Targeting Cathepsin C in PR3-ANCA Vasculitis

Area of Science:

• Immunology
• Vascular Biology
• Genetics

Background:

• Autoimmune vasculitis involves ANCA-mediated activation of neutrophils and monocytes, releasing neutrophil serine proteases (NSPs) that cause vascular injury.
• Cathepsin C (CatC) is crucial for activating NSPs, including proteinase 3 (PR3), a key autoantigen in ANCA-associated vasculitis (AAV).
• Reduced NSP activation leads to lower NSP levels in neutrophils.

Purpose of the Study:

• To investigate the consequences of inhibiting CatC-mediated NSP activation in the context of AAV.
• To assess the impact of CatC deficiency on myeloid cells and endothelial cell injury relevant to AAV.
• To evaluate the efficacy of pharmacologic CatC inhibition versus prednisolone in reducing AAV pathogenesis markers.

Main Methods:

• Utilized myeloid cells from Papillon-Lefèvre syndrome patients (genetic CatC deficiency) and pharmacologic CatC inhibition in human hematopoietic stem cells.
• Assessed NSP levels, PR3 expression on cell surfaces, and endothelial cell damage.
• Examined neutrophil differentiation, activation, and transfer of proteolytically active NSPs to endothelial cells.

Main Results:

• Genetic CatC deficiