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Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system. Most NMOSD patients are seropositive for immunoglobulin G (IgG) autoantibodies against astrocyte water channel aquaporin-4 (AQP4), called AQP4-IgG. AQP4-IgG binding to aquaporin-4 caus...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578624/ https://www.ncbi.nlm.nih.gov/pubmed/34753987 http://dx.doi.org/10.1038/s41598-021-01294-3 |
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author | Tradtrantip, Lukmanee Yeaman, Michael R. Verkman, A. S. |
author_facet | Tradtrantip, Lukmanee Yeaman, Michael R. Verkman, A. S. |
author_sort | Tradtrantip, Lukmanee |
collection | PubMed |
description | Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system. Most NMOSD patients are seropositive for immunoglobulin G (IgG) autoantibodies against astrocyte water channel aquaporin-4 (AQP4), called AQP4-IgG. AQP4-IgG binding to aquaporin-4 causes complement-dependent cytotoxicity (CDC), leading to inflammation and demyelination. Here, CDC was measured in AQP4-expressing cells exposed to human complement and heat-inactivated sera from 108 AQP4-IgG seropositive NMOSD subjects and 25 non-NMOSD controls. AQP4-IgG positive sera produced a wide range of CDC, with 50% maximum cytotoxicity produced by as low as 0.2% serum concentration. Unexpectedly, 58 samples produced no cytotoxicity, and of those, four sera were cytoprotective against cytotoxic AQP4-IgG. Cytoprotection was found against different cytotoxic monoclonal AQP4-IgGs and NMOSD patient sera, and in primary astrocyte cultures. Mechanistic studies revealed that the protective factor is an IgG antibody that did not inhibit complement directly, but interfered with binding of cytotoxic AQP4-IgG to AQP4 and consequent C1q binding and complement activation. Further studies suggested that non-pathogenic AQP4-IgG, perhaps with altered glycosylation, may contribute to reduced or ineffectual binding of cytotoxic AQP4-IgG, as well as reduced cell-surface AQP4. The presence of natural cytoprotective antibodies in AQP4-IgG seropositive sera reveals an added level of complexity in NMOSD disease pathogenesis, and suggests the potential therapeutic utility of ‘convalescent’ serum or engineered protective antibody to interfere with pathogenic antibody in AQP4-IgG seropositive NMOSD. |
format | Online Article Text |
id | pubmed-8578624 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85786242021-11-10 Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder Tradtrantip, Lukmanee Yeaman, Michael R. Verkman, A. S. Sci Rep Article Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system. Most NMOSD patients are seropositive for immunoglobulin G (IgG) autoantibodies against astrocyte water channel aquaporin-4 (AQP4), called AQP4-IgG. AQP4-IgG binding to aquaporin-4 causes complement-dependent cytotoxicity (CDC), leading to inflammation and demyelination. Here, CDC was measured in AQP4-expressing cells exposed to human complement and heat-inactivated sera from 108 AQP4-IgG seropositive NMOSD subjects and 25 non-NMOSD controls. AQP4-IgG positive sera produced a wide range of CDC, with 50% maximum cytotoxicity produced by as low as 0.2% serum concentration. Unexpectedly, 58 samples produced no cytotoxicity, and of those, four sera were cytoprotective against cytotoxic AQP4-IgG. Cytoprotection was found against different cytotoxic monoclonal AQP4-IgGs and NMOSD patient sera, and in primary astrocyte cultures. Mechanistic studies revealed that the protective factor is an IgG antibody that did not inhibit complement directly, but interfered with binding of cytotoxic AQP4-IgG to AQP4 and consequent C1q binding and complement activation. Further studies suggested that non-pathogenic AQP4-IgG, perhaps with altered glycosylation, may contribute to reduced or ineffectual binding of cytotoxic AQP4-IgG, as well as reduced cell-surface AQP4. The presence of natural cytoprotective antibodies in AQP4-IgG seropositive sera reveals an added level of complexity in NMOSD disease pathogenesis, and suggests the potential therapeutic utility of ‘convalescent’ serum or engineered protective antibody to interfere with pathogenic antibody in AQP4-IgG seropositive NMOSD. Nature Publishing Group UK 2021-11-09 /pmc/articles/PMC8578624/ /pubmed/34753987 http://dx.doi.org/10.1038/s41598-021-01294-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Tradtrantip, Lukmanee Yeaman, Michael R. Verkman, A. S. Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder |
title | Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder |
title_full | Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder |
title_fullStr | Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder |
title_full_unstemmed | Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder |
title_short | Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder |
title_sort | cytoprotective igg antibodies in sera from a subset of patients with aqp4-igg seropositive neuromyelitis optica spectrum disorder |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578624/ https://www.ncbi.nlm.nih.gov/pubmed/34753987 http://dx.doi.org/10.1038/s41598-021-01294-3 |
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