Phosphatidylinositol 3-Kinase δ Deficiency Protects From Antimyeloperoxidase Vasculitis

Fernanda Florez Barros, Simon Freeley, El Li Tham, Michael Robson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Antineutrophil cytoplasmic antibody–associated vasculitis (AAV) is a systemic autoimmune disease in which glomerulonephritis is an important manifestation. Antibodies against myeloperoxidase (MPO) or proteinase 3 are thought to be important in pathogenesis. Phosphoinositide 3-kinase δ (PI3Kδ) mediates a number of effects in lymphocytes, but its role in myeloid cell responses is less clear. Therefore, this study was undertaken to assess this in a preclinical model of glomerulonephritis induced by the transfer of antibodies to MPO. Methods: D910A mice with inactive PI3Kδ were compared with wild-type controls. Disease protocols allowed for a comparison of experimental groups in the setting of both mild and more severe disease. Adoptive transfer experiments were performed, with flow cytometric analysis of digested kidneys taken at the end of the experiment. Results: With mild disease, D910A mice had fewer glomerular macrophages, fewer glomerular neutrophils, and reduced albuminuria compared with wild-type controls. With more severe disease, they also had fewer glomerular crescents and lower serum creatinine levels, indicating protection from acute kidney injury. Adoptive transfer experiments showed a defect in the recruitment of D910A monocytes to the diseased kidney. Conclusion: Mice with inactive PI3Kδ were protected from anti-MPO vasculitis. This is due to cell intrinsic defect in the recruitment of monocytes to the kidney. These findings suggest that PI3Kδ is a potential therapeutic target in AAV.

Original languageEnglish
Pages (from-to)64-70
Number of pages7
JournalArthritis & rheumatology
Volume75
Issue number1
DOIs
Publication statusPublished - 1 Jan 2023

Fingerprint

Dive into the research topics of 'Phosphatidylinositol 3-Kinase δ Deficiency Protects From Antimyeloperoxidase Vasculitis'. Together they form a unique fingerprint.

Cite this