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

PLD4 Deficiency and Lupus: When Nuclease Failure Ignites Autoimmunity Music:Enjoy the music based on this article at the end of the episode. 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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/pld4-deficiency-and-lupus-when-nuclease-failure-ignites-autoimmunity QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-15. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the core scientific narrative from mutation discovery to mechanistic function, single-cell analyses, mouse model phenotypes, and therapeutic implications.- transcript topics: PLD4 mutations and monogenic lupus; Endosomal nucleic acid sensing and TLR7/9 signaling; PLD4 exonuclease activity assays; scRNA-seq of patient PBMCs and IFN signatures; CyTOF cytokine profiling in PBMCs; Pld4−/− mice autoimmunity and nephritis QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Five SLE patients with biallelic PLD4 mutations were identified.- PLD4 functions as a 5′ exonuclease that cleaves ssDNA and ssRNA in endosomes to limit TLR7/9 signaling.- Mutations in PLD4 impair exonuclease activity in vitro (loss of catalytic function observed for patient-derived variants).- scRNA-seq and CyTOF show IFN/TLR pathway activation predominantly in dendritic cells and monocytes.- Pld4−/− mice display autoimmunity and nephritis with expansion of plasmacytoid dendritic cells (pDCs) and plasma cells.- Baricitinib (a JAK inhibitor) reduces type I IFN signaling and rescues phenotypes in PLD4-deficient models (mice and patient-derived cells). QC result: Pass.