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

Area of Science:

• Genetics and Immunology
• Molecular Biology
• Autoimmune Diseases

Background:

• Monogenic lupus provides critical insights into systemic lupus erythematosus (SLE) mechanisms and treatments.
• Phospholipase D family member 4 (PLD4) has been implicated in immune regulation.

Purpose of the Study:

• To investigate the role of PLD4 mutations in patients with SLE.
• To elucidate the molecular mechanisms by which PLD4 dysfunction contributes to SLE pathogenesis.

Main Methods:

• Genetic sequencing to identify PLD4 variants in SLE patients.
• In vitro and ex vivo assays to assess PLD4 exonuclease activity.
• Analysis of Toll-like receptor (TLR) activation and downstream signaling pathways, including type I interferon.
• Phenotyping of Pld4-deficient mouse models for autoimmunity and immune cell populations.

Main Results:

• Five SLE patients with recessive PLD4 mutations were identified.
• PLD4 variants caused loss-of-function, impairing single-stranded nucleic acid exonuclease activity.
• Mutations led to excessive TLR7 and TLR9 activation, with hyperactivated type I interferon signaling in patient dendritic cells.
• Pld4-deficient mice exhibited autoimmunity and expansion of plasmacytoid dendritic cells and plasma cells.

Conclusions:

• Recessive PLD4 loss-of-function mutations are a novel cause of monogenic SLE.
• PLD4 deficiency disrupts nucleic acid metabolism, leading to aberrant TLR signaling and type I interferonopathy.
• Targeting type I interferon, potentially with JAK inhibitors like baricitinib, may be a therapeutic strategy for PLD4-deficient SLE.