Objectives Unraveling the mechanisms underlying treatment response for targeted therapeutics in systemic lupus erythematosus (SLE) patients is challenging due to the limited understanding of diverse responses of circulating immune cells, particularly B cells. We investigated B lymphocyte dynamics during anti-BAFF treatment, utilizing longitudinal single-cell transcriptome data. Methods We conducted single-cell RNA sequencing on PBMCs in four Korean SLE patients before and after belimumab treatment at the following time points: 2 weeks, 1, 3, 6, and 12 months. Results Analyzing over 73 000 PBMCs, we identified 8 distinct subsets of B cells and plasmablasts and analyzed dynamic changes within these cell subsets: initial declines in naive and transitional B cells followed by an increase at three months, contrasted by an initial increase and subsequent decrease in memory B cells by the third month. Meanwhile, plasmablasts exhibited a consistent decline throughout treatment. B cell activation pathways, specifically in naive and memory B cells, were downregulated during the third and sixth months. These findings were validated at the protein level throughout the first four weeks of treatment using flow cytometry. Comparative analysis with bulk transcriptome data from 22 Japanese SLE patients showed increased NR4A1 expression six months post-belimumab treatment, indicating its role in restricting self-reactive B cells, thereby contributing to the biological responses of anti-BAFF treatment. Conclusion The observed B cell dynamics provided insights into the immunological mechanisms underlying the therapeutic effects of anti-BAFF in SLE patients. Furthermore, it underscores the need for research in predicting drug responses based on immune profiling.

中文翻译：

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通过纵向单细胞 RNA 测序揭示接受贝利尤单抗治疗的系统性红斑狼疮患者 B 淋巴细胞的动态


目的 由于对循环免疫细胞（特别是 B 细胞）的不同反应了解有限，阐明系统性红斑狼疮 (SLE) 患者靶向治疗的治疗反应机制具有挑战性。我们利用纵向单细胞转录组数据研究了抗 BAFF 治疗期间 B 淋巴细胞的动态。方法 我们在贝利尤单抗治疗前后的以下时间点对 4 名韩国 SLE 患者的 PBMC 进行了单细胞 RNA 测序：2 周、1、3、6 和 12 个月。结果 通过分析超过 73,000 个 PBMC，我们确定了 8 个不同的 B 细胞和浆母细胞亚群，并分析了这些细胞亚群内的动态变化：初始 B 细胞和过渡 B 细胞最初下降，随后在三个月时增加，而与最初的增加和随后的减少形成鲜明对比到第三个月时，记忆 B 细胞中就会出现这种情况。与此同时，浆母细胞在整个治疗过程中表现出持续下降。 B 细胞激活途径，特别是初始 B 细胞和记忆 B 细胞，在第三个月和第六个月期间下调。在治疗的前四个星期中，使用流式细胞术在蛋白质水平上验证了这些发现。对 22 名日本 SLE 患者的大量转录组数据进行的比较分析显示，贝利木单抗治疗六个月后 NR4A1 表达增加，表明其在限制自身反应性 B 细胞中的作用，从而有助于抗 BAFF 治疗的生物反应。结论 观察到的 B 细胞动力学为了解抗 BAFF 对 SLE 患者治疗效果背后的免疫机制提供了见解。此外，它强调需要进行基于免疫分析预测药物反应的研究。