Age-Associated Expansion of Natural IgM? Fcrl5? B Cell Clones: Drivers of Progressive MS and Targets for Therapy
openNINDS - National Institute of Neurological Disorders and Stroke
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.
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