G-CSF drives autoinflammation in APLAID

Mulazzani, E; Kong, K; Ar&#243;stegui, JI; Ng, AP; Ranathunga, N; Abeysekera, W; Garnham, AL; Ng, SL; Baker, PJ; Jackson, JT; Lich, JD; Hibbs, ML; Wicks, IP; Louis, C; Masters, SL

Author(s): Mulazzani, E; Kong, K; Aróstegui, JI; Ng, AP; Ranathunga, N; Abeysekera, W; Garnham, AL; Ng, SL; Baker, PJ; Jackson, JT; Lich, JD; Hibbs, ML; Wicks, IP; Louis, C; Masters, SL;
Details: Publication Year 2023-03-30,Volume 24,Issue #5,Page 814-826
Journal Title: Nature Immunology
Abstract: 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.
Publisher: NPG
Keywords: Animals; Mice; Bone Marrow Transplantation; Cytokines; Granulocyte Colony-Stimulating Factor; Interleukin-1; Tumor Necrosis Factor-alpha/genetics; Immunologic Deficiency Syndromes/genetics/immunology/metabolism
Research Division(s): Inflammation; Bioinformatics; Immunology; Blood Cells And Blood Cancer; Blood Cells and Blood Cancer; Bioinformatics; Immunology
PubMed ID: 36997670
Publisher's Version: https://doi.org/10.1038/s41590-023-01473-6
Open Access at Publisher's Site: https://doi.org/10.1038/s41590-023-01473-6.
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41590-023-01473-6.pdf - (14.63MB, application/pdf)

Creation Date: 2023-04-18 01:58:50

Last Modified: 2023-06-13 01:17:49