Abstract: FR-PO794
B Cells Are Essential for Proteinuria Induction in a Mouse Model of Autoimmune Idiopathic Nephrotic Syndrome
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
- Leclerc, Simon, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Aoudjit, Lamine, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Takano, Tomoko, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
Background
The idiopathic nephrotic syndrome (INS) is defined by heavy proteinuria, hypoalbuminemia, and edema. This occurs when the kidney’s specialized epithelial cell, the podocyte, is injured by mechanisms that are still unknown. The recent discovery of autoantibodies targeting podocyte proteins like nephrin and Crb2 in human patients hints at the role of B cells and autoantibodies in INS, but their exact role is still unclear. Our objective is to establish if B cells are essential for the induction of proteinuria in a mouse model of autoimmune INS.
Methods
As previously published (Hada et al., J Am Soc Nephrol, 2022), 19 C3H/HeN mice were immunized three times at 2-wks intervals with recombinant Crb2, a transmembrane protein expressed at the podocyte slit diaphragm. One week after the first immunization, 10 mice received anti-CD20 (MB-11, BioXCell) to deplete B cells and 9 an isotype control. Serum and urine were tested for anti-Crb2 antibody and albuminuria, respectively. Inguinal lymph nodes and spleens were immunophenotyped at 6 wks.
Results
Mice that received anti-CD20 (‘treated’) showed a 95% decrease in circulating CD19+ B cells at 2 and 4 wks. At 6 wks, no treated mice (0/10) developed INS compared to 88% (8/9) of the mice receiving the isotype control (‘control’). Anti-Crb2 antibody titers were lower in treated mice (1591±759 vs. 7207±3985 µg/mL, p<0.003). In the inguinal lymph nodes of treated mice, a respective 50% and 80% decrease in the number of CD4+ and CD19+ cells (p<0.001) were observed compared to controls. This was driven by a 75% decrease in switched memory B cells (CD19+ IgD- IgM- IgG+; p<0.005). The germinal centers in the inguinal lymph nodes of treated mice were reduced in size (p<0.007) and showed a reduced number of IgG+ positive B cells (p<0.003).
Conclusion
These results suggest that autoantibody-producing B cells are essential for proteinuria induction in this mouse model of autoimmune INS. Moreover, their role may not be limited to autoantibody production, as their crosstalk with T cells is likely significant. A better understanding of these mechanisms is crucial to develop targeted treatments for patients with autoimmune INS.
Funding
- Private Foundation Support