Glomerulonephritis (GN) is a group of immune-mediated kidney disorders that damage the glomeruli, causing proteinuria, hematuria, and reduced kidney function. GN is a leading cause of chronic kidney disease and the third leading cause of end-stage renal disease. Lupus nephritis (LN) — the kidney manifestation of systemic lupus erythematosus (SLE) — is a major form of GN. SLE affects over 3 million people in Western countries, and many develop LN, with about 20% reaching end-stage renal disease within 10 years of diagnosis. Despite therapeutic advances, a subset of patients remains unresponsive to treatment, and the mechanisms behind this resistance remain poorly understood.
This creates an urgent need for biomarkers that can predict LN severity and guide personalized immunosuppressive therapy, as well as deeper insight into disease progression to reveal new treatment targets. The authors' group previously found that autoantibodies against Formin-like Protein 1 (FMNL1) — a protein absent from podocytes — were linked to lower remission rates in idiopathic membranous nephropathy, suggesting a role for FMNL1 in disease progression.
This thesis investigates whether the FMNL1 axis similarly drives lupus nephritis, aiming to eventually build an FMNL1-based diagnostic-therapeutic platform for LN and other chronic inflammatory diseases.
Key findings: Anti-FMNL1 autoantibodies were detected in lupus patients, and their baseline levels correlated with LN outcomes, supporting FMNL1's role in disease progression. To probe this further, an FMNL1-knockout mouse was combined with two nephropathy models (aristolochic acid and pristane), assessing functional and histological readouts. Anti-FMNL1 autoantibodies emerged spontaneously in pristane-treated mice, making this model particularly useful for further study. The team also developed an in vitro platform to study FMNL1 biology in macrophages and the effects of anti-FMNL1 autoantibodies on FMNL1-expressing cells. Finally, they engineered an FMNL1 mimotope prototype mimicking the native epitope's structure, capable of binding patient autoantibodies — an early step toward diagnostic and therapeutic tools.
Overall, the thesis identifies anti-FMNL1 autoantibodies as a promising biomarker for lupus patient stratification and a potential therapeutic target, combining clinical correlation, animal models, in vitro studies, and mimotope engineering to support future clinical tools for managing lupus nephritis.
