Anti-CD20 B cell depletion is associated with elevated mucosal-originating circulating regulatory IgA B cells in multiple sclerosis

Therapy with anti-CD20 monoclonal antibodies is highly efficacious in various autoimmune diseases including multiple sclerosis (MS), a prototypic autoimmune inflammatory disease of the central nervous system (CNS). However, which B cell subsets and altered B cell–regulating factors mediate the clinical efficacy of anti-CD20 treatment is unclear. To address this gap in knowledge, we performed longitudinal high-dimensional single-cell transcriptomic and proteomic profiling of blood, cerebrospinal fluid (CSF), and intestinal samples from people with MS (pwMS), combined with immune profiling in a preclinical autoimmune encephalomyelitis model during anti-CD20 therapy. CSF analyses were performed using previously published datasets. Multisite intestinal profiling was conducted in one anti-CD20–treated patient with MS and one control participant. By applying algorithm-guided analyses of flow cytometry, single-cell transcriptomic, and immune receptor repertoire data, we found that anti-CD20 B cell depletion was associated with increased frequencies of regulatory mucosal-derived IgA-producing B cells in the periphery and CSF, together with increased B cell receptor clonal overlap between mucosal and systemic compartments, indicating enhanced trafficking of IgA B cells from gut mucosal tissues to the systemic circulation and the CNS. Moreover, we demonstrated that higher levels of B cell–activating factor and a proliferation-inducing ligand were related to favorable outcomes in pwMS during anti-CD20 treatment. Together, our findings suggest that mucosal immune regulatory mechanisms may be harnessed by anti-CD20 B cell depletion, opening previously unknown therapeutic avenues for MS.

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Publication Details

Journal
Science Translational Medicine
Published
2026-07-22
DOI
https://doi.org/10.1126/scitranslmed.aee1580
Primary Topic
Multiple Sclerosis Research Studies
Type
article
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article

Anti-CD20 B cell depletion is associated with elevated mucosal-originating circulating regulatory IgA B cells in multiple sclerosis

David A. Hafler, Samuel Jones, Sabine Schädelin, A. Wang et al.
Science Translational Medicine
Multiple Sclerosis Research Studies
article

Anti-CD20 B cell depletion is associated with elevated mucosal-originating circulating regulatory IgA B cells in multiple sclerosis

David A. Hafler, Samuel Jones, Sabine Schädelin, A. Wang, Jennifer L. Gommerman, Yoshiaki Yasumizu, Tradite Neziraj, Paul Saary, Jens Kühle, Michelle Zuo, Amandine Mathias, Adrian-Minh Schumacher, Florian Ingelfinger, Antje Bischof, Renaud Du Pasquier, Charlotte Elisabeth Teunissen, Joep Killestein, Pascal Benkert, Caroline Pot, Anne‐Katrin Pröbstel, Cristina Granziera, Magdalena Filipowicz Sinnreich, Edoardo Galli, Vasiliki Pantazou, Elisabeth Pössnecker, Jan Hendrik Niess, Marco Häfelfinger, Tobias Derfuss
article en

Abstract

Therapy with anti-CD20 monoclonal antibodies is highly efficacious in various autoimmune diseases including multiple sclerosis (MS), a prototypic autoimmune inflammatory disease of the central nervous system (CNS). However, which B cell subsets and altered B cell–regulating factors mediate the clinical efficacy of anti-CD20 treatment is unclear. To address this gap in knowledge, we performed longitudinal high-dimensional single-cell transcriptomic and proteomic profiling of blood, cerebrospinal fluid (CSF), and intestinal samples from people with MS (pwMS), combined with immune profiling in a preclinical autoimmune encephalomyelitis model during anti-CD20 therapy. CSF analyses were performed using previously published datasets. Multisite intestinal profiling was conducted in one anti-CD20–treated patient with MS and one control participant. By applying algorithm-guided analyses of flow cytometry, single-cell transcriptomic, and immune receptor repertoire data, we found that anti-CD20 B cell depletion was associated with increased frequencies of regulatory mucosal-derived IgA-producing B cells in the periphery and CSF, together with increased B cell receptor clonal overlap between mucosal and systemic compartments, indicating enhanced trafficking of IgA B cells from gut mucosal tissues to the systemic circulation and the CNS. Moreover, we demonstrated that higher levels of B cell–activating factor and a proliferation-inducing ligand were related to favorable outcomes in pwMS during anti-CD20 treatment. Together, our findings suggest that mucosal immune regulatory mechanisms may be harnessed by anti-CD20 B cell depletion, opening previously unknown therapeutic avenues for MS.

Science Translational MedicineVol. 18(859)
University of Basel (CH), University of Toronto (CA), University Hospital Bonn (DE), University Medical Center Freiburg (DE), German Center for Neurodegenerative Diseases (DE), University Hospital of Basel (CH), Yale University (US), Kantonsspital Baselland (CH), Psychiatry Baselland (CH), Amsterdam Neuroscience (NL), Department of Biomedicine Basel (CH), University of Lausanne (CH)
Good health and well-being
Openalex Percentile: Top 8%
Multiple Sclerosis Research Studies
DOISourceOpenAlex
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