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A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles,...

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Autores principales: Ramesh, Akshaya, Schubert, Ryan D., Greenfield, Ariele L., Dandekar, Ravi, Loudermilk, Rita, Sabatino, Joseph J., Koelzer, Matthew T., Tran, Edwina B., Koshal, Kanishka, Kim, Kicheol, Pröbstel, Anne-Katrin, Banerji, Debarko, Guo, Chu-Yueh, Green, Ari J., Bove, Riley M., DeRisi, Joseph L., Gelfand, Jeffrey M., Cree, Bruce A. C., Zamvil, Scott S., Baranzini, Sergio E., Hauser, Stephen L., Wilson, Michael R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502747/
https://www.ncbi.nlm.nih.gov/pubmed/32859762
http://dx.doi.org/10.1073/pnas.2008523117
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author Ramesh, Akshaya
Schubert, Ryan D.
Greenfield, Ariele L.
Dandekar, Ravi
Loudermilk, Rita
Sabatino, Joseph J.
Koelzer, Matthew T.
Tran, Edwina B.
Koshal, Kanishka
Kim, Kicheol
Pröbstel, Anne-Katrin
Banerji, Debarko
Guo, Chu-Yueh
Green, Ari J.
Bove, Riley M.
DeRisi, Joseph L.
Gelfand, Jeffrey M.
Cree, Bruce A. C.
Zamvil, Scott S.
Baranzini, Sergio E.
Hauser, Stephen L.
Wilson, Michael R.
author_facet Ramesh, Akshaya
Schubert, Ryan D.
Greenfield, Ariele L.
Dandekar, Ravi
Loudermilk, Rita
Sabatino, Joseph J.
Koelzer, Matthew T.
Tran, Edwina B.
Koshal, Kanishka
Kim, Kicheol
Pröbstel, Anne-Katrin
Banerji, Debarko
Guo, Chu-Yueh
Green, Ari J.
Bove, Riley M.
DeRisi, Joseph L.
Gelfand, Jeffrey M.
Cree, Bruce A. C.
Zamvil, Scott S.
Baranzini, Sergio E.
Hauser, Stephen L.
Wilson, Michael R.
author_sort Ramesh, Akshaya
collection PubMed
description Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood–brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein–Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.
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spelling pubmed-75027472020-09-28 A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis Ramesh, Akshaya Schubert, Ryan D. Greenfield, Ariele L. Dandekar, Ravi Loudermilk, Rita Sabatino, Joseph J. Koelzer, Matthew T. Tran, Edwina B. Koshal, Kanishka Kim, Kicheol Pröbstel, Anne-Katrin Banerji, Debarko Guo, Chu-Yueh Green, Ari J. Bove, Riley M. DeRisi, Joseph L. Gelfand, Jeffrey M. Cree, Bruce A. C. Zamvil, Scott S. Baranzini, Sergio E. Hauser, Stephen L. Wilson, Michael R. Proc Natl Acad Sci U S A Biological Sciences Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood–brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein–Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype. National Academy of Sciences 2020-09-15 2020-08-28 /pmc/articles/PMC7502747/ /pubmed/32859762 http://dx.doi.org/10.1073/pnas.2008523117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Ramesh, Akshaya
Schubert, Ryan D.
Greenfield, Ariele L.
Dandekar, Ravi
Loudermilk, Rita
Sabatino, Joseph J.
Koelzer, Matthew T.
Tran, Edwina B.
Koshal, Kanishka
Kim, Kicheol
Pröbstel, Anne-Katrin
Banerji, Debarko
Guo, Chu-Yueh
Green, Ari J.
Bove, Riley M.
DeRisi, Joseph L.
Gelfand, Jeffrey M.
Cree, Bruce A. C.
Zamvil, Scott S.
Baranzini, Sergio E.
Hauser, Stephen L.
Wilson, Michael R.
A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis
title A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis
title_full A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis
title_fullStr A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis
title_full_unstemmed A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis
title_short A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis
title_sort pathogenic and clonally expanded b cell transcriptome in active multiple sclerosis
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502747/
https://www.ncbi.nlm.nih.gov/pubmed/32859762
http://dx.doi.org/10.1073/pnas.2008523117
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