小核糖核蛋白自身抗体与格林-巴利综合征血神经屏障破坏相关。

IF 7.8 1区 医学 Q1 CLINICAL NEUROLOGY
Fumitaka Shimizu, Michiaki Koga, Yoichi Mizukami, Kenji Watanabe, Ryota Sato, Yukio Takeshita, Toshihiko Maeda, Takashi Kanda, Masayuki Nakamori
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引用次数: 0

摘要

背景和目的:在格林-巴-罗综合征(GBS)患者中观察到血神经屏障(BNB)的破坏;然而,这一现象背后的分子机制尚不清楚。本研究的目的是鉴定针对在GBS患者中启动BNB分解的BNB内皮细胞的抗体。方法:我们从急性期GBS患者(n = 77)、疾病对照(n = 51)和健康对照(n = 24)的血清样本中纯化igg。IgG培养人周围神经微血管内皮细胞(PnMECs)。使用RNA-seq和高含量成像系统评估GBS-IgG暴露后pnmec的分子变化。采用酶联免疫吸附法检测u1snrnp自身抗体。验证了u1snrnp抗体阳性的GBS患者的临床资料。结果:与DC-IgGs和HC-IgGs相比,GBS-IgGs显著增加了pnmec中NF-κB核易位和10-kDa葡聚糖的通透性。pnmes的RNA-seq分析表明,NF-κB p65处于网络分析的中心位置,snRNPs作为NF-κB p65的上游基因,CXCR5作为NF-κB p65的下游基因是GBS-IgG暴露后的重要分子。GBS患者IgG孵育后,claudin-5和U1-snRNP蛋白水平较hc显著降低,CXCR5蛋白水平较hc显著升高。GBS患者中U1-snRNP抗体阳性率为36% (77 / 28),dc患者为7% (28 / 2),hc患者为0%(16 / 0)。治疗后血清snRNP抗体滴度降低。snRNP抗体阳性的GBS患者脑脊液蛋白和白蛋白商(QALB)/QALBLIM均高于snRNP抗体阴性的GBS患者。在体外BNB共培养模型中,来自u1snrnp抗体阳性的GBS患者的IgG比来自hc的IgG更能降低屏障功能和claudin-5的表达。U1-snRNP抗体的降低降低了U1-snRNP抗体的GBS患者IgG对pnmec通透性增加的生物学效应。讨论:u1snrnp自身抗体通过降低u1snrnp和claudin-5,诱导BNB内皮细胞中NF-κB活化,与GBS中BNB的分解相关。针对snRNP的临时自身抗体反应可能通过对GBS感染的周期性反应而增强。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Small Nuclear Ribonucleoprotein Autoantibody Associated With Blood-Nerve Barrier Breakdown in Guillain-Barré Syndrome.

Background and objectives: Breakdown of the blood-nerve barrier (BNB) is observed in patients with Guillain-Barré syndrome (GBS); however, the molecular mechanism underlying this phenomenon remains unclear.The aim of this study was to identify antibodies against the BNB-endothelial cells that initiate BNB breakdown in patients with GBS.

Methods: We purified IgGs from the serum samples of patients with GBS (n = 77) during the acute phase, disease controls ([DCs], n = 51), and healthy controls ([HCs], n = 24). Human peripheral nerve microvascular endothelial cells (PnMECs) were incubated with IgG. Molecular changes in PnMECs after GBS-IgG exposure were evaluated using RNA-seq and a high-content imaging system. U1-small nuclear ribonucleoprotein (U1-snRNP) autoantibodies were detected using an ELISA. The clinical information of U1-snRNP antibody-positive GBS patients was verified.

Results: GBS-IgGs significantly increased NF-κB nuclear translocation and permeability of the 10-kDa dextran in PnMECs compared with DC-IgGs or HC-IgGs. RNA-seq analyses of PnMECs demonstrated that NF-κB p65 in the center of the network analysis, snRNPs as upstream genes of NF-κB p65, and CXCR5 as downstream genes of NF-κB p65 were important molecules after GBS-IgG exposure. The protein level of claudin-5 and U1-snRNP was significantly reduced while that of CXCR5 was significantly increased after incubation with IgG from patients with GBS, compared with that from HCs. The rate of U1-snRNP antibody positivity was 36% (28 of 77) in patients with GBS, 7% (2 of 28) in DCs, and 0% (0 of 16) in HCs. The serum titer of snRNP antibody decreased after treatment. Both cerebral spinal fluid protein and albumin quotient (QALB)/QALBLIM were higher in snRNP antibody-positive GBS patients than in snRNP antibody-negative GBS patients. IgG from U1-snRNP antibody-positive GBS patients decreased the barrier function and claudin-5 expression more than that from HCs in an in vitro BNB coculture model. The reduction in U1-snRNP antibody decreased the biological effect of IgG from GBS patients with U1-snRNP antibody on the increased permeability of PnMECs.

Discussion: U1-snRNP autoantibodies are associated with the breakdown of BNB in GBS, through the reduction of U1-snRNP and claudin-5 and the induction of NF-κB activation in BNB-endothelial cells. A temporary autoantibody response against snRNP may be boosted by the periodic response to infection in GBS.

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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
219
审稿时长
8 weeks
期刊介绍: Neurology Neuroimmunology & Neuroinflammation is an official journal of the American Academy of Neurology. Neurology: Neuroimmunology & Neuroinflammation will be the premier peer-reviewed journal in neuroimmunology and neuroinflammation. This journal publishes rigorously peer-reviewed open-access reports of original research and in-depth reviews of topics in neuroimmunology & neuroinflammation, affecting the full range of neurologic diseases including (but not limited to) Alzheimer's disease, Parkinson's disease, ALS, tauopathy, and stroke; multiple sclerosis and NMO; inflammatory peripheral nerve and muscle disease, Guillain-Barré and myasthenia gravis; nervous system infection; paraneoplastic syndromes, noninfectious encephalitides and other antibody-mediated disorders; and psychiatric and neurodevelopmental disorders. Clinical trials, instructive case reports, and small case series will also be featured.
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