Anti-double stranded DNA antibodies (anti-dsDNA) are a hallmark of SLE but their role in disease pathogenesis is not fully resolved. Anti-dsDNA in serum are highly heterogeneous therefore in this study, we aimed to dissect the functional specificities of anti-dsDNA using a panel of human monoclonal antibodies (humAbs) generated from patients with active lupus nephritis. A total of 46 ANA reactive humAbs were isolated and divided into four broad classes based on their reactivity to histones, DNA and Crithidia. Functional analysis indicated that one subclass of antibodies bound strongly to decondensed DNA areas in neutrophil extracellular traps (NETs) and protected NETs from nuclease digestion, similar to the sera from active SLE patients. In addition, these anti-dsDNA antibodies could stimulate type I interferon responses in mononuclear phagocytic cells, or NF-kB activity in endothelial cells, by uptake of NETs-anti-NETs immune complexes and subsequently trigging inflammatory responses in an Fc-gamma receptor (Fcg-R)-dependant manner. Together our data suggest that only a subset of anti-dsDNA antibodies is capable to amplify inflammatory responses by deposit in the nephritic kidney in vivo, protecting NETs digestion as well as uptake of NETs immune complexes into Fcg-R-expressing cells in vitro.

抗双链 DNA 抗体（抗 dsDNA）是 SLE 的标志，但其在疾病发病机制中的作用尚未完全解决。血清中的抗 dsDNA 具有高度异质性，因此在本研究中，我们旨在使用一组从活动性狼疮肾炎患者体内产生的人单克隆抗体 (humAb) 来剖析抗 dsDNA 的功能特异性。总共分离出 46 种 ANA 反应性 humAb，并根据其对组蛋白、DNA 和Crithidia的反应性分为四大类。功能分析表明，一类抗体与中性粒细胞胞外陷阱 (NET) 中的解压缩 DNA 区域强烈结合，并保护 NET 免受核酸酶消化，类似于活动性 SLE 患者的血清。此外，这些抗 dsDNA 抗体可以通过摄取 NETs-抗 NETs 免疫复合物并随后触发 Fc-gamma 受体中的炎症反应，刺激单核吞噬细胞中的 I 型干扰素反应或内皮细胞中的 NF-kB 活性。 Fcg-R)依赖方式。我们的数据表明，只有一部分抗 dsDNA 抗体能够通过体内沉积在肾病肾中来放大炎症反应，保护 NET 消化以及体外将 NET 免疫复合物摄取到表达 Fcg-R 的细胞中。