G-CSF drives autoinflammation in APLAID.

Autor: Mulazzani E; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia., Kong K; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Aróstegui JI; Department of Immunology, Hospital Clínic-IDIBAPS, Barcelona, Spain., Ng AP; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Clinical Haematology Department, Royal Melbourne Hospital, Melbourne, Victoria, Australia.; Peter MacCallum Cancer Centre, Parkville, Victoria, Australia., Ranathunga N; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.; Division of Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Abeysekera W; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.; Division of Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Garnham AL; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.; Division of Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Ng SL; Immunology Research Unit, GlaxoSmithKline, Collegeville, PA, USA., Baker PJ; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia., Jackson JT; Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Lich JD; Immunology Research Unit, GlaxoSmithKline, Collegeville, PA, USA., Hibbs ML; Department of Immunology and Pathology, Monash University, Clayton, Victoria, Australia., Wicks IP; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.; Rheumatology Unit, Royal Melbourne Hospital, Parkville, Victoria, Australia., Louis C; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Masters SL; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. masters@wehi.edu.au.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia. masters@wehi.edu.au.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2023 May; Vol. 24 (5), pp. 814-826. Date of Electronic Publication: 2023 Mar 30.
DOI: 10.1038/s41590-023-01473-6
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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