Natalizumab and fingolimod are effective multiple sclerosis (MS) therapies that disrupt lymphocyte migration but have differential effects on B cell maturation and trafficking. We investigated their effects on peripheral blood (PB) and cerebrospinal fluid (CSF) B cell repertoires using next-generation deep sequencing. Paired CSF and PB B cell subsets (naïve, CD27⁺ memory, and CD27⁻IgD⁻ double-negative B cells and plasmablasts) were collected by applying flow cytometry at baseline and after 6 months of treatment and their respective heavy-chain variable region repertoires assessed by Illumina MiSeq. Treatment with fingolimod contracted, whereas natalizumab expanded circulating PB B cells. CSF B cell numbers remained stable following fingolimod treatment but decreased with natalizumab therapy. Clonal overlap between CSF and PB B cells was reduced with natalizumab treatment but remained stable with fingolimod therapy. Lineage analyses of pre- and posttreatment CSF B cell repertoires revealed large, clonally expanded B cell clusters in natalizumab-treated MS patients but no intrathecal clonal expansion following fingolimod therapy. Our findings suggest that natalizumab diminishes the exchange of peripheral and intrathecal B cells without impacting intrathecal clonal expansion. In contrast, fingolimod treatment fails to alter blood–brain barrier B cell exchange but diminishes intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may alter intrathecal B cell biology in MS.

那他珠单抗和芬戈莫德是有效的多发性硬化症 (MS) 疗法，可破坏淋巴细胞迁移，但对 B 细胞成熟和运输具有不同影响。我们使用下一代深度测序研究了它们对外周血 (PB) 和脑脊液 (CSF) B 细胞库的影响。配对的 CSF 和 PB B 细胞亚群（幼稚、CD27 ⁺记忆和 CD27 ^- IgD ^-通过在基线和治疗 6 个月后应用流式细胞术收集双阴性 B 细胞和浆母细胞，并通过 Illumina MiSeq 评估它们各自的重链可变区库。芬戈莫德治疗收缩，而那他珠单抗扩大循环 PB B 细胞。CSF B 细胞数量在芬戈莫德治疗后保持稳定，但随着那他珠单抗治疗而减少。那他珠单抗治疗减少了 CSF 和 PB B 细胞之间的克隆重叠，但芬戈莫德治疗保持稳定。治疗前和治疗后 CSF B 细胞库的谱系分析显示，那他珠单抗治疗的 MS 患者中有大量的、克隆性扩增的 B 细胞簇，但在芬戈莫德治疗后没有鞘内克隆性扩增。我们的研究结果表明，那他珠单抗在不影响鞘内克隆扩增的情况下减少了外周和鞘内 B 细胞的交换。相比之下，芬戈莫德治疗不能改变血脑屏障 B 细胞交换，但会减少鞘内克隆扩增。鞘氨醇 1 磷酸受体抑制可能会改变 MS 的鞘内 B 细胞生物学。