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ResearchIn-Press PreviewAutoimmunityImmunology Open Access | 10.1172/JCI182790

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

Jessica Wei,1 Jeonghyeon Moon,1 Yoshiaki Yasumizu,1 Le Zhang,1 Khadir Raddassi,1 Nicholas C. Buitrago-Pocasangre,1 M. Elizabeth Deerhake,1 Nicolas Strauli,2 Chun-Wei Chen,2 Ann Herman,2 Rosetta Pedotti,3 Catarina Raposo,3 Isaiah Yim,4 Jenna L. Pappalardo,1 Erin E. Longbrake,1 Tomokazu S. Sumida,1 Pierre-Paul Axisa,1 and David A. Hafler1

1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

Find articles by Wei, J. in: JCI | PubMed | Google Scholar

1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

Find articles by Buitrago-Pocasangre, N. in: JCI | PubMed | Google Scholar |

1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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1Department of Neurology, Yale University School of Medicine, New Haven, United States of America

2Genentech, Inc., San Francisco, United States of America

3F. Hoffmann-La Roche, Basel, Switzerland

4Department of Biomedical Engineering, Yale University, New Haven, United States of America

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Published March 11, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI182790.
Copyright © 2025, Wei et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 11, 2025 - Version history
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Abstract

Multiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how B cell depleting therapies modulate the immune landscape using single-cell RNA sequencing (scRNAseq). We demonstrate that B cell depletion leads to cell type-specific changes in the abundance and function of CSF macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an anti-inflammatory transcriptomic signature and peripheral CD16+ monocytes increased in frequency post-B cell depletion. This was accompanied by increases in TNFα messenger RNA and protein in monocytes post-B cell depletion, consistent with the finding that anti-TNFα treatment exacerbates autoimmune activity in MS. In parallel, B cell depletion induced changes in peripheral CD4+ T cell populations, including increases in the frequency of TIGIT+ regulatory T cells 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 in MS.

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  • Version 1 (March 11, 2025): In-Press Preview
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