Longitudinally persistent cerebrospinal fluid B-cells can resist treatment in multiple sclerosis

• DOI: 10.1172/jci.insight.126599
• Publication Date: 2019-02-12T17:01:32Z
• Authors: Ariele L. Greenfield; Ravi Dandekar; Akshaya Ramesh; Erica L. Eggers; Hao Wu; Sarah Laurent; William Harkin; Natalie S. Pierson; Martin S. Weber; Roland G. Henry; Antje Bischof; Bruce A.C. Cree; Stephen L. Hauser; Michael R. Wilson; H.-Christian von ...
• Keywords: Adult; Male; Multiple Sclerosis; Immunology; B-Lymphocyte Subsets; Immunoglobulin Variable Region; Neurodegenerative; Lymphocyte Activation; Autoimmune Disease; Multiple sclerosis; Young Adult; 03 medical and health sciences; 0302 clinical medicine; Clinical Research; 2.1 Biological and endogenous factors; Humans; Aetiology; Cerebrospinal Fluid; B cells; B-Lymphocytes; B cell receptor; Inflammatory and immune system; Neurosciences; Middle Aged; Brain Disorders; 3. Good health; Neurological; Female; Neuroscience

AbstractB-cells are key contributors to chronic autoimmune pathology in multiple sclerosis (MS). Clonally related B-cells exist in the cerebrospinal fluid (CSF), meninges, and central nervous system (CNS) parenchyma of MS patients. Longitudinally stable CSF oligoclonal band (OCB) antibody patterns suggest some local CNS B-cell persistence; however, the longitudinal B-cell dynamics within and between the CSF and blood remain unknown. We sought to address this by performing immunoglobulin heavy chain variable region repertoire sequencing on B-cells from longitudinally collected blood and CSF samples of MS patients (n=10). All patients were untreated at the time of the initial sampling; the majority (n=7) were treated with immune modulating therapies 1.2 (+/−0.3 SD) years later during the second sampling. We found clonal persistence of B-cells in the CSF of five patients; these B-cells were frequently immunoglobulin (Ig) class-switched and CD27+. We identified specific blood B-cell subsets that appear to provide input into CNS repertoires over time. We demonstrate complex patterns of clonal B-cell persistence in CSF and blood, even in patients on high-efficacy immune modulating therapy. Our findings support the concept that peripheral B-cell activation and CNS-compartmentalized immune mechanisms are in part therapy-resistant.