Comprehensive cerebrospinal fluid analysis indicates key roles for B cells in multiple sclerosis

Multiple sclerosis (MS) is a complex inflammatory and neurodegenerative disease of the central nervous system (CNS) with a multifaceted pathophysiology, likely involving a variety of mechanisms and effectors. To characterize the spectrum of cellular and molecular factors involved in MS at an unprecedented level, we here performed a comprehensive analysis of cerebrospinal fluid (CSF) and peripheral blood using multiple high-dimensional technologies, including mass cytometry, metabolomics and proteomics (NULISA and Olink Explore® 3072). Enriched B cells and proteins involved in B cell functions in the CSF separated MS patients from other neurological disease entities. Specific B cell subpopulations and molecular markers including gut-microbiota-derived metabolites and neurofilament light protein, a marker of neuroaxonal damage, in CSF correlated with clinical (acute vs. stable disease) and/or radiological (gadolinium enhancement) disease activity. Altogether, unbiased broad phenotyping suggests key roles of diverse B subpopulations and B cell related molecular markers in MS, which are associated with both, inflammatory and degenerative aspects of the disease and may serve as disease activity and treatment response biomarkers.