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, Gong Cheng, Qing Zhou, Xiaomin Yu, Zhihong Liu
Abstract
. 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.