{"title":"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。","authors":"Fumitaka Shimizu, Michiaki Koga, Yoichi Mizukami, Kenji Watanabe, Ryota Sato, Yukio Takeshita, Toshihiko Maeda, Takashi Kanda, Masayuki Nakamori","doi":"10.1212/NXI.0000000000200405","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Discussion: </strong>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.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 4","pages":"e200405"},"PeriodicalIF":7.8000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092546/pdf/","citationCount":"0","resultStr":"{\"title\":\"Small Nuclear Ribonucleoprotein Autoantibody Associated With Blood-Nerve Barrier Breakdown in Guillain-Barré Syndrome.\",\"authors\":\"Fumitaka Shimizu, Michiaki Koga, Yoichi Mizukami, Kenji Watanabe, Ryota Sato, Yukio Takeshita, Toshihiko Maeda, Takashi Kanda, Masayuki Nakamori\",\"doi\":\"10.1212/NXI.0000000000200405\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Discussion: </strong>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.</p>\",\"PeriodicalId\":19472,\"journal\":{\"name\":\"Neurology® Neuroimmunology & Neuroinflammation\",\"volume\":\"12 4\",\"pages\":\"e200405\"},\"PeriodicalIF\":7.8000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092546/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurology® Neuroimmunology & Neuroinflammation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1212/NXI.0000000000200405\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/5/19 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurology® Neuroimmunology & Neuroinflammation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1212/NXI.0000000000200405","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
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.
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.