G-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 par...

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Published inNature immunology Vol. 24; no. 5; pp. 814 - 826
Main Authors Mulazzani, Elisabeth, Kong, Klara, Aróstegui, Juan I., Ng, Ashley P., Ranathunga, Nishika, Abeysekera, Waruni, Garnham, Alexandra L., Ng, Sze-Ling, Baker, Paul J., Jackson, Jacob T., Lich, John D., Hibbs, Margaret L., Wicks, Ian P., Louis, Cynthia, Masters, Seth L.
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.05.2023
Nature Publishing Group
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Summary: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 individuals with APLAID. Remarkably, treatment with a G-CSF antibody completely reversed established disease in APLAID mice. Furthermore, excessive myelopoiesis was normalized and lymphocyte numbers rebounded. APLAID mice were also fully rescued by bone marrow transplantation from healthy donors, associated with reduced G-CSF production, predominantly from non-hematopoietic cells. In summary, we identify APLAID as a G-CSF-driven autoinflammatory disease, for which targeted therapy is feasible. APLAID is a rare autoinflammatory disorder driven by mutations in PLCG2 . Here the authors provide a new mouse model using the human APLAID p.Ser707Tyr mutation. The mouse recapitulates clinical features of APLAID that can be prevented by anti-G-CSF. Individuals with APLAID were also shown to have high circulating levels of G-CSF suggesting this might be a suitable target for the clinic.
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ISSN:1529-2908
1529-2916
1529-2916
DOI:10.1038/s41590-023-01473-6