GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica
Abstract Background We previously reported the association between blood–brain barrier (BBB) dysfunction and glucose‐regulated protein 78 (GRP 78) autoantibodies in neuromyelitis optica (NMO). Objective We clarify whether the BBB‐endothelial cell activation induced by immunoglobulin G (IgG) is assoc...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2019-10-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.50905 |
| _version_ | 1818607547987263488 |
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| author | Fumitaka Shimizu Yukio Takeshita Yuka Hamamoto Hideaki Nishihara Yasuteru Sano Masaya Honda Ryota Sato Toshihiko Maeda Toshiyuki Takahashi Susumu Fujikawa Takashi Kanda |
| author_facet | Fumitaka Shimizu Yukio Takeshita Yuka Hamamoto Hideaki Nishihara Yasuteru Sano Masaya Honda Ryota Sato Toshihiko Maeda Toshiyuki Takahashi Susumu Fujikawa Takashi Kanda |
| author_sort | Fumitaka Shimizu |
| collection | DOAJ |
| description | Abstract Background We previously reported the association between blood–brain barrier (BBB) dysfunction and glucose‐regulated protein 78 (GRP 78) autoantibodies in neuromyelitis optica (NMO). Objective We clarify whether the BBB‐endothelial cell activation induced by immunoglobulin G (IgG) is associated with the clinical phenotype, disease activity, and markers of BBB disruption. Methods We purified serum IgG from 24 serum samples from patients with NMO spectrum disorder (NMOSD), who were positive for anti‐AQP4 antibodies (longitudinally extensive transverse myelitis [LETM], n = 14; optic neuritis [ON], n = 6; other phenotype, n = 4) and nine healthy controls. IgG was exposed to human brain microvascular endothelial cells (TY10) and the number of nuclear NF‐κB p65‐positive cells, as a marker of endothelial cell activation, was analyzed using a high‐content imaging system. Change in BBB permeability was also measured. The presence of GRP78 autoantibodies was detected by Western blotting. Results In the LETM group, IgG significantly induced the nuclear translocation of NF‐κB p65 in comparison to the ON and healthy control groups. A significant correlation was observed between the number of NF‐κB nuclear‐positive cells and clinical markers of BBB disruption, including Gd enhancement in spinal MRI and the cerebrospinal fluid/serum albumin ratio. This effect was significantly reduced at the remission phase in the individual NMOSD patients. Furthermore, GRP78 antibody positivity was associated with the LETM phenotype and disease severity in NMOSD patients. Conclusion Endothelial cell activation was associated with the LETM phenotype, clinical markers of BBB disruption and disease activity. These observations may explain the phenotypic differences between the NMOSD subtypes, LETM, and isolated ON. |
| first_indexed | 2024-12-16T14:28:30Z |
| format | Article |
| id | doaj.art-763ff5551f9148fbab12dc840298da21 |
| institution | Directory Open Access Journal |
| issn | 2328-9503 |
| language | English |
| last_indexed | 2024-12-16T14:28:30Z |
| publishDate | 2019-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj.art-763ff5551f9148fbab12dc840298da212022-12-21T22:28:17ZengWileyAnnals of Clinical and Translational Neurology2328-95032019-10-016102079208710.1002/acn3.50905GRP 78 antibodies are associated with clinical phenotype in neuromyelitis opticaFumitaka Shimizu0Yukio Takeshita1Yuka Hamamoto2Hideaki Nishihara3Yasuteru Sano4Masaya Honda5Ryota Sato6Toshihiko Maeda7Toshiyuki Takahashi8Susumu Fujikawa9Takashi Kanda10Department of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube JapanDepartment of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube JapanDepartment of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube JapanDepartment of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube JapanDepartment of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube JapanDepartment of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube JapanDepartment of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube JapanDepartment of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube JapanDepartment of Neurology Tohoku University Graduate School of Medicine Miyagi JapanDepartment of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube JapanDepartment of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube JapanAbstract Background We previously reported the association between blood–brain barrier (BBB) dysfunction and glucose‐regulated protein 78 (GRP 78) autoantibodies in neuromyelitis optica (NMO). Objective We clarify whether the BBB‐endothelial cell activation induced by immunoglobulin G (IgG) is associated with the clinical phenotype, disease activity, and markers of BBB disruption. Methods We purified serum IgG from 24 serum samples from patients with NMO spectrum disorder (NMOSD), who were positive for anti‐AQP4 antibodies (longitudinally extensive transverse myelitis [LETM], n = 14; optic neuritis [ON], n = 6; other phenotype, n = 4) and nine healthy controls. IgG was exposed to human brain microvascular endothelial cells (TY10) and the number of nuclear NF‐κB p65‐positive cells, as a marker of endothelial cell activation, was analyzed using a high‐content imaging system. Change in BBB permeability was also measured. The presence of GRP78 autoantibodies was detected by Western blotting. Results In the LETM group, IgG significantly induced the nuclear translocation of NF‐κB p65 in comparison to the ON and healthy control groups. A significant correlation was observed between the number of NF‐κB nuclear‐positive cells and clinical markers of BBB disruption, including Gd enhancement in spinal MRI and the cerebrospinal fluid/serum albumin ratio. This effect was significantly reduced at the remission phase in the individual NMOSD patients. Furthermore, GRP78 antibody positivity was associated with the LETM phenotype and disease severity in NMOSD patients. Conclusion Endothelial cell activation was associated with the LETM phenotype, clinical markers of BBB disruption and disease activity. These observations may explain the phenotypic differences between the NMOSD subtypes, LETM, and isolated ON.https://doi.org/10.1002/acn3.50905 |
| spellingShingle | Fumitaka Shimizu Yukio Takeshita Yuka Hamamoto Hideaki Nishihara Yasuteru Sano Masaya Honda Ryota Sato Toshihiko Maeda Toshiyuki Takahashi Susumu Fujikawa Takashi Kanda GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica Annals of Clinical and Translational Neurology |
| title | GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica |
| title_full | GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica |
| title_fullStr | GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica |
| title_full_unstemmed | GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica |
| title_short | GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica |
| title_sort | grp 78 antibodies are associated with clinical phenotype in neuromyelitis optica |
| url | https://doi.org/10.1002/acn3.50905 |
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