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

Authors

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

Published in

Science translational medicine. Volume 18. Issue 859. Pages eaee1580. Jul 22, 2026. Epub Jul 22, 2026.

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.

PMID:
42485437
Bibliographic data and abstract were imported from PubMed on 23 Jul 2026.

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