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A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion

The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficac...

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Autores principales: Salvador, Florent, Deramoudt, Laure, Leprêtre, Frédéric, Figeac, Martin, Guerrier, Thomas, Boucher, Julie, Bas, Mathilde, Journiac, Nathalie, Peters, Anneli, Mars, Lennart T., Zéphir, Hélène
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8850296/
https://www.ncbi.nlm.nih.gov/pubmed/35185870
http://dx.doi.org/10.3389/fimmu.2022.755900
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author Salvador, Florent
Deramoudt, Laure
Leprêtre, Frédéric
Figeac, Martin
Guerrier, Thomas
Boucher, Julie
Bas, Mathilde
Journiac, Nathalie
Peters, Anneli
Mars, Lennart T.
Zéphir, Hélène
author_facet Salvador, Florent
Deramoudt, Laure
Leprêtre, Frédéric
Figeac, Martin
Guerrier, Thomas
Boucher, Julie
Bas, Mathilde
Journiac, Nathalie
Peters, Anneli
Mars, Lennart T.
Zéphir, Hélène
author_sort Salvador, Florent
collection PubMed
description The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-A(s): MOG(92-106) specific transgenic T cell receptor (TCR(1640)) spontaneously develop a chronic paralytic EAE between the age of 60-500 days. The immune response is triggered by the microbiota in the gut-associated lymphoid tissue, while there is evidence that the maturation of the autoimmune demyelinating response might occur in the cervical lymph nodes owing to local brain drainage. Using MOG-protein-tetramers we tracked the autoantigen-specific B cells and localized their enrichment to the cervical lymph nodes and among the brain immune infiltrate. MOG-specific IgG1 antibodies were detected in the serum of diseased TCR(1640) mice and proved pathogenic upon adoptive transfer into disease-prone recipients. The ontogeny of the MOG-specific humoral response preceded disease onset coherent with their contribution to EAE initiation. This humoral response was, however, not sufficient for disease induction as MOG-antibodies could be detected at the age of 69 days in a model with an average age of onset of 197 days. To assess the MOG-specific B cell repertoire we FACS-sorted MOG-tetramer binding cells and clonally expand them in vitro to sequence the paratopes of the IgG heavy chain and kappa light chains. Despite the fragility of clonally expanding MOG-tetramer binding effector B cells, our results indicate the selection of a common CDR-3 clonotype among the Igk light chains derived from both disease-free and diseased TCR(1640) mice. Our study demonstrates the pre-clinical mobilization of the MOG-specific B cell response within the brain-draining cervical lymph nodes, and reiterates that MOG antibodies are a poor biomarker of disease onset and progression.
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spelling pubmed-88502962022-02-18 A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion Salvador, Florent Deramoudt, Laure Leprêtre, Frédéric Figeac, Martin Guerrier, Thomas Boucher, Julie Bas, Mathilde Journiac, Nathalie Peters, Anneli Mars, Lennart T. Zéphir, Hélène Front Immunol Immunology The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-A(s): MOG(92-106) specific transgenic T cell receptor (TCR(1640)) spontaneously develop a chronic paralytic EAE between the age of 60-500 days. The immune response is triggered by the microbiota in the gut-associated lymphoid tissue, while there is evidence that the maturation of the autoimmune demyelinating response might occur in the cervical lymph nodes owing to local brain drainage. Using MOG-protein-tetramers we tracked the autoantigen-specific B cells and localized their enrichment to the cervical lymph nodes and among the brain immune infiltrate. MOG-specific IgG1 antibodies were detected in the serum of diseased TCR(1640) mice and proved pathogenic upon adoptive transfer into disease-prone recipients. The ontogeny of the MOG-specific humoral response preceded disease onset coherent with their contribution to EAE initiation. This humoral response was, however, not sufficient for disease induction as MOG-antibodies could be detected at the age of 69 days in a model with an average age of onset of 197 days. To assess the MOG-specific B cell repertoire we FACS-sorted MOG-tetramer binding cells and clonally expand them in vitro to sequence the paratopes of the IgG heavy chain and kappa light chains. Despite the fragility of clonally expanding MOG-tetramer binding effector B cells, our results indicate the selection of a common CDR-3 clonotype among the Igk light chains derived from both disease-free and diseased TCR(1640) mice. Our study demonstrates the pre-clinical mobilization of the MOG-specific B cell response within the brain-draining cervical lymph nodes, and reiterates that MOG antibodies are a poor biomarker of disease onset and progression. Frontiers Media S.A. 2022-02-03 /pmc/articles/PMC8850296/ /pubmed/35185870 http://dx.doi.org/10.3389/fimmu.2022.755900 Text en Copyright © 2022 Salvador, Deramoudt, Leprêtre, Figeac, Guerrier, Boucher, Bas, Journiac, Peters, Mars and Zéphir https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Salvador, Florent
Deramoudt, Laure
Leprêtre, Frédéric
Figeac, Martin
Guerrier, Thomas
Boucher, Julie
Bas, Mathilde
Journiac, Nathalie
Peters, Anneli
Mars, Lennart T.
Zéphir, Hélène
A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion
title A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion
title_full A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion
title_fullStr A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion
title_full_unstemmed A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion
title_short A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion
title_sort spontaneous model of experimental autoimmune encephalomyelitis provides evidence of mog-specific b cell recruitment and clonal expansion
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8850296/
https://www.ncbi.nlm.nih.gov/pubmed/35185870
http://dx.doi.org/10.3389/fimmu.2022.755900
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