Talk abstracts
Talk on Thursday 09:30-09:45am submitted by Hayley Groover
Age-Associated Expansion of FCRL5+ IgM+ B1 Cell Clones: Drivers of Progressive MS and Targets for Therapy
Hayley Groover (Neuroscience Graduate Program, The Ohio State University), Jeffrey Atkinson, PhD (Department of Neurology, The Ohio State University), Shane Chen (Department of Neurology, The Ohio State University), Tom Liu, PhD, Andreas Wieland, PhD (Department of Otolaryngology, The Ohio State University), Benjamin Segal, MD (Department of Neurology, The Ohio State University)
Abstract:
Age is the strongest determinant of whether multiple sclerosis (MS)the most common inflammatory demyelinating disease of the central nervous system (CNS)manifests as relapsingremitting (RRMS) or progressive (PMS) disease. Young adults typically develop RRMS, characterized by episodic neurological dysfunction with recovery, whereas middle-aged individuals more often experience PMS, marked by a gradual and relentless accumulation of disability. The efficacy of B celltargeting therapies across both forms underscores a central role for B cells in MS pathogenesis, yet the mechanisms by which B cells drive disease, and how these functions evolve with aging, remain poorly defined. Our prior work shows that experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, similarly exhibits age-dependent divergence in clinical phenotype. Young adult mice develop a self-limited episode of inflammatory demyelination, whereas middle-aged mice develop chronic disease marked by persistent neuroinflammation. In this setting, we identified a striking accumulation of a novel B cell subset in the CNS of middle-aged mice during chronic EAE. These cells, defined by FCRL5 expression and exhibiting innate B1-like features, were clonally expanded in the CNS and enriched for transcriptional programs associated with antigen presentation and proinflammatory cytokine production. These innate-like clonally expanded (ICE) B cells localized to meningeal lymphoid aggregates resembling ectopic follicles characteristic of progressive MS, and their abundance correlated with clinical severity. One dominant clone expressed immunoglobulins previously described in peritoneal B1 cells reactive to phosphatidylcholine (PtC), a major myelin lipid. Recombinant antibodies derived from ICE clones converted remitting EAE into a chronic progressive course. Importantly, human counterparts of ICE B cells were identified in CSF from individuals with MS. Together, these findings define a previously unrecognized population of innate-like, clonally expanded B cells that accumulate in the aging CNS, produce autoreactive antibodies targeting myelin lipids, and drive persistent neuroinflammationlinking aging to disease progression and identifying a new therapeutic target for progressive MS.
Keywords: Multiple Sclerosis, B-cells, Neuroimmunology