{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:27:57Z","timestamp":1791041277955,"version":"4.1.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T00:00:00Z","timestamp":1561420800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Yamaguchi University","award":["J29008"],"award-info":[{"award-number":["J29008"]}]},{"name":"Yamaguchi University","award":["18K07526"],"award-info":[{"award-number":["18K07526"]}]},{"name":"Yamaguchi University","award":["K2529006"],"award-info":[{"award-number":["K2529006"]}]},{"name":"Yamaguchi University","award":["17K09787"],"award-info":[{"award-number":["17K09787"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17H04197"],"award-info":[{"award-number":["17H04197"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health and Labour Sciences Research"},{"name":"Neuroimmunological Disease Research Committee"},{"name":"Ministry of Health, Labour and Welfare of Japan"},{"name":"Neurological and Psychiatric Disorders"},{"name":"National Center of Neurology and Psychiatry, Novartis research","award":["J29018"],"award-info":[{"award-number":["J29018"]}]},{"name":"National Center of Neurology and Psychiatry, Novartis research","award":["J29025"],"award-info":[{"award-number":["J29025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction caused by autoantibodies binding to P\/Q-type voltage-gated calcium channels. Breakdown of the blood\u2013brain barrier and diffusion of cerebellar granule\/Purkinje cell-reactive autoantibodies into the CNS are critical for the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome. We recently found evidence that glucose-regulated protein 78 (GRP78) autoantibodies in the plasma of patients with neuromyelitis optica promote the CNS access of AQP4 autoantibodies. In the present study, we investigated whether the GRP78 autoantibodies in PCD-LEMS IgG boost the brain uptake of cerebellar cell-reactive antibodies across the blood\u2013brain barrier and facilitate cerebellar dysfunction. We first evaluated the effects of purified IgG from PCD-LEMS or PCD patients on the blood\u2013brain barrier function in human brain microvascular endothelial cells using a high content imaging system with nuclear factor \u03baB p65 and intracellular adhesion molecule 1 (ICAM1) immunostaining. Next, we identified GRP78 autoantibodies causing blood\u2013brain barrier permeability in PCD-LEMS IgG by co-immunoprecipitation and the living cell-based antibody binding assays. Exposure of brain microvascular endothelial cells to IgG from PCD-LEMS patients induced nuclear factor \u03baB p65 nuclear translocation, ICAM1 upregulation, reduced claudin-5 expression, increased permeability and increased autocrine IL-1\u03b2 and IL-8 secretion; the IgG from patients with Lambert-Eaton myasthenic syndrome did not have these effects. We detected GRP78 autoantibodies in the IgG of LEMS-PCD (83.3%, n = 18), but observed fewer in patients with LEMS (6.6%, n = 15) and none were observed in the control subjects (n = 8). The depletion of GRP78 autoantibodies reduced the biological effect of LEMS-PCD IgG on brain microvascular endothelial cells. These findings suggest that GRP78 autoantibodies play a role beyond neuromyelitis optica and that they have direct implications in the phenotypic differences between PCD-LEMS and LEMS.<\/jats:p>","DOI":"10.1093\/brain\/awz168","type":"journal-article","created":{"date-parts":[[2019,6,1]],"date-time":"2019-06-01T07:13:24Z","timestamp":1559373204000},"page":"2253-2264","source":"Crossref","is-referenced-by-count":31,"title":["GRP78 antibodies damage the blood\u2013brain barrier and relate to cerebellar degeneration in Lambert-Eaton myasthenic syndrome"],"prefix":"10.1093","volume":"142","author":[{"given":"Fumitaka","family":"Shimizu","sequence":"first","affiliation":[{"name":"Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Takeshita","sequence":"additional","affiliation":[{"name":"Department of Neurology and Clinical Neuroscience, Yamaguchi 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School of Medicine, Ube, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susumu","family":"Fujikawa","sequence":"additional","affiliation":[{"name":"Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Nishihara","sequence":"additional","affiliation":[{"name":"Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Kitanosono","sequence":"additional","affiliation":[{"name":"Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Tsujino","sequence":"additional","affiliation":[{"name":"Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakatsu","family":"Motomura","sequence":"additional","affiliation":[{"name":"Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki, Japan"},{"name":"Medical Engineering Course, Department of Engineering, Faculty of Engineering, Nagasaki Institute of Applied Science, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kanda","sequence":"additional","affiliation":[{"name":"Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,6,24]]},"reference":[{"key":"2019072604002392200_awz168-B1","doi-asserted-by":"crossref","first-page":"21180","DOI":"10.1074\/jbc.M117.799908","article-title":"Autoantibodies against the cell surface-associated chaperone GRP78 stimulate tumor growth via tissue factor","volume":"292","author":"Al-Hashimi","year":"2017","journal-title":"J Biol Chem"},{"key":"2019072604002392200_awz168-B2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.12998\/wjcc.v3.i3.293","article-title":"Voltage gated calcium channel antibody-related neurological diseases","volume":"3","author":"Bekircan-Kurt","year":"2015","journal-title":"World J Clin 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