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

Authors: Akshaya Ramesh, Ryan Schubert, Ariele L. Greenfield, Ravi Dandekar, Rita P. Loudermilk, Joseph J. Sabatino, Matthew T. Koelzer, Edwina B. Tran, Kanishka Koshal, Kicheol Kim, Anne‐Katrin Pröbstel, Debarko Banerji, Chu‐Yueh Guo, Ari Green, Riley Bove, Joseph L. DeRisi, Jeffrey M. Gelfand, Bruce Cree, Scott S. Zamvil, Sergio E. Baranzini, Stephen L. Hauser, Michael R. Wilson - Proceedings of the National Academy of Sciences, PNAS 2020 cited by 198

= 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.