Abstract: TH-OR052
Bowman Capsule Provides Protective Podocyte Niche: Implications for Crescentic Glomerulonephritis
Session Information
- Glomerular Diseases: Spotlighting Immunology and Inflammation - I
October 25, 2018 | Location: 8, San Diego Convention Center
Abstract Time: 04:42 PM - 04:54 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Chen, Anqun, ZhongShan Hospital, Xiamen University, XiaMen, China
- Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- D'Agati, Vivette D., Columbia University College of Physicians and Surgeons, New York, New York, United States
- Guan, Tianjun, ZhongShan Hospital, Xiamen University, XiaMen, China
- He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Agudo, Judith, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Schlondorff, Detlef O., Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background
A role for CD8+ cytotoxic T cells (CTLs) in peri-glomerular infiltrates during glomerulonephritis (GN) has been proposed, but how and if CTLs can enter Bowman’s space remains unclear.
Methods
CD8+ T cells from a newly generated transgenic mouse, termed Jedi (for Just EGFP Death Inducing) T cells that are cytotoxic for any EGFP expressing cells were used. Jedi T cells and lentivirus expressing EGFP were injected into transgenic mice with podocyte-specific EGFP expression mice in normal conditions and in a nephrotoxic serum nephritis (NTSN) model. 4 days after induction of NTSN, Jedi or control CD8+T cells were injected, and the mice were sacrificed at day 12.Proteinuria and blood urea were measured. EGFP+ podocyte areas were analyzed. In biopsies from patients with crescentic GN co-staining of CD8+ T cells and Bowman’s capsule were performed.
Results
In control mice, Jedi T cells could not access EGFP+ podocytes. Conversely, when we induced NTSN and injected Jedi T cells, EGFP+ podocyte transgenic mice showed enhanced proteinuria and higher blood urea levels. Morphometric analysis showed greater loss of EGFP+ podocytes, which was associated with severe crescentic and necrotizing GN. Notably, only glomeruli with disrupted Bowman’s capsule displayed massive CD8+ T cell infiltrates that were in direct contact with EGFP+ podocytes, causing their apoptosis. Comparable findings were obtained in biopsies from patients with crescentic GN, where infiltration of CD8+ T cells inside Bowman’s capsule also only occurred after breaches in the capsule allowed access of CD8+ T cells to the glomerular tuft, resulting in its destruction.
Conclusion
Under control conditions Bowman’s capsule provides an immunologically protected niche for podocytes from CTL. However any breach in Bowman’s capsule, as occurs during crescentic GN, allows access of CTLs to Bowman’s space with catastrophic consequences for the glomerulus, converting a potentially reversible GN into a rapidly progressive GN leading to end stage kidney disease. Translating these mechanistic insights to human crescentic nephritis should direct future therapeutic interventions at blocking CD8+ T cells, especially in progressive stages of rapidly progressive GN.
Funding
- Other NIH Support