Deciphering immune-epithelial interactions in crescentic glomerulonephritis
Crescentic glomerulonephritis (crescentic GN) is a devastating glomerular disease characterized by the development of hypercellular glomerular lesions (crescents). These crescents often mark irreversible glomerular damage and the extent of crescent formation directly predetermines the prognosis and outcome of crescentic GN. We hypothesize that immune cells provide key signals (ie. cytokines) that trigger and perpetuate parietal epithelial cell (PEC) activation, a process defined by an increased potential for migration and proliferation that is likely governed by some of the molecular pathways being similar to those observed in epithelial metastasis (ie. glycoprotein CD44, tetraspanin CD9, podoplanin, and proto-oncogene c-Src). We further propose that mutual cytokine gradients and immune-epithelial interactions are directly facilitated by the loss of basement membrane integrity (ie. glomerular basement membrane and Bowman’s capsule). Thus, this project aims to: (1) characterize highdimensional immune-PEC interactions during the course of crescentic GN; (2) systematically analyze the integrity of the major glomerular barriers during the formation of crescentic lesions; and (3) modulate immune-PEC interactions in crescentic GN via novel genetic and pharmacological strategies. Collectively, the understanding of epithelial-, immune- and extracellular matrix interactions during crescent formation, will provide a novel road map to target, halt and prevent irreversible glomerular destruction in crescentic glomerulonephritis.