Annals of neurology · 2026
From Marginal to Central: Marginal Zone-like B Cells as Critical Targets in Cladribine-Treated Multiple Sclerosis.
СтатьяНазвание и аннотация: Перевод в очереди
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Pirronello Marta, Picozza Mario, Guerrera Gisella, Corbisiero Silvia, Misiti Andrea, Placido Roberta C, Verdiani Alice, de Marco Lorenzo, Sambucci Manolo, Olivieri Elena, Angelini Daniela F, Quartuccio Esmeralda, Prosperini Luca, Tortorella Carla, Buscarinu Maria C, Zancan Valeria, de Masi Francesca, Salvetti Marco, Gasperini Claudio, Borsellino Giovanna, Battistini Luca
Аннотация
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;100:808-823.
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;100:808-823.