title: Intrathecal B-cell clonal expansion, an early sign of humoral immunity, in the cerebrospinal fluid of patients with clinically isolated syndrome suggestive of multiple sclerosis.
abstract: The development of somatically mutated memory and plasma B cells is a consequence of T cell-dependent antigen-challenged humoral immunity. To investigate the role of B cell-mediated humoral immunity in the initiation and evolution of multiple sclerosis (MS), we analyzed Ig variable heavy chain genes of intrathecal B cells derived from patients with a first clinical manifestation suggestive of MS. Sequences of Ig variable regions showed that B cells in the cerebrospinal fluid from most of these patients were clonally expanded and carried somatic hypermutated variable heavy chain genes. The mutations showed a high replacement-to-silent ratio and were distributed in a way suggesting that these clonally expanded B cells had been positively selected through their antigen receptor. In comparison, intrathecal B-cell clonal expansion often precedes both oligoclonal IgG bands and multiple magnetic resonance imaging lesions. Clinical follow-up study showed that patients with clonally expanded intrathecal B cells had a high rate of conversion to clinically definite MS. The findings provide direct evidence of recruitment of germinal center differentiated B lymphocytes into the central nervous system during the initiation of MS. These results indicate B cell-mediated immune response in the cerebrospinal fluid is an early event of inflammatory reaction in the central nervous system of MS. This procedure also provides a more sensitive method to evaluate the association of humoral immunity in the evolution of MS.
authors.affiliation: Department of Neurology, University of California Irvine, Irvine, California 92697, USA. qiny@uci.edu
authors.forename: Yufen
authors.initials: Y
authors.lastname: Qin
authors.forename: Pierre
authors.initials: P
authors.lastname: Duquette
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Olek
authors.forename: Reng-Rong
authors.initials: RR
authors.lastname: Da
authors.forename: John
authors.initials: J
authors.lastname: Richardson
authors.forename: Jack P
authors.initials: JP
authors.lastname: Antel
authors.forename: Pierre
authors.initials: P
authors.lastname: Talbot
authors.forename: Neil R
authors.initials: NR
authors.lastname: Cashman
authors.forename: Wallace W
authors.initials: WW
authors.lastname: Tourtellotte
authors.forename: Hartmut
authors.initials: H
authors.lastname: Wekerle
authors.forename: Stanley
authors.initials: S
authors.lastname: Van Den Noort
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005803:Genes, Immunoglobulin / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000276:immunology*; D009154:Mutation; D016133:Polymerase Chain Reaction; D016415:Sequence Alignment; D013577:Syndrome
chemical_list: D017931:DNA Primers; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region