title: Plasmablasts as migratory IgG-producing cells in the pathogenesis of neuromyelitis optica.
abstract: Neuromyelitis optica (NMO) is an inflammatory disease characterized by recurrent attacks of optic neuritis and myelitis. It is generally accepted that autoantibodies against aquaporin 4 water channel protein play a pathogenic role in neuromyelitis optica. We have recently reported that plasmablasts are increased in the peripheral blood of this autoimmune disease, and are capable of producing autoantibodies against aquaporin 4. Here, we demonstrate that CD138(+)HLA-DR(+) plasmablasts, a subset of IgG-producing cells, are increased in the peripheral blood and are enriched among the cerebrospinal fluid (CSF) lymphocytes during the relapse of neuromyelitis optica. Notably, these CD138(+)HLA-DR(+) plasmablasts overexpress CXCR3, whose ligands are present in the cerebrospinal fluid during the relapse of neuromyelitis optica. These results led us to speculate that plasmablasts producing anti-aquaporin 4 autoantibodies might traffic toward the central nervous system (CNS). Furthermore, we performed single-cell sorting of plasmablasts from peripheral blood and CSF samples from NMO and sequenced the complementarity-determining regions (CDRs) of the IgG heavy chain expressed by the sorted plasmablast clones. There were high frequencies of mutations in the CDRs compared with framework regions, indicating that these plasmablast clones would represent a post-germinal center B-cell lineage. Consistent with the preceding results, the plasmablast clones from the peripheral blood shared the same CDR sequences with the clones from the CSF. These results indicate that IgG-producing plasmablasts, which are guided by helper T-cells, may migrate from the peripheral blood preferentially to the CSF. Since migratory plasmablasts could be involved in the inflammatory pathology of NMO, the B-cell subset and their migration might be an attractive therapeutic target.
authors: Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan ; Department of Neurology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Norio
authors: N
authors: Chihara
authors: Toshimasa
authors: T
authors: Aranami
authors: Shinji
authors: S
authors: Oki
authors: Takako
authors: T
authors: Matsuoka
authors: Masakazu
authors: M
authors: Nakamura
authors: Hitaru
authors: H
authors: Kishida
authors: Kazumasa
authors: K
authors: Yokoyama
authors: Yoshiyuki
authors: Y
authors: Kuroiwa
authors: Nobutaka
authors: N
authors: Hattori
authors: Tomoko
authors: T
authors: Okamoto
authors: Miho
authors: M
authors: Murata
authors: Tatsushi
authors: T
authors: Toda
authors: Sachiko
authors: S
authors: Miyake
authors: Takashi
authors: T
authors: Yamamura
mesh_terms: D000328:Adult; D051401:Aquaporin 4 / Q000378:metabolism; D002465:Cell Movement; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007249:Inflammation; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology; D009154:Mutation; D009471:Neuromyelitis Optica / Q000276:immunology* / Q000473:pathology; D010950:Plasma Cells / Q000166:cytology*; D054367:Receptors, CXCR3 / Q000276:immunology; D012008:Recurrence; D053668:Syndecan-1 / Q000378:metabolism
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; C515187:CXCR3 protein, human; D006684:HLA-DR Antigens; D007074:Immunoglobulin G; D008024:Ligands; D054367:Receptors, CXCR3; D053668:Syndecan-1