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Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation

Multiple sclerosis is an autoimmune disease of the central nervous system. Yet, the autoimmune targets are still undefined. The extracellular e1 sequence of KCNJ10, the inwardly rectifying potassium channel 4.1, has been subject to fierce debate for its role as a candidate autoantigen in multiple sc...

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Autores principales: Nicot, Arnaud B, Harb, Jean, Garcia, Alexandra, Guillot, Flora, Mai, Hoa-Le, Mathé, Camille V, Morille, Jérémy, Vallino, Amélie, Dugast, Emilie, Shah, Sita P, Lefrère, Fabienne, Moyon, Mélinda, Wiertlewski, Sandrine, Le Berre, Ludmilla, Renaudin, Karine, Soulillou, Jean-Paul, van Pesch, Vincent, Brouard, Sophie, Berthelot, Laureline, Laplaud, David-Axel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9994600/
https://www.ncbi.nlm.nih.gov/pubmed/36910419
http://dx.doi.org/10.1093/braincomms/fcad044
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author Nicot, Arnaud B
Harb, Jean
Garcia, Alexandra
Guillot, Flora
Mai, Hoa-Le
Mathé, Camille V
Morille, Jérémy
Vallino, Amélie
Dugast, Emilie
Shah, Sita P
Lefrère, Fabienne
Moyon, Mélinda
Wiertlewski, Sandrine
Le Berre, Ludmilla
Renaudin, Karine
Soulillou, Jean-Paul
van Pesch, Vincent
Brouard, Sophie
Berthelot, Laureline
Laplaud, David-Axel
author_facet Nicot, Arnaud B
Harb, Jean
Garcia, Alexandra
Guillot, Flora
Mai, Hoa-Le
Mathé, Camille V
Morille, Jérémy
Vallino, Amélie
Dugast, Emilie
Shah, Sita P
Lefrère, Fabienne
Moyon, Mélinda
Wiertlewski, Sandrine
Le Berre, Ludmilla
Renaudin, Karine
Soulillou, Jean-Paul
van Pesch, Vincent
Brouard, Sophie
Berthelot, Laureline
Laplaud, David-Axel
author_sort Nicot, Arnaud B
collection PubMed
description Multiple sclerosis is an autoimmune disease of the central nervous system. Yet, the autoimmune targets are still undefined. The extracellular e1 sequence of KCNJ10, the inwardly rectifying potassium channel 4.1, has been subject to fierce debate for its role as a candidate autoantigen in multiple sclerosis. Inwardly rectifying potassium channel 4.1 is expressed in the central nervous system but also in peripheral tissues, raising concerns about the central nervous system-specificity of such autoreactivity. Immunization of C57Bl6/J female mice with the e1 peptide (amino acids 83–120 of Kir4.1) induced anti-e1 immunoglobulin G- and T-cell responses and promoted demyelinating encephalomyelitis with B cell central nervous system enrichment in leptomeninges and T cells/macrophages in central nervous system parenchyma from forebrain to spinal cord, mostly in the white matter. Within our cohort of multiple sclerosis patients (n = 252), 6% exhibited high anti-e1 immunoglobulin G levels in serum as compared to 0.7% in the control cohort (n = 127; P = 0.015). Immunolabelling of inwardly rectifying potassium channel 4.1-expressing white matter glia with the anti-e1 serum from immunized mice increased during murine autoimmune neuroinflammation and in multiple sclerosis white matter as compared with controls. Strikingly, the mouse and human anti-e1 sera labelled astrocytoma cells when N-glycosylation was blocked with tunicamycin. Western blot confirmed that neuroinflammation induces Kir4.1 expression, including its shorter aglycosylated form in murine experimental autoencephalomyelitis and multiple sclerosis. In addition, recognition of inwardly rectifying potassium channel 4.1 using mouse anti-e1 serum in Western blot experiments under unreduced conditions or in cells transfected with the N-glycosylation defective N104Q mutant as compared to the wild type further suggests that autoantibodies target an e1 conformational epitope in its aglycosylated form. These data highlight the e1 sequence of inwardly rectifying potassium channel 4.1 as a valid central nervous system autoantigen with a disease/tissue-specific post-translational antigen modification as potential contributor to autoimmunity in some multiple sclerosis patients.
