The role of unconventional memory B cells in the pathogenesis of multiple sclerosis

The role of unconventional memory B cells in the pathogenesis of multiple sclerosis Multiple sclerosis (MS) is not classically regarded as an autoantibody-driven disease; nevertheless, the presence of oligoclonal IgG and IgM bands in the cerebrospinal fluid and the clinical efficacy of CD20+ B cell depleting therapies underscore a central role for B cells in disease pathogenesis through antibody-independent mechanisms. In this longitudinal study, we show that cladribine treatment induces durable clinical stability and a selective, sustained remodeling of the B cell compartment rather than indiscriminate lymphocyte depletion. Cladribine preferentially depleted both conventional and unconventional memory B cell subsets, including marginal zone like (MZ-like) and doublenegative type 2 (DN2) B cells, while preserving bone marrow output and allowing gradual reconstitution of naïve and transitional B cells. Among memory populations, MZ-like B cells exhibited the most profound and persistent depletion. Functionally, MZ-like B cells displayed a highly pathogenic profile characterized by efficient lipid antigen presentation, polyfunctional proinflammatory cytokine production, and dominant IgM secretion, with heightened activity in MS compared to healthy donors (HDs). These features link MZ-like B cells to intrathecal IgM responses, ectopic meningeal follicle formation, and sustained CNS inflammation. In contrast, DN2 B cells demonstrated strong protein antigen presenting capacity but limited cytokine production and antibody secretion and reconstituted more rapidly following treatment, consistent with a transient, EBV-associated role in amplifying T-cell activation rather than maintaining chronic inflammation. Overall, our findings define distinct pathogenic roles for unconventional memory B-cell subsets in MS and suggest that the long-term efficacy of cladribine arises from its ability to selectively eliminate highly pathogenic memory B cells, particularly MZ-like B cells, while permitting regeneration of antigen unexperienced populations. This targeted immune reorganization provides a mechanistic explanation for cladribine’s durable therapeutic effects and identifies unconventional memory B cells as potential targets for future personalized therapies.