Wang Qintao, Zhu Honghao, Sun Xiangwei, Zhang Changming, Ma Shuangyue, Jin Ying, Fu Jinjian, Liu Chenlu, Peng Jiahui, Wang Ruoran, Liu Lin, Zeng Yi, Gong Cheng, Zhou Qing, Yu Xiaomin, Liu Zhihong
Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Nature. 2025 Sep 10. doi: 10.1038/s41586-025-09513-x.
Monogenic lupus offers valuable insights into the underlying mechanisms and therapeutic approaches for systemic lupus erythematosus (SLE). Here we report on five patients with SLE carrying recessive mutations in phospholipase D family member 4 (PLD4). Deleterious variants in PLD4 resulted in impaired single-stranded nucleic acid exonuclease activity in in vitro and ex vivo assays. PLD4 loss-of-function mutations led to excessive activation of Toll-like receptor 7 (TLR7) and TLR9. Downstream inflammatory signalling pathways, especially type I interferon signalling, were hyperactivated in patient dendritic cells. Pld4-deficient mice presented with autoimmunity and cell-intrinsic expansion of plasmacytoid dendritic cells and plasma cells. Pld4-deficient mice responded to the JAK inhibitor baricitinib, suggesting that targeting type I interferon may be a potential therapy for patients with PLD4 deficiency.
单基因狼疮为系统性红斑狼疮（SLE）的潜在机制和治疗方法提供了宝贵的见解。在此，我们报告了5例携带磷脂酶D家族成员4（PLD4）隐性突变的SLE患者。在体外和体内实验中，PLD4中的有害变异导致单链核酸外切酶活性受损。PLD4功能丧失突变导致Toll样受体7（TLR7）和TLR9过度激活。在患者树突状细胞中，下游炎症信号通路，尤其是I型干扰素信号通路被过度激活。Pld4基因缺陷小鼠表现出自身免疫以及浆细胞样树突状细胞和浆细胞的细胞内在性扩增。Pld4基因缺陷小鼠对JAK抑制剂巴瑞替尼有反应，这表明靶向I型干扰素可能是治疗PLD4缺陷患者的一种潜在疗法。
