Transcriptomic profiling after B cell depletion reveals central and peripheral immune cell changes in multiple sclerosis

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Abstract

Multiple sclerosis (MS) is a complex, genetically mediated autoimmune disease of the CNS, in which anti-CD20–mediated B cell depletion is remarkably effective in the treatment of early disease. Although previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry–based methods, the therapeutic effect on the patient’s immune landscape is unknown. In this study, we explored how B cell–depleting therapies modulate the immune landscape using single-cell RNA-Seq. We demonstrate that B cell depletion led to cell-type–specific changes in the abundance and function of cerebrospinal fluid (CSF) macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an antiinflammatory transcriptomic signature and peripheral CD16+ monocytes increased in frequency after B cell depletion. This was accompanied by increases in TNF-α mRNA and protein levels in monocytes following B cell depletion, consistent with the finding that anti–TNF-α treatment exacerbated autoimmune activity in MS. In parallel, B cell depletion induced changes in peripheral CD4+ T cell populations, including increases in the frequency of TIGIT+ Tregs and marked decreases in the frequency of myelin peptide–loaded, tetramer-binding CD4+ T cells. Collectively, this study provides an exhaustive transcriptomic map of immunological changes, revealing different cell-type–specific reprogramming as a result of B cell depletion treatment of MS.

Authors

Jessica Wei, Jeonghyeon Moon, Yoshiaki Yasumizu, Le Zhang, Khadir Radassi, Nicholas Buitrago-Pocasangre, M. Elizabeth Deerhake, Nicolas Strauli, Chun-Wei Chen, Ann Herman, Rosetta Pedotti, Catarina Raposo, Isaiah Yim, Jenna Pappalardo, Erin E. Longbrake, Tomokazu S. Sumida, Pierre-Paul Axisa, David A. Hafler