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spelling pubmed-99946002023-03-09 Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation Nicot, Arnaud B Harb, Jean Garcia, Alexandra Guillot, Flora Mai, Hoa-Le Mathé, Camille V Morille, Jérémy Vallino, Amélie Dugast, Emilie Shah, Sita P Lefrère, Fabienne Moyon, Mélinda Wiertlewski, Sandrine Le Berre, Ludmilla Renaudin, Karine Soulillou, Jean-Paul van Pesch, Vincent Brouard, Sophie Berthelot, Laureline Laplaud, David-Axel Brain Commun Original Article Multiple sclerosis is an autoimmune disease of the central nervous system. Yet, the autoimmune targets are still undefined. The extracellular e1 sequence of KCNJ10, the inwardly rectifying potassium channel 4.1, has been subject to fierce debate for its role as a candidate autoantigen in multiple sclerosis. Inwardly rectifying potassium channel 4.1 is expressed in the central nervous system but also in peripheral tissues, raising concerns about the central nervous system-specificity of such autoreactivity. Immunization of C57Bl6/J female mice with the e1 peptide (amino acids 83–120 of Kir4.1) induced anti-e1 immunoglobulin G- and T-cell responses and promoted demyelinating encephalomyelitis with B cell central nervous system enrichment in leptomeninges and T cells/macrophages in central nervous system parenchyma from forebrain to spinal cord, mostly in the white matter. Within our cohort of multiple sclerosis patients (n = 252), 6% exhibited high anti-e1 immunoglobulin G levels in serum as compared to 0.7% in the control cohort (n = 127; P = 0.015). Immunolabelling of inwardly rectifying potassium channel 4.1-expressing white matter glia with the anti-e1 serum from immunized mice increased during murine autoimmune neuroinflammation and in multiple sclerosis white matter as compared with controls. Strikingly, the mouse and human anti-e1 sera labelled astrocytoma cells when N-glycosylation was blocked with tunicamycin. Western blot confirmed that neuroinflammation induces Kir4.1 expression, including its shorter aglycosylated form in murine experimental autoencephalomyelitis and multiple sclerosis. In addition, recognition of inwardly rectifying potassium channel 4.1 using mouse anti-e1 serum in Western blot experiments under unreduced conditions or in cells transfected with the N-glycosylation defective N104Q mutant as compared to the wild type further suggests that autoantibodies target an e1 conformational epitope in its aglycosylated form. These data highlight the e1 sequence of inwardly rectifying potassium channel 4.1 as a valid central nervous system autoantigen with a disease/tissue-specific post-translational antigen modification as potential contributor to autoimmunity in some multiple sclerosis patients. Oxford University Press 2023-02-22 /pmc/articles/PMC9994600/ /pubmed/36910419 http://dx.doi.org/10.1093/braincomms/fcad044 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Nicot, Arnaud B
Harb, Jean
Garcia, Alexandra
Guillot, Flora
Mai, Hoa-Le
Mathé, Camille V
Morille, Jérémy
Vallino, Amélie
Dugast, Emilie
Shah, Sita P
Lefrère, Fabienne
Moyon, Mélinda
Wiertlewski, Sandrine
Le Berre, Ludmilla
Renaudin, Karine
Soulillou, Jean-Paul
van Pesch, Vincent
Brouard, Sophie
Berthelot, Laureline
Laplaud, David-Axel
Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation
title Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation
title_full Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation
title_fullStr Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation
title_full_unstemmed Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation
title_short Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation
title_sort aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (kcnj10) provides a target for autoimmune neuroinflammation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9994600/
https://www.ncbi.nlm.nih.gov/pubmed/36910419
http://dx.doi.org/10.1093/braincomms/fcad044
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