Abstract: TH-PO0665
Cytotoxic T Cell Dysregulation in the Pathogenesis of Idiopathic Membranous Nephropathy
Session Information
- Glomerular Diseases: Immunopathogenesis and Targeted Therapeutics
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Sabapathy, Vikram, University of Virginia School of Medicine, Charlottesville, Virginia, United States
- Ghosh, Siddhartha S., VCU School of Medicine, Richmond, Virginia, United States
- Pelletier, Oliver B., University of Virginia School of Medicine, Charlottesville, Virginia, United States
- Gehr, Todd W., VCU School of Medicine, Richmond, Virginia, United States
- Kidd, Jason M., VCU School of Medicine, Richmond, Virginia, United States
- Sharma, Rahul, University of Virginia School of Medicine, Charlottesville, Virginia, United States
Background
Idiopathic Membranous Nephropathy (MN) is an autoimmune disorder affecting kidneys. It is manifested by autoantibodies against anti-Phospholipase receptor A2 in >60% cases, but the etiopathology remains poorly understood. We hypothesized that T-cell dysregulation is a contributor to disease pathology of MN.
Methods
We compared peripheral blood mononuclear cells (PBMC) of MN patients (n=11) with donors with hypertensive kidney disease (HTN; n=7). Characteristics of T-cell subsets and their cytokine production was analyzed by flow cytometry and single-cell RNA sequencing (scRNAseq).
Results
Although, there was no significant difference in serum creatinine of the groups, urine protein-creatinine ratio (UPCR; Mean±SD) was close to significance (HTN=0.14±0.3, MN=3.1±3.8; p=0.058). There were significantly more T-cells in MN (51.8±14%) compared to HTN=32.4±10%; p=0.006). This accompanied with a skewing towards expansion of CD8+ T-cells in MN (29.6±10% vs 15.4±3%; p=0.003) in HTN, such that the ratio of CD4+ to CD8+ T-cells was lower (in MN (2.7±2.2%) compared to HTN (5.1±1.4%; p=0.0192). There was a trend towards lower ratio of T-regulatory cells (Tregs) to the CD8α T-cells, which did not reach significance. Both CD4+ and CD8+ T-cells from MN donors produced significantly higher levels of Tumor necrosis factor (TNF)-α upon stimulation with Phorbol myristate acetate (PMA) and ionomycin with non-significant trend for higher IL-17 production in MN as compared to HTN. In scRNAseq data, MN donors exhibited higher frequencies of CD14+ monocytes, CD8+ effector memory T cells and double-negative T cells, alongside a reduction in regulatory T cells and naive B-cells. This was accompanied by higher expression of pro-inflammatory mediators, including IL1B, CXCL2/3/5/8, and CCL3, and fibrosis-associated genes such as ACTA2. Correlating with the flow-cytometry analysis, pathway enrichment analysis highlights activation of TNFα, NOD-like receptors, NF-κB, and chemokine signaling pathways.
Conclusion
Our data based on flow cytometric and transcriptomics comparison suggests that compared to non-autoimmune renal disease, T-cell dysregulation, highlighted by expansion of proinflammatory cytotoxic T-cells and innate inflammasome activation may contribute to the pathogenesis of MN and offer novel targets for intervention.
Funding
- Private Foundation Support