Baylor Institute for Immunology Research, Dallas, TX 752014, USA.
Sci Transl Med. 2011 Mar 9;3(73):73ra20. doi: 10.1126/scitranslmed.3001201.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)-induced and neutrophil-related transcripts. Increased production and/or bioavailability of IFN-α and associated alterations in dendritic cell (DC) homeostasis have been linked to lupus pathogenesis. Although neutrophils have long been shown to be associated with lupus, their potential role in disease pathogenesis remains elusive. Here, we show that mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophil extracellular traps (NETs). SLE NETs contain DNA as well as large amounts of LL37 and HMGB1, neutrophil proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid DCs (pDCs). Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and TLR9 (Toll-like receptor 9)-dependent manner. Our results reveal an unsuspected role for neutrophils in SLE pathogenesis and identify a novel link between nucleic acid-recognizing antibodies and type I IFN production in this disease.
系统性红斑狼疮（SLE）是一种系统性自身免疫性疾病，其特征是对核抗原的耐受性丧失和免疫复合物的形成。基因组方法表明，人类 SLE 白细胞均匀表达 I 型干扰素（IFN）诱导和中性粒细胞相关的转录本。IFN-α的产生增加和/或生物利用度增加以及树突状细胞（DC）稳态的相关改变与狼疮发病机制有关。尽管中性粒细胞长期以来一直与狼疮有关，但它们在疾病发病机制中的潜在作用仍不清楚。在这里，我们表明，成熟的 SLE 中性粒细胞在体内被 I 型 IFN 预先激活，并在暴露于 SLE 来源的抗核糖核蛋白抗体时死亡，释放中性粒细胞胞外陷阱（NETs）。SLE NETs 含有 DNA 以及大量的 LL37 和 HMGB1，这些中性粒细胞蛋白有助于浆细胞样 DC（pDC）摄取和识别哺乳动物 DNA。事实上，SLE NETs 以 DNA 和 TLR9（Toll 样受体 9）依赖性方式激活 pDCs 产生高水平的 IFN-α。我们的研究结果揭示了中性粒细胞在 SLE 发病机制中的一个意想不到的作用，并确定了在这种疾病中核酸识别抗体和 I 型 IFN 产生之间的新联系。
