Emerging evidence indicates that memory B cells are dysfunctional in systemic lupus erythematosus (SLE). They are hyporesponsive to signalling through the B cell receptor (BCR) but retain responsiveness to Toll-like receptor (TLR) and type I interferon signalling, as well as to T cell-mediated activation via CD40–CD154. Chronic exposure to immune complexes of ribonucleoprotein (RNP)-specific autoantibodies and TLR-engaging or BCR-engaging cargo is likely to contribute to this partially anergic phenotype. TLR7 or TLR8 signalling and the resulting production of type I interferon, as well as the sustained activation by bystander T cells, fuel a positive feedforward loop in memory B cells that can evade negative selection and permit preferential expansion of anti-RNP autoantibodies. Clinical trials of autologous stem cell transplantation or of B cell-targeted monoclonal antibodies and chimeric antigen receptor (CAR) T cells have correlated replenishment of the memory B cell population with relapse of SLE. Moreover, the BCR hyporesponsiveness of memory B cells might explain the failure of non-depleting B cell-targeting approaches in SLE, including BTK inhibitors and anti-CD22 monoclonal antibodies. Thus, targeting of dysfunctional memory B cells might prove effective in SLE, while also avoiding the adverse events of broad-spectrum targeting of B cell and plasma cell subsets that are not directly involved in disease pathogenesis.

新出现的证据表明，系统性红斑狼疮 （SLE） 患者的记忆 B 细胞功能障碍。它们对通过 B 细胞受体 （BCR） 的信号传导反应低，但对 Toll 样受体 （TLR） 和 I 型干扰素信号传导以及通过 CD40-CD154 的 T 细胞介导的激活保持反应性。长期暴露于核糖核蛋白 （RNP） 特异性自身抗体和 TLR 参与或 BCR 参与货物的免疫复合物可能导致这种部分无能表型。TLR7 或 TLR8 信号传导和由此产生的 I 型干扰素的产生，以及旁观者 T 细胞的持续激活，在记忆 B 细胞中推动了正前馈回路，该回路可以逃避负选择并允许抗 RNP 自身抗体的优先扩增。自体干细胞移植或 B 细胞靶向单克隆抗体和嵌合抗原受体 （CAR） T 细胞的临床试验显示，记忆 B 细胞群的补充与 SLE 的复发相关。此外，记忆 B 细胞的 BCR 低反应性可能解释了 SLE 中非耗竭性 B 细胞靶向方法的失败，包括 BTK 抑制剂和抗 CD22 单克隆抗体。因此，靶向功能失调的记忆 B 细胞可能被证明对 SLE 有效，同时也避免了广谱靶向 B 细胞和浆细胞亚群的不良事件，这些细胞和浆细胞亚群不直接参与疾病发病机制。