biostudies-literatureMulazzani EDeutsche ForschungsgemeinschaftHoward Hughes Medical InstituteEC | European Regional Development FundSylvia and Charles Viertel Charitable FoundationWellcome TrustDepartment of Health | National Health and Medical Research Council814-826https://www.ebi.ac.uk/biostudies/studies/S-EPMC10154231biostudies-literatureUnknown24(5)Missense mutations in PLCG2 can cause autoinflammation with phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID). Here, we generated a mouse model carrying an APLAID mutation (p.Ser707Tyr) and found that inflammatory infiltrates in the skin and lungs were only partially ameliorated by removing inflammasome function via the deletion of caspase-1. Also, deleting interleukin-6 or tumor necrosis factor did not fully prevent APLAID mutant mice from autoinflammation. Overall, these findings are in accordance with the poor response individuals with APLAID have to treatments that block interleukin-1, JAK1/2 or tumor necrosis factor. Cytokine analysis revealed increased granulocyte colony-stimulating factor (G-CSF) levels as the most distinct feature in mice and Nature immunologyG-CSF drives autoinflammation in APLAID.PMC10154231PID2021-125106OB-C31SCHU 3126/ 3-1208694/Z/17/Z115432520031591113577VTL2016F0272003756Arostegui JIKong KBaker PJNg APGarnham ALLich JDWicks IPJackson JTRanathunga NAbeysekera WMulazzani ENg SLHibbs MLLouis CMasters SLfalseG-CSF drives autoinflammation in APLAID.Missense mutations in PLCG2 can cause autoinflammation with phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID). Here, we generated a mouse model carrying an APLAID mutation (p.Ser707Tyr) and found that inflammatory infiltrates in the skin and lungs were only partially ameliorated by removing inflammasome function via the deletion of caspase-1. Also, deleting interleukin-6 or tumor necrosis factor did not fully prevent APLAID mutant mice from autoinflammation. Overall, these findings are in accordance with the poor response individuals with APLAID have to treatments that block interleukin-1, JAK1/2 or tumor necrosis factor. Cytokine analysis revealed increased granulocyte colony-stimulating factor (G-CSF) levels as the most distinct feature in mice and 2023-01-01T00:00:00Z2023 May2025-04-04T14:45:01.057Z2025-04-04T14:45:01.057ZS-EPMC101542313699767010.1038/s41590-023-01473-6