A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis.
Akshaya RameshRyan D SchubertAriele L GreenfieldRavi DandekarRita P LoudermilkJoseph J SabatinoMatthew T KoelzerEdwina B TranKanishka KoshalKicheol KimAnne-Katrin PröbstelDebarko Banerjinull nullChu-Yueh GuoAri J GreenRiley M BoveJoseph L DeRisiJeffrey M GelfandBruce A C CreeScott S ZamvilSergio E BaranziniStephen L HauserMichael R WilsonPublished in: Proceedings of the National Academy of Sciences of the United States of America (2020)
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.
Keyphrases
- single cell
- multiple sclerosis
- rna seq
- cerebrospinal fluid
- nuclear factor
- blood brain barrier
- epstein barr virus
- high throughput
- induced apoptosis
- white matter
- oxidative stress
- toll like receptor
- working memory
- cell cycle arrest
- transforming growth factor
- stem cells
- diffuse large b cell lymphoma
- signaling pathway
- sars cov
- cell death
- gene expression
- brain injury
- inflammatory response
- risk assessment
- pi k akt
- genetic diversity
- single molecule
- human health
- cerebral ischemia
- case report