Neutrophils and monocytes are the only cells that produce the ANCA autoantigens proteinase 3 (PR3) and myeloperoxidase (MPO). In ANCA-associated vasculitis (AAV), ANCA-mediated activation of these cells is the primary driver of the vascular damage process, and neutrophil serine proteases (NSPs) are disease mediators. Cathepsin C (CatC) from zymogens stimulates the proteolytic activity of NSPs, including PR3. In the absence of NSP zymogen activation, neutrophils have significantly decreased NSP proteins.

For a study, researchers sought to investigate the AAV-relevant effects of inhibiting NSP zymogen activation by CatC, they assessed NSPs and NSP-mediated endothelial cell damage in myeloid cells from patients with Papillon-Lefèvre syndrome, a genetic lack of CatC. Pharmacologic CatC inhibition was also investigated in neutrophil-differentiated human hematopoietic stem cells, essential human umbilical vein cells, and primary glomerular microvascular endothelial cells. 

NSPs in neutrophils and monocytes were significantly decreased in patients with Papillon-Lefèvre syndrome. These patients’ neutrophils failed the PR3-ANCA test, had less PR3 on the surface of viable and apoptotic cells and caused considerably less damage to human umbilical vein cells. In human stem cells, a highly selective CatC inhibitor, but not prednisolone, decreased NSPs without impacting neutrophil differentiation, membrane PR3, and neutrophil activation in response to PR3-ANCA but not MPO-ANCA stimulation. Papillon-Lefèvre syndrome neutrophils transmitted less proteolytically active NSPs to glomerular microvascular endothelial cells, the cell type targeted in ANCA-induced necrotizing crescentic glomerulonephritis. Finally, genetic data loss and pharmacologic inhibition decreased neutrophil-induced glomerular microvascular endothelial cell damage, but not prednisolone. The findings might pave the way for therapeutic trials of supplemental CatC inhibitors in PR3-AAV patients.