Age-Associated Expansion of Natural IgM? Fcrl5? B Cell Clones: Drivers of Progressive MS and Targets for Therapy - Progressive multiple sclerosis (PMS) is a leading cause of neurological disability and remains a critical unmet clinical need, particularly among older adults. In contrast to relapsing-remitting MS (RRMS), which typically begins in young adulthood, PMS emerges more commonly in middle age and is characterized by gradual, irreversible neurological decline driven by chronic, compartmentalized inflammation and neurodegeneration within the central nervous system (CNS). With over half of individuals with MS in the United States now between ages 55 and 64, elucidating the mechanisms that underlie disease progression is essential for improving diagnosis, monitoring, and treatment. Current immunotherapies that effectively target peripheral immune pathways in RRMS offer limited benefit in PMS. In particular, broadly depleting B cell therapies such as anti-CD20 antibodies poorly penetrate the CNS, confer modest efficacy in PMS, and increase infectious risk— particularly concerning in the older PMS population. These challenges highlight the need for therapies that more precisely target CNS-resident immune mechanisms. Emerging evidence, including the recent success of a CNS-penetrant Bruton’s tyrosine kinase inhibitor in non-relapsing PMS, implicates CNS-resident B cells—especially those within meningeal ectopic lymphoid structures—in PMS pathogenesis. However, the identity, antigen specificity, and pathogenic functions of these CNS- compartmentalized B cell subsets remain poorly understood. Our preliminary studies have unexpectedly identified a novel population of clonally expanded, innate-like Fcrl5⁺IgM⁺ B cells—termed Baci cells—in the meninges of middle-aged mice with chronic experimental autoimmune encephalomyelitis (EAE), an animal model that recapitulates key features of PMS. Notably, a hyperexpanded Baci clone produces IgM antibodies reactive to phosphatidylcholine, a major myelin lipid, suggesting potential autoreactivity. We hypothesize that Baci cells contribute to chronic neuroinflammation, cortical demyelination, and disease progression via natural autoreactive IgM antibody production, antigen presentation to autoreactive T cells, and pro-inflammatory cytokine secretion. Aim 1 will determine the role of Baci cells in CNS-compartmentalized inflammation by selectively depleting them using a novel Fcrl5-Cre transgenic mouse during chronic EAE, and evaluating their role in the reactivation of encephalitogenic T cells. Aim 2 will define the antigen specificity and pathogenic potential of natural IgM antibodies produced by clonally expanded Baci cells in the CNS. Aim 3 will investigate the presence of a human analog of Baci cells in cerebrospinal fluid from individuals with MS and examine its correlation with progressive disease phenotype and extent of neurological disability. This proposal advances a novel concept in PMS pathogenesis by uncovering and functionally characterizing an unconventional age- associated, innate-like B cell subset. Using innovative genetic tools and mechanistic approaches, it aims to define how Baci cells drive progression, paving the way for safer, more targeted therapies.
