Abstract: FR-PO814
CD89 Triggers APRIL Activation in Pediatric IgA Nephropathy
Session Information
- Glomerular Diseases: Inflammation and Immunology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Alexandra, Cambier, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
- Lachize Neanne, Lison, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
- Patey, Natalie, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
- Monteiro, Renato C., Centre de Recherche sur l'Inflammation, Paris, France
- Boyer, Olivia, Hopital Universitaire Necker-Enfants Malades, Paris, France
- Hogan, Julien, Emory University, Atlanta, Georgia, United States
Group or Team Name
- Cambier's Laboratory.
Background
IgAN, characterized by renal deposition of IgA, involves a multi-hit development with formation of circulating immune complexes (CICs) containing Gd-IgA1 and sCD89, contributing to renal inflammation. A Proliferation-Inducing Ligand (APRIL) is implicated in the immune response.
The aim of this study is to investigate APRIL implication, especially in children with IgAN (cIgAN), who often exhibit more inflammation than adults.
Methods
First, we evaluated APRIL levels in human mesangial cells (HMC) after stimulation with recombinant sCD89 (rsCD89) or plasma from cIgAN patients.
Subsequently, we conducted a comprehensive international cross-sectional study involving 86 cIgAN patients and 48 control recruited from France and Canada. Our investigation included quantification of APRIL plasma levels and CICs, which were then compared with biological, clinical, and histological characteristics of the disease.
Additionally, we performed immunohistochemistry analysis on kidney biopsies from cIgAN patients to visualize APRIL staining patterns.
Results
We demonstrated first that stimulations with cIgAN plasma and rsCD89 induced inflammation in HMC, leading to increased APRIL mRNA and protein production.
We observed elevated levels of Gd-IgA1, sCD89-IgA1, sCD89 and soluble APRIL in the plasma of cIgAN patients compared to control subjects.
Moreover, we found evidence suggesting that APRIL may be trapped within CICs, colocalizing with IgA in same-size complexes in Western blot experiments.Plus, IgA-APRIL and CD89-APRIL complexes were detected in cIgAN samples using ELISA and immunoprecipitation techniques. Levels of CICs correlated with plasma APRIL levels, and presence of IgA-APRIL and CD89-APRIL in CICs was linked to a worst initial clinical presentation, prognosis with kidney failure and relapses with persistent proteinuria.
Staining of cIgAN biopsies revealed the presence of APRIL deposits within the glomerulus in the mesangium and near the Bowman capsule.
Conclusion
Our research highlights the role of APRIL in the pathways of cIgAN, with sCD89 as a potential trigger of APRIL activation in HMCs. APRIL holds promise as a valuable biomarker, offering a non-invasive means to detect forms of cIgAN with the worst progression, thereby potentially reducing reliance on biopsy.
APRIL inhibition as therapeutic strategy presents an exciting opportunity for cIgAN treatment.