DNA 传感器 AIM2 和 IFI16 是结合中性粒细胞胞外诱捕网的 SLE 自身抗原。
The DNA sensors AIM2 and IFI16 are SLE autoantigens that bind neutrophil extracellular traps.
机构信息
Johns Hopkins University School of Medicine, Division of Rheumatology, Baltimore, United States.
Nephrology Unit, Parma University Hospital, Department of Medicine and Surgery, Parma, Italy.
出版信息
Elife. 2022 May 24;11:e72103. doi: 10.7554/eLife.72103.
BACKGROUND
Nucleic acid binding proteins are frequently targeted as autoantigens in systemic lupus erythematosus (SLE) and other interferon (IFN)-linked rheumatic diseases. The AIM-like receptors (ALRs) are IFN-inducible innate sensors that form supramolecular assemblies along double-stranded (ds)DNA of various origins. Here, we investigate the ALR absent in melanoma 2 (AIM2) as a novel autoantigen in SLE, with similar properties to the established ALR autoantigen interferon-inducible protein 16 (IFI16). We examined neutrophil extracellular traps (NETs) as DNA scaffolds on which these antigens might interact in a pro-immune context.
METHODS
AIM2 autoantibodies were measured by immunoprecipitation in SLE and control subjects. Neutrophil extracellular traps were induced in control neutrophils and combined with purified ALR proteins in immunofluorescence and DNase protection assays. SLE renal tissues were examined for ALR-containing NETs by confocal microscopy.
RESULTS
AIM2 autoantibodies were detected in 41/131 (31.3%) SLE patients and 2/49 (4.1%) controls. Our SLE cohort revealed a frequent co-occurrence of anti-AIM2, anti-IFI16, and anti-DNA antibodies, and higher clinical measures of disease activity in patients positive for antibodies against these ALRs. We found that both ALRs bind NETs in vitro and in SLE renal tissues. We demonstrate that ALR binding causes NETs to resist degradation by DNase I, suggesting a mechanism whereby extracellular ALR-NET interactions may promote sustained IFN signaling.
CONCLUSIONS
Our work suggests that extracellular ALRs bind NETs, leading to DNase resistant nucleoprotein fibers that are targeted as autoantigens in SLE.
FUNDING
These studies were funded by NIH R01 DE12354 (AR), P30 AR070254, R01 GM 129342 (JS), K23AR075898 (CM), K08AR077100 (BA), the Jerome L. Greene Foundation and the Rheumatology Research Foundation. Dr. Antiochos and Dr. Mecoli are Jerome L. Greene Scholars. The Hopkins Lupus Cohort is supported by NIH grant R01 AR069572. Confocal imaging performed at the Johns Hopkins Microscopy Facility was supported by NIH Grant S10 OD016374.
背景
核酸结合蛋白通常被视为系统性红斑狼疮（SLE）和其他干扰素（IFN）相关风湿性疾病中的自身抗原。AIM 样受体（ALR）是 IFN 诱导的先天传感器，可沿各种来源的双链（ds）DNA 形成超分子组装。在这里，我们研究了黑色素瘤 2（AIM2）缺失的 ALR 作为 SLE 中的一种新型自身抗原，其特性与已建立的 ALR 自身抗原干扰素诱导蛋白 16（IFI16）相似。我们检查了中性粒细胞胞外陷阱（NETs），作为这些抗原可能在促免疫环境中相互作用的 DNA 支架。
方法
通过免疫沉淀法在 SLE 和对照受试者中测量 AIM2 自身抗体。在对照中性粒细胞中诱导中性粒细胞胞外陷阱，并在免疫荧光和 DNase 保护测定中与纯化的 ALR 蛋白结合。通过共聚焦显微镜检查 SLE 肾组织中含 ALR 的 NETs。
结果
在 131 名 SLE 患者中的 41 名（31.3%）和 49 名对照中的 2 名（4.1%）检测到 AIM2 自身抗体。我们的 SLE 队列显示抗-AIM2、抗-IFI16 和抗-DNA 抗体的频繁共同发生，并且对这些 ALR 抗体呈阳性的患者的疾病活动的临床指标更高。我们发现两种 ALR 都在体外和 SLE 肾组织中结合 NETs。我们证明，ALR 结合导致 NET 抵抗 DNase I 的降解，这表明细胞外 ALR-NET 相互作用可能促进持续的 IFN 信号传导的机制。
结论
我们的工作表明，细胞外 ALR 结合 NETs，导致 DNase 抗性核蛋白纤维成为 SLE 中的自身抗原。
经费
这些研究由 NIH R01 DE12354（AR）、P30 AR070254、R01 GM 129342（JS）、K23AR075898（CM）、K08AR077100（BA）、杰罗姆 L. 格林基金会和风湿病研究基金会资助。Antiochos 博士和 Mecoli 博士是 Jerome L. Greene 学者。霍普金斯狼疮队列由 NIH 授予 R01 AR069572 资助。在约翰霍普金斯显微镜设施进行的共焦成像由 NIH 授予 S10 OD016374 资助。
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