fibrils, which are retained in the early endosomes to activate TLR9, leading to high IFN alpha/beta production. In mice treated with DNA-containing amyloid fibrils, a rapid IFN response correlated with pDC infiltration and activation. Immunization of nonautoimmune mice with DNA-containing amyloid fibrils induced antinuclear serology against a panel of self-antigens. The mice exhibited positive proteinuria and deposited antibodies in their kidneys. Intriguingly, pDC depletion obstructed IFN-I response and selectively abolished autoantibody generation. Our study reveals an innate immune function of nucleic acid- containing amyloid fibrils and provides a potential link between compromised protein homeostasis and autoimmunity via a pDC-IFN axis.