Loss-of-function mutations in PLD4 lead to systemic lupus erythematosus
- Qintao Wang
- Honghao Zhu
- Xiangwei Sun
- Changming Zhang
- Shuangyue Ma
- Ying Jin
- Jinjian Fu
- Chenlu Liu
- Jiahui Peng
- Ruoran Wang
- Lin Liu
- Yi Zeng
- Cheng Gong
- Qing Zhou
- Xiaomin Yu
- Zhihong Liu
2025-09-10
Monogenic lupus offers valuable insights into the underlying mechanisms and therapeutic approaches for systemic lupus erythematosus (SLE) 1–3 . 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.