Plasmablasts as migratory IgG-producing cells in the pathogenesis of neuromyelitis optica.
Plasmablasts as migratory IgG-producing cells in the pathogenesis of neuromyelitis optica.
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DOI：
10.1371/journal.pone.0083036
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yamamura T
中科院分区：
文献类型：
--
作者：
Chihara N;Aranami T;Oki S;Matsuoka T;Nakamura M;Kishida H;Yokoyama K;Kuroiwa Y;Hattori N;Okamoto T;Murata M;Toda T;Miyake S;Yamamura T
视神经脊髓炎(NMO)是一种以反复发作的视神经炎和脊髓炎为特征的炎症性疾病。一般认为，抗水通道蛋白4自身抗体在视神经脊髓炎中起致病作用。我们最近报道了这种自身免疫性疾病的外周血中浆母细胞增多，并能够产生针对水通道蛋白4的自身抗体。在这里，我们证明了在视神经脊髓炎复发期间，外周血中产生免疫球蛋白的细胞亚群CD138+人类白细胞抗原-DR+浆母细胞增加，并在脑脊液(CSF)淋巴细胞中浓缩。值得注意的是，这些CD138+HLA-DR+浆母细胞过度表达CXCR3，其配体存在于视神经脊髓炎复发期间的脑脊液中。这些结果使我们推测，产生抗水通道蛋白4自身抗体的浆母细胞可能向中枢神经系统(CNS)运输。此外，我们对来自NMO的外周血和脑脊液中的浆母细胞进行了单细胞分选，并对分选后的浆母细胞克隆表达的免疫球蛋白重链的互补决定区(CDR)进行了测序。与骨架区域相比，CDRs的突变频率较高，表明这些浆母细胞克隆将代表生发中心后B细胞谱系。与前面的结果一致，来自外周血的浆母细胞克隆与来自脑脊液的克隆具有相同的CDR序列。这些结果表明，在辅助性T细胞的引导下，产生免疫球蛋白的浆母细胞可能优先从外周血迁移到脑脊液。由于移行性浆母细胞可能参与NMO的炎症病理过程，B细胞亚群及其移行可能是一个有吸引力的治疗靶点。
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.
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影响因子：
11.2
作者：
Bennett, Jeffrey L.;Lam, Chiwah;Kalluri, Sudhakar Reddy;Saikali, Philippe;Bautista, Katherine;Dupree, Cecily;Glogowska, Magdalena;Case, David;Antel, Jack P.;Owens, Gregory P.;Gilden, Don;Nessler, Stefan;Stadelmann, Christine;Hemmer, Bernhard
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20.3
作者：
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Dörner, T
影响因子：
3.7
作者：
Ratelade J;Bennett JL;Verkman AS
通讯作者：
Verkman AS
影响因子：
11.2
作者：
Polman CH;Reingold SC;Banwell B;Clanet M;Cohen JA;Filippi M;Fujihara K;Havrdova E;Hutchinson M;Kappos L;Lublin FD;Montalban X;O'Connor P;Sandberg-Wollheim M;Thompson AJ;Waubant E;Weinshenker B;Wolinsky JS
通讯作者：
Wolinsky JS