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

Proc Natl Acad Sci U S A. 2020 Sep 15;117(37):22932-22943. doi: 10.1073/pnas.2008523117. Epub 2020 Aug 28.


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.

Keywords: B cell; immune repertoire; multiple sclerosis; neuroimmunology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Central Nervous System / immunology
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Female
  • Flow Cytometry
  • Humans
  • Immunoglobulin G / metabolism
  • Immunoglobulin Heavy Chains / metabolism
  • Inflammation / pathology
  • Male
  • Middle Aged
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / pathology
  • Transcriptome


  • Chemokines
  • Cytokines
  • Immunoglobulin G
  • Immunoglobulin Heavy Chains