Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14550-5. doi: 10.1073/pnas.1206923109. Epub 2012 Aug 17.
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 IFNα/β 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.
系统性自身免疫的免疫病理生理学发展涉及许多因素，其通过复杂的机制尚不完全清楚。在系统性红斑狼疮中，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作用，严重促进自身免疫。然而，使异常 IFN-I 产生和初始免疫耐受破坏的宿主来源因素在很大程度上是未知的。以前，我们发现淀粉样前体蛋白在存在核酸的情况下形成淀粉样纤维。在这里，我们报告含有核酸的淀粉样纤维可以强烈激活 pDC，并使它们对自身 DNA、自身 RNA 和死细胞碎片产生 IFN-I。pDC 可以摄取含有 DNA 的淀粉样纤维，这些纤维保留在早期内体中以激活 TLR9，导致 IFNα/β 的大量产生。在用含有 DNA 的淀粉样纤维处理的小鼠中，快速的 IFN 反应与 pDC 浸润和激活相关。用含有 DNA 的淀粉样纤维免疫非自身免疫小鼠会诱导针对一系列自身抗原的抗核血清学反应。这些小鼠表现出阳性蛋白尿，并在肾脏中沉积抗体。有趣的是，pDC 耗竭阻断了 IFN-I 反应，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纤维的先天免疫功能，并通过 pDC-IFN 轴提供了蛋白稳态受损与自身免疫之间的潜在联系。
