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SLE 中抗体依赖的炎症放大。

Autoantibody-dependent amplification of inflammation in SLE.

机构信息

Division of Immunology and Inflammation, Department of Medicine, Hammersmith Campus, Imperial College London, London, W12 0NN, UK.

Department of Medicine, Centre for Immunology & Vaccinology, Chelsea and Westminster Hospital, Imperial College London, London, SW10 9NH, UK.

出版信息

Cell Death Dis. 2020 Sep 9;11(9):729. doi: 10.1038/s41419-020-02928-6.

DOI:10.1038/s41419-020-02928-6
PMID:32908129
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7481301/
Abstract

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.

摘要

抗双链 DNA 抗体（抗 dsDNA）是 SLE 的标志，但它们在疾病发病机制中的作用尚未完全明确。血清中的抗 dsDNA 高度异质，因此在这项研究中，我们旨在使用从活动性狼疮肾炎患者中产生的一组人单克隆抗体（humAbs）来剖析抗 dsDNA 的功能特异性。总共分离出 46 种 ANA 反应性 humAbs，并根据它们与组蛋白、DNA 和克鲁氏锥虫的反应性分为四大类。功能分析表明，一类抗体强烈结合中性粒细胞细胞外陷阱（NETs）中的去凝聚 DNA 区域，并保护 NETs 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，在单核吞噬细胞中刺激 I 型干扰素反应，或在血管内皮细胞中刺激 NF-kB 活性，随后以 Fc-γ 受体（Fcg-R）依赖性方式引发炎症反应。总之，我们的数据表明，只有一部分抗 dsDNA 抗体能够通过在体内沉积在肾炎肾脏中放大炎症反应，从而保护 NETs 的消化以及 NETs 免疫复合物在体外被 Fcg-R 表达细胞摄取。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/b8072c0e4ba7/41419_2020_2928_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/cdf7e60f71ee/41419_2020_2928_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/df22498b17bf/41419_2020_2928_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/58763a42905f/41419_2020_2928_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/db87eb0ac8c3/41419_2020_2928_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/b8072c0e4ba7/41419_2020_2928_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/cdf7e60f71ee/41419_2020_2928_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/df22498b17bf/41419_2020_2928_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/58763a42905f/41419_2020_2928_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/db87eb0ac8c3/41419_2020_2928_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32f2/7481301/b8072c0e4ba7/41419_2020_2928_Fig5_HTML.jpg

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