Transcriptomic profiling after B cell depletion reveals central and peripheral immune cell changes in multiple sclerosis
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
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
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Research Article Autoimmunity Immunology

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

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

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Figure 2

Enriched CSF macrophages present an antiinflammatory phenotype in patients with MS following B cell depletion therapy.

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Enriched CSF macrophages present an antiinflammatory phenotype in patien...
Gene expression analyses of CSF macrophages were conducted by comparing cells from healthy donors (n = 6) and pre– and post–B cell depletion therapy MS patient samples (n = 5). (A) Mean abundance plot depicting DEGs (FDR <0.1) in the Mac 1 cluster from patients with MS before and after B cell depletion. Blue indicates downregulation after treatment; red indicates upregulation after treatment. (B) MHC class I and class II gene module scores for healthy donor, MS pre-treatment, and MS post-treatment Mac 1 cells. (C) Dot plot depicting myeloid inflammatory and antiinflammatory gene expression in healthy donors and patients with MS before and after treatment. (D) Gene module scores for all CSF myeloid clusters against peripheral monocyte gene signatures. Top: classical monocyte module score, middle: intermediate monocyte module score; bottom: nonclassical monocyte module score.