Selective CAR-T cell mediated B cell depletion suppresses interferon signature in SLE [PBMC]

Applying advanced molecular profiling together with highly specific targeted therapies offers the possibility to better dissect the mechanisms underlying immune mediated inflammatory diseases such as systemic lupus erythematosus (SLE) in humans. Here we apply a combination of single cell RNA sequencing and T/B cell repertoire analysis to perform an in-depth characterization of molecular changes in the immune-signature upon CD19 CAR T cell-mediated depletion of B cells in SLE patients. The resulting datasets do not only confirm a selective CAR T cell-mediated reset of the B cell response, but simultaneously reveal consequent changes in the transcriptional signature of monocyte and T cell subsets that respond with a profound reduction in type 1 interferon signaling. Our current data thus provide evidence for a causal relationship between the B cell response and the increased interferon signature observed in SLE and additionally demonstrate the usefulness of combining targeted therapies and novel analytic approaches to decipher molecular mechanisms of immune-mediated inflammatory diseases in humans. Overall design: We generated single cell sequencing data of SLE patients prior to and after anti CD19 CAR-T cell therapy

将先进的分子谱分析技术与高特异性靶向疗法相结合，可为深入解析人类自身免疫介导的炎症性疾病（如系统性红斑狼疮（systemic lupus erythematosus, SLE））的发病机制提供新的可能。本研究采用单细胞RNA测序与T/B细胞受体库分析相结合的策略，对系统性红斑狼疮患者接受CD19嵌合抗原受体T细胞（CD19 CAR T cell）介导的B细胞耗竭后，免疫特征的分子变化进行深度表征。所得数据集不仅证实了CAR T细胞介导的B细胞应答发生选择性重置，同时揭示了单核细胞与T细胞亚群的转录特征随之改变，其1型干扰素信号通路呈现显著下调。因此，本研究数据证实了B细胞应答与SLE患者中观察到的干扰素特征上调之间存在因果关系，并进一步证明了将靶向疗法与新型分析方法相结合，可用于解析人类自身免疫介导的炎症性疾病的分子机制。
整体实验设计：我们获得了SLE患者接受抗CD19 CAR T细胞治疗前后的单细胞测序数据。