Interleukin-6 Signaling Blockade Induces Regulatory Plasmablasts in Neuromyelitis Optica Spectrum Disorder.

IF 7.8 1区 医学 Q1 CLINICAL NEUROLOGY
Ritsu Akatani, Norio Chihara, Atsushi Hara, Asato Tsuji, Shusuke Koto, Kazuhiro Kobayashi, Tatsushi Toda, Riki Matsumoto
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引用次数: 0

Abstract

Background and objectives: Interleukin-6 receptor antibodies (IL-6R Abs), including satralizumab, are increasingly used to prevent relapse for neuromyelitis optica spectrum disorder (NMOSD). However, the detailed mechanism of action of this treatment on the lymphocyte phenotype remains unclear. This study focused on B cells in patients with NMOSD, hypothesizing that IL-6R Ab enables B cells to acquire regulatory functions by producing the anti-inflammatory cytokine IL-10.

Methods: Peripheral blood mononuclear cells were stimulated in vitro to induce the expansion of B-cell subsets, double-negative B cells (DNs; CD19+ IgD-, CD27-) and plasmablasts (PBs; CD19+, CD27hi, CD38hi). Whole B cells, DNs, or PBs were isolated after culture with IL-6R Ab, and IL-10 expression was quantified using quantitative PCR and a cytometric bead array. RNA sequencing was performed to identify the marker of regulatory PBs induced by IL-6R Ab.

Results: DNs and PBs were observed to expand in patients with NMSOD during the acute attacks. In the in vitro model, IL-6R Ab increased IL-10 expression in B cells. Notably, IL-10 expression increased in PBs but not in DNs. Using RNA sequencing, CD200 was identified as a marker of regulatory PBs among the differentially expressed upregulated genes. CD200+ PBs produced more IL-10 than CD200- PBs. Furthermore, patients with NMOSD who received satralizumab had a higher proportion of CD200+ PBs than patients during the acute attacks.

Discussion: Treatment with IL-6 signaling blockade elicited a regulatory phenotype in B cells and PBs. CD200+ PBs may be a marker of treatment responsiveness in the context of NMOSD pathophysiology.

白细胞介素-6 信号传导阻断诱导神经脊髓炎视网膜频谱紊乱症中的调节性浆细胞
背景和目的:包括萨妥珠单抗在内的白细胞介素-6受体抗体(IL-6R Abs)越来越多地被用于预防神经脊髓炎视网膜频谱紊乱症(NMOSD)的复发。然而,这种疗法对淋巴细胞表型的详细作用机制仍不清楚。本研究的重点是 NMOSD 患者的 B 细胞,假设 IL-6R Ab 能使 B 细胞通过产生抗炎细胞因子 IL-10 获得调节功能:体外刺激外周血单核细胞以诱导 B 细胞亚群、双阴性 B 细胞(DNs;CD19+ IgD-,CD27-)和浆细胞(PBs;CD19+,CD27hi,CD38hi)的扩增。用 IL-6R Ab 培养后分离出整个 B 细胞、DNs 或 PBs,并用定量 PCR 和细胞计数珠阵列对 IL-10 的表达进行定量。进行了 RNA 测序,以确定 IL-6R Ab 诱导的调节性 PBs 的标记:结果:观察到NMSOD患者的DNs和PBs在急性发作期扩张。在体外模型中,IL-6R Ab 增加了 B 细胞中 IL-10 的表达。值得注意的是,IL-10在PB中的表达增加了,但在DN中却没有增加。通过 RNA 测序,CD200 被确定为不同表达上调基因中调节性 PB 的标记。CD200+ PB 比 CD200- PB 产生更多的 IL-10。此外,与急性发作期的患者相比,接受萨妥珠单抗治疗的NMOSD患者的CD200+ PB比例更高:讨论:用IL-6信号传导阻断剂治疗可诱发B细胞和PB的调节表型。CD200+ PBs可能是NMOSD病理生理学背景下治疗反应性的标志。
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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
219
审稿时长
8 weeks
期刊介绍: Neurology Neuroimmunology & Neuroinflammation is an official journal of the American Academy of Neurology. Neurology: Neuroimmunology & Neuroinflammation will be the premier peer-reviewed journal in neuroimmunology and neuroinflammation. This journal publishes rigorously peer-reviewed open-access reports of original research and in-depth reviews of topics in neuroimmunology & neuroinflammation, affecting the full range of neurologic diseases including (but not limited to) Alzheimer's disease, Parkinson's disease, ALS, tauopathy, and stroke; multiple sclerosis and NMO; inflammatory peripheral nerve and muscle disease, Guillain-Barré and myasthenia gravis; nervous system infection; paraneoplastic syndromes, noninfectious encephalitides and other antibody-mediated disorders; and psychiatric and neurodevelopmental disorders. Clinical trials, instructive case reports, and small case series will also be featured.
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