Association of the Leukocyte Immunoglobulin-like Receptor A3 Gene With Neutrophil Activation and Disease Susceptibility in Adult-Onset Still's Disease.
Association of the Leukocyte Immunoglobulin-like Receptor A3 Gene With Neutrophil Activation and Disease Susceptibility in Adult-Onset Still's Disease.
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成人斯蒂尔病患者白细胞免疫球蛋白样受体A3基因与神经元活化和疾病易感性的相关性
DOI：
10.1002/art.41635
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Hu Q
中科院分区：
文献类型：
--
作者：
Wang M;Liu M;Jia J;Shi H;Teng J;Liu H;Sun Y;Cheng X;Ye J;Su Y;Chi H;Liu T;Wang Z;Wan L;Meng J;Ma Y;Yang C;Hu Q
成人发病的斯蒂尔氏病（AOSD）是一种严重的自身炎症性疾病。中性粒细胞激活与中性粒细胞胞外陷阱（NET）形成增强参与了AOSD的发病机制。功能性白细胞免疫球蛋白样受体A3 （LIR‐A3；基因名称LILRA3）已被报道与许多自身免疫性疾病相关。我们的目的是研究LILRA3与AOSD的疾病易感性和中性粒细胞激活的关系。对164例AOSD患者和305例健康对照进行了LILRA3缺失多态性及其标记单核苷酸多态性rs103294的基因分型。评估LILRA3对临床特征和信使RNA表达的影响。采用酶联免疫吸附试验（ELISA）检测血浆LIR‐A3水平，并研究血浆LIR‐A3水平与疾病活动性和循环NET‐DNA水平的相关性。利用PicoGreen双链DNA染色和免疫荧光分析，在转染了LIR‐B2小干扰RNA的人中性粒细胞和中性粒细胞样分化的NB4细胞系中测定了LIR‐a3诱导的NETs。基因分型结果显示，功能性LILRA3是AOSD的危险因素（AOSD患者为11%，健康对照组为5.6%；优势比为2.089[95%可信区间1.030-4.291],P = 0.034），并与白细胞增多（P = 0.039）和循环中性粒细胞水平升高（P = 0.027）相关。LILRA3 +/+患者外周血单个核细胞和中性粒细胞的功能性LILRA3信使RNA表达量较高（P < 0.0001）。AOSD患者血浆LIR‐A3水平升高（P < 0.0001），并与疾病活跃性指标和循环NET-DNA复合物水平相关。最后，在LIR‐A3刺激中性粒细胞后，在健康对照和非活性AOSD患者的中性粒细胞中发现了增强的NET形成。此外，敲低LILRB2基因表达后，NB4细胞的NET形成受损。我们的研究首次证明了功能性LILRA3是AOSD发生的一个新的遗传危险因素，并且功能性LIR‐A3可能通过诱导NETs的形成而发挥致病作用。
Adult‐onset Still’s disease (AOSD) is a severe autoinflammatory disease. Neutrophil activation with enhanced neutrophil extracellular trap (NET) formation is involved in the pathogenesis of AOSD. Functional leukocyte immunoglobulin‐like receptor A3 (LIR‐A3; gene name LILRA3) has been reported to be associated with many autoimmune diseases. We aimed to investigate the association of LILRA3 with disease susceptibility and neutrophil activation in AOSD. The LILRA3 deletion polymorphism and its tagging single‐nucleotide polymorphism rs103294 were genotyped in 164 patients with AOSD and 305 healthy controls. The impact of LILRA3 on clinical features and messenger RNA expression was evaluated. Plasma levels of LIR‐A3 were detected using enzyme‐linked immunosorbent assay (ELISA), and the correlation between LIR‐A3 plasma levels and disease activity and levels of circulating NET‐DNA was investigated. LIR‐A3–induced NETs were determined using PicoGreen double‐stranded DNA dye and immunofluorescence analysis in human neutrophils and a neutrophil‐like differentiated NB4 cell line transfected with LIR‐B2 small interfering RNA. The findings from genotyping demonstrated that functional LILRA3 was a risk factor for AOSD (11% in AOSD patients versus 5.6% in healthy controls; odds ratio 2.089 [95% confidence interval 1.030–4.291], P = 0.034), and associated with leukocytosis (P = 0.039) and increased levels of circulating neutrophils (P = 0.027). Functional LILRA3 messenger RNA expression was higher in the peripheral blood mononuclear cells (P < 0.0001) and neutrophils (P < 0.001) of LILRA3 +/+ patients. Plasma levels of LIR‐A3 were elevated in patients with AOSD (P < 0.0001) and correlated with disease activity indicators and levels of circulating NET–DNA complexes. Finally, enhanced NET formation was identified in neutrophils from healthy controls and patients with inactive AOSD after stimulation of the neutrophils with LIR‐A3. Moreover, NET formation was impaired in NB4 cells after knockdown of LILRB2 gene expression. Our study provides the first evidence that functional LILRA3 is a novel genetic risk factor for the development of AOSD and that functional LIR‐A3 may play a pathogenic role by inducing formation of NETs.
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多发性硬化症患者血清白细胞免疫球蛋白样受体 A3 (LILRA3) 升高，是疾病严重程度的一个强有力的独立指标； 6.7kbp LILRA3 基因缺失与疾病易感性无关。
影响因子：
3.7
作者：
An H;Lim C;Guillemin GJ;Vollmer-Conna U;Rawlinson W;Bryant K;Tedla N
通讯作者：
Tedla N
DOI：
10.1038/nrrheum.2011.132
发表时间：
2011-09-27
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.1908576116
发表时间：
2019-12-10
影响因子：
11.1
作者：
Mistry, Pragnesh;Nakabo, Shuichiro;Kaplan, Mariana J.
通讯作者：
Kaplan, Mariana J.
影响因子：
3.3
作者：
Low, Hui Zhi;Ahrenstorf, Gerrit;Witte, Torsten
通讯作者：
Witte, Torsten
LILRA3 缺失与 B-NHL 的关联以及免疫刺激分子的功能表征。
影响因子：
3.7
作者：
Low HZ;Reuter S;Topperwien M;Dankenbrink N;Peest D;Kabalak G;Stripecke R;Schmidt RE;Matthias T;Witte T
通讯作者：
Witte T