title: Specific peripheral B cell tolerance defects in patients with multiple sclerosis.
abstract: Multiple sclerosis (MS) is a genetically mediated autoimmune disease of the central nervous system. B cells have recently emerged as major contributors to disease pathogenesis, but the mechanisms responsible for the loss of B cell tolerance in patients with MS are largely unknown. In healthy individuals, developing autoreactive B cells are removed from the repertoire at 2 tolerance checkpoints during early B cell development. Both of these central and peripheral B cell tolerance checkpoints are defective in patients with rheumatoid arthritis (RA) and type 1 diabetes (T1D). Here, we found that only the peripheral, but not the central, B cell tolerance checkpoint is defective in patients with MS. We show that this specific defect is accompanied by increased activation and homeostatic proliferation of mature naive B cells. Interestingly, all of these MS features parallel defects observed in FOXP3-deficient IPEX patients, who harbor nonfunctional Tregs. We demonstrate that in contrast to patients with RA or T1D, bone marrow central B cell selection in MS appears normal in most patients. In contrast, patients with MS suffer from a specific peripheral B cell tolerance defect that is potentially attributable to impaired Treg function and that leads to the accumulation of autoreactive B cell clones in their blood.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Tuure
authors.initials: T
authors.lastname: Kinnunen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chamberlain
authors.forename: Henner
authors.initials: H
authors.lastname: Morbach
authors.forename: Tineke
authors.initials: T
authors.lastname: Cantaert
authors.forename: Megan
authors.initials: M
authors.lastname: Lynch
authors.forename: Paula
authors.initials: P
authors.lastname: Preston-Hurlburt
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Kevin C
authors.initials: KC
authors.lastname: O'Connor
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D005434:Flow Cytometry; D006801:Humans; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D061166:Peripheral Tolerance; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D001324:Autoantigens