Precision Medicine in Pediatric Autoimmunity: Leniolisib Treatment of Childhood-Onset Lupus Nephritis Due to Activated PI3K-Delta Syndrome (APDS).

Abstract

OBJECTIVE To investigate the mechanistic underpinnings and treatment response of lupus nephritis (LN) in activated PI3K-delta syndrome type 1 (APDS1) using pathway-specific therapy and advanced spatial proteomics. METHOD We conducted mechanistic investigation of refractory class V LN in an 18-year-old female with genetically confirmed APDS1 (PIK3CD c.3061G>A, p.E1021K mutation). Response to leniolisib, a selective 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 Time-of-Flight Spectrometry (MIBI-TOF), comparing the APDS1-LN tissue signature with 12 childhood-onset LN patients (cLN) and 5 healthy controls (HC). RESULTS Leniolisib treatment normalized hyperactive PI3Kδ signaling, resulting in significant improvements in proteinuria, complement levels, and peripheral edema after failing three years of conventional immunosuppressives. MIBI-TOF spatial proteomics 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. CONCLUSION 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.