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Publications

Journal Article Ahead of print 1 citation

PubMed: 42312812 DOI: 10.1002/ana.78277

From Marginal to Central: Marginal Zone-like B Cells as Critical Targets in Cladribine-Treated Multiple Sclerosis.

Ann Neurol

Authors: Marta Pirronello, Mario Picozza, Gisella Guerrera, Silvia Corbisiero, Andrea Misiti, Roberta C Placido, Alice Verdiani, Lorenzo de Marco, Manolo Sambucci, Elena Olivieri, Daniela F Angelini, Esmeralda Quartuccio, Luca Prosperini, Carla Tortorella, Maria C Buscarinu, Valeria Zancan, Francesca de Masi, Marco Salvetti, Claudio Gasperini, Giovanna Borsellino, Luca Battistini

Affiliations

  • Neuroimmunology Unit, European Centre for Brain Research, Fondazione Santa Lucia IRCCS, Rome, Italy.
  • Department of Internal Medicine and Medical Specialities (DIMI), University of Genova, Genoa, Italy.
  • Neuroscience Department, San Camillo-Forlanini Hospital, Rome, Italy.
  • Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy.
  • Neuroimaging Unit, Fondazione Santa Lucia IRCSS, Rome, Italy.
  • Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.

Abstract

OBJECTIVE

Multiple sclerosis (MS) is a chronic autoimmune disease where B cells play a central pathogenic role. Cladribine, an oral therapy, provides durable benefits by reshaping lymphocyte populations, yet its specific long-term impact on distinct B-cell subsets is not fully understood. This study aimed to define cladribine's longitudinal effects on B-cell subsets and characterize their inflammatory properties.

METHODS

We conducted a 48-month longitudinal study of 36 persons with relapsing-remitting MS treated with cladribine who had completed 2 annual treatment cycles, using high-parameter flow cytometry to track B-cell subset dynamics. In a parallel cross-sectional analysis, B cells from 16 untreated patients and 16 healthy donors were profiled for polyfunctional cytokine production granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and key surface markers.

RESULTS

Cladribine induced profound, sustained depletion of memory B cells, with marginal zone-like (MZ-like) cells showing the deepest and most persistent loss, alongside reconstitution of transitional and naïve populations. Functionally, MZ-like B cells were the most potent polyfunctional producers of proinflammatory cytokines and immunoglobulin M (IgM), a capacity significantly enhanced in persons with MS compared to healthy donors, and expressed the highest levels of CD1c and CD1d, consistent with specialization in lipid antigen presentation.

INTERPRETATION

MZ-like B cells are a dominant, polyfunctional inflammatory subset in MS, equipped for non-canonical lipid antigen presentation and IgM secretion. They represent a preferential pharmacological target of cladribine. Sustained reduction of this pathogenic memory pool, followed by repopulation with less inflammatory B cells, offers a mechanistic basis for cladribine's durable clinical benefit and nominates MZ-like cells as biomarkers of response and therapeutic targets. ANN NEUROL 2026.

MeSH

Cytokines, Cells, Sclerosis, Multiple Sclerosis, Granulocyte-Macrophage Colony-Stimulating Factor, Interleukin-6, Antigen Presentation, Cladribine, B-Lymphocyte Subsets, Therapeutics, Memory, B-Lymphocytes