Loss-of-function mutations in PLD4 lead to systemic lupus erythematosus

Monogenic lupus offers valuable insights into the underlying mechanisms and therapeutic approaches for systemic lupus erythematosus (SLE)<sup>1-3</sup>. 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.

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Publication Details

Journal
Nature
Published
2025-09-10
DOI
https://doi.org/10.1038/s41586-025-09513-x
Citations
10
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
7.97
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article

Loss-of-function mutations in PLD4 lead to systemic lupus erythematosus

Jiahui Peng, Honghao Zhu, Gong Cheng, Changming Zhang et al.
10 citations
Nature
Immune Cell Function and Interaction
7.97
article

Loss-of-function mutations in PLD4 lead to systemic lupus erythematosus

Jiahui Peng, Honghao Zhu, Gong Cheng, Changming Zhang, Qintao Wang, Ruoran Wang, Lin Liu, Zhihong Liu, Jinjian Fu, Shuangyue Ma, Qing Zhou, Xiangwei Sun, Ying Jin, Xiaomin Yu, Yi Zeng, Chenlu Liu
article en
10 citations

Abstract

Monogenic lupus offers valuable insights into the underlying mechanisms and therapeutic approaches for systemic lupus erythematosus (SLE)<sup>1-3</sup>. 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.

NatureVol. 647(8089)
Nanjing General Hospital of Nanjing Military Command (CN), Sir Run Run Shaw Hospital (CN), Zhejiang Provincial People's Hospital (CN), Hangzhou Medical College (CN), Zhejiang University (CN), Nanjing University (CN)
Openalex Percentile: Top 2%
Immune Cell Function and Interaction
7.97
DOIOpen Access PDFOpenAlex
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