Exploring Progressive Multiple Sclerosis and the Therapeutic Potential of BTK Inhibitors Based on EBV-driven B Cell-microglia Interactions.

Progressive Multiple Sclerosis (PMS) remains a major cause of irreversible disability in Multiple Sclerosis (MS), yet current disease-modifying therapies incompletely address the compartmentalized Central Nervous System (CNS) inflammation, sustained microglial activation, chronic demyelination, and axonal degeneration that characterize progression. This topic is timely because the evidence linking Epstein-Barr Virus (EBV) to MS susceptibility, the recognition of B cell-myeloid interactions within the CNS, and the clinical development of CNS-penetrant Bruton's Tyrosine Kinase inhibitors (BTKi) now converge on a common translational question: whether a connected EBV- B cell-microglia-BTK axis can explain part of progression independent of relapse activity and inform therapy for PMS. EBV establishes lifelong latency in memory B cells and may contribute to MS through molecular mimicry, aberrant antigen presentation, and persistent pro-inflammatory signaling. In progressive disease, B cells can interact with microglia and macrophages to sustain compartmentalized inflammation, while BTK links B-cell receptor and myeloid Fc receptor signaling. This review synthesizes EBV-associated B-cell dysregulation, B cell-microglia crosstalk, BTK biology, BTKi trial evidence, biomarkers, and safety considerations in an evidence-stratified framework. Rather than presenting a linear causal model, we distinguish established observations from emerging mechanisms and speculative hypotheses. We propose that this integrated pathophysiological framework may help clarify patient stratification, CNS target engagement, and rational therapeutic development for PMS while defining the limits that future studies must address.