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.
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.
Qin
Yufen
Y
Department of Neurology, University of California Irvine, Irvine, California 92697, USA. qiny@uci.edu
Duquette
Pierre
P
Zhang
Yiping
Y
Olek
Michael
M
Da
Reng-Rong
RR
Richardson
John
J
Antel
Jack P
JP
Talbot
Pierre
P
Cashman
Neil R
NR
Tourtellotte
Wallace W
WW
Wekerle
Hartmut
H
Van Den Noort
Stanley
S
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
D017931:DNA Primers; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region