Precision Medicine in Pediatric Autoimmunity: Leniolisib Treatment of Childhood-Onset Lupus Nephritis Due to Activated Phosphoinositide 3-Kinase δ Syndrome.

Abstract

The objective of this study was to investigate the mechanistic underpinnings and treatment response of lupus nephritis (LN) in activated phosphoinositide 3-kinase δ syndrome type 1 (APDS1) using pathway-specific therapy and advanced spatial proteomics. We conducted mechanistic investigation of refractory class V LN in an 18-year-old female patient with genetically confirmed APDS1 (PIK3CD c.3061G>A, p.E1021K mutation). Response to leniolisib, a selective phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, was evaluated through clinical parameters and flow cytometry of peripheral blood lymphocytes. Kidney tissue immune architecture was characterized using multiplexed ion beam imaging by time-of-flight (MIBI-TOF) spectrometry, comparing the APDS1-LN tissue signature with 12 patients with childhood-onset LN and 5 healthy controls. Following three years of unsuccessful treatment with conventional immunosuppressives, leniolisib treatment normalized hyperactive PI3Kδ signaling, resulting in significant improvements in proteinuria, complement levels, and peripheral edema. Multiplexed Ion Beam Imaging (MIBI)-Time-of-Flight (TOF) revealed a distinct tissue-specific immunopathology with significantly increased proportions of CD8⁺ T cells (21.6% in APDS1 vs 12.0% in typical LN; P = 0.0410) and M1 macrophages (42.0% in APDS1 vs 9.0% in typical LN; P = 0.1445) clustering around glomeruli with immune complex deposition. This immune signature aligns with the constitutively active PI3Kδ pathway's effect on lymphocyte exhaustion and inflammatory phenotype. This investigation advances rheumatology by demonstrating that APDS1-associated LN displays a specific tissue immune signature and responds to targeted inhibition of the causative molecular pathway. Our findings provide mechanistic insights into genetic drivers of autoimmunity and support pathway-specific therapeutic approaches for refractory autoimmune manifestations in primary immunodeficiencies.