title: Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients.
abstract: Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as a clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Rivas
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Ireland
authors.affiliation: Department of Pathology, UT Southwestern, Dallas, TX, USA.
authors.forename: Rati
authors.initials: R
authors.lastname: Chkheidze
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Rounds
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: Denise M O
authors.initials: DM
authors.lastname: Ramirez
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Ligocki
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Guzman
authors.affiliation: Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Woodhall
authors.affiliation: Department of Biomedical Sciences, University of Chicago, Chicago, IL, USA.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.affiliation: Department of Pathology, UT Southwestern, Dallas, TX, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: White
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Greenberg
authors.affiliation: Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Waters
authors.affiliation: Department of Clinical Science, UT Southwestern, Dallas, TX, USA.
authors.forename: Lindsay G
authors.initials: LG
authors.lastname: Cowell
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Stowe
authors.affiliation: Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, TX, USA. Nancy.Monson@UTSouthwestern.edu.|Department of Immunology, UT Southwestern, Dallas, TX, USA. Nancy.Monson@UTSouthwestern.edu.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Monson
mesh_terms: D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001921:Brain / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D005260:Female; D066128:Gray Matter / Q000276:immunology / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D009471:Neuromyelitis Optica / Q000276:immunology / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000473:pathology; D010950:Plasma Cells / Q000276:immunology* / Q000502:physiology; D020521:Stroke / Q000276:immunology / Q000473:pathology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G
keywords: Antigen receptor genetics; Autoantibody; B cell; Multiple sclerosis; Plasmablast