From the Division of Neurology (R.A., N.C., A.H., A.T., S.K., R.M.); Division of Molecular Brain Science (K.K.), Kobe University Graduate School of Medicine; and Department of Neurology (T.T.), Graduate School of Medicine, The University of Tokyo, Japan.
Neurol Neuroimmunol Neuroinflamm. 2024 Jul;11(4):e200266. doi: 10.1212/NXI.0000000000200266. Epub 2024 Jun 18.
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.
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, CD27, CD38). 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.
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.
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 受体抗体（IL-6R Abs），包括 satralizumab，越来越多地用于预防视神经脊髓炎谱系障碍（NMOSD）的复发。然而，这种治疗对淋巴细胞表型的详细作用机制尚不清楚。本研究聚焦于 NMOSD 患者的 B 细胞，假设 IL-6R Ab 通过产生抗炎细胞因子 IL-10 使 B 细胞获得调节功能。
体外刺激外周血单核细胞，诱导 B 细胞亚群（双阴性 B 细胞[DN；CD19 IgD，CD27]和浆母细胞[PB；CD19，CD27，CD38]）的扩增。在培养 IL-6R Ab 后分离出全 B 细胞、DN 或 PB，并通过定量 PCR 和流式细胞术检测细胞因子 IL-10 的表达。进行 RNA 测序以鉴定 IL-6R Ab 诱导的调节性 PB 的标志物。
在 NMOSD 患者的急性发作期间观察到 DNs 和 PB 扩增。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 表达仅在 PB 中增加，而在 DN 中则没有。通过 RNA 测序，CD200 被鉴定为差异上调基因中调节性 PB 的标志物。CD200 PB 比 CD200 PB 产生更多的 IL-10。此外，接受 satralizumab 治疗的 NMOSD 患者的 CD200 PB 比例高于急性发作期间的患者。
IL-6 信号阻断治疗在 B 细胞和 PB 中诱导出调节表型。CD200 PB 可能是 NMOSD 发病机制中治疗反应的标志物。
