Journal Article

DZNE-2026-00801

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Anti-CD20 B cell depletion is associated with elevated mucosal-originating circulating regulatory IgA B cells in multiple sclerosis.

Neziraj, T. ; Pössnecker, E. ; Wang, A. A. ; Saary, P. ; Schumacher, A.-M. ; Ingelfinger, F. ; Mathias, A. ; Galli, E. ; Häfelfinger, M. ; Zuo, M. ; Jones, S. ; Pantazou, V. ; Killestein, J. ; Schädelin, S. ; Benkert, P. ; Granziera, C. ; Pot, C. ; Bischof, A.DZNE* ; Niess, J. H. ; Filipowicz Sinnreich, M. ; Derfuss, T. ; Teunissen, C. E. ; Kuhle, J. ; Hafler, D. A. ; Du Pasquier, R. ; Yasumizu, Y. ; Gommerman, J. L. ; Pröbstel, A.-K. (Last author)DZNE*

2026
AAAS Washington, DC

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Please use a persistent id in citations: doi:10.1126/scitranslmed.aee1580

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.

Keyword(s): Humans (MeSH) ; Multiple Sclerosis: immunology (MeSH) ; Multiple Sclerosis: blood (MeSH) ; Multiple Sclerosis: cerebrospinal fluid (MeSH) ; Antigens, CD20: immunology (MeSH) ; Antigens, CD20: metabolism (MeSH) ; B-Lymphocytes: immunology (MeSH) ; Immunoglobulin A: metabolism (MeSH) ; Immunoglobulin A: blood (MeSH) ; Animals (MeSH) ; Female (MeSH) ; Lymphocyte Depletion (MeSH) ; Adult (MeSH) ; Encephalomyelitis, Autoimmune, Experimental: immunology (MeSH) ; Transcriptome: genetics (MeSH) ; Antigens, CD20 ; Immunoglobulin A

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Contributing Institute(s):

1. Clinical Neurology and Neuroimmunology (AG Pröbstel)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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