️ Episode 199: PLD4 Deficiency and Lupus: When Nuclease Failure Ignites Autoimmunity

In this episode of PaperCast Base by Base, we explore how loss-of-function mutations in the endolysosomal exonuclease PLD4 cause a monogenic form of systemic lupus erythematosus, reshaping our understanding of nucleic acid sensing and interferon-driven autoimmunity.

Study Highlights:
This study identifies biallelic loss-of-function PLD4 mutations in five patients with systemic lupus erythematosus, all presenting with severe lupus nephritis and hematologic involvement. Using whole-exome sequencing, structural modelling and biochemical assays, the authors show that these PLD4 variants markedly impair single-stranded DNA and RNA exonuclease activity, leading to accumulation of nucleic acid ligands in endolysosomes. Patient immune profiling with bulk and single-cell RNA sequencing, flow cytometry and CyTOF reveals hyperactivation of Toll-like receptor 7 and 9 pathways, with a strong type I interferon signature centered in plasmacytoid dendritic cells and monocytes. In Pld4-deficient mice, the team demonstrates lupus-like autoimmunity with nephritis, expansion of plasmacytoid dendritic cells and plasma cells, and upregulation of interferon-stimulated genes in kidney immune and parenchymal cells. Finally, pharmacologic JAK inhibition with baricitinib dampens type I interferon signalling, reduces autoantibody levels and renal inflammation in Pld4−/− mice, and suppresses interferon and NF-κB pathway activation in patient cells ex vivo.

Conclusion:
By defining PLD4 deficiency as a new monogenic cause of systemic lupus erythematosus and showing that JAK inhibition can reverse key interferon-driven features in experimental models and patient cells, this work points toward precision diagnostics and targeted therapies for a subset of patients with lupus driven by dysregulated endosomal nucleic acid clearance.

Music:
Enjoy the music based on this article at the end of the episode.

Reference:
Wang Q, Zhu H, Sun X, Zhang C, Ma S, Jin Y, et al. Loss-of-function mutations in PLD4 lead to systemic lupus erythematosus. Nature. 2025;647:498–505. https://doi.org/10.1038/s41586-025-09513-x

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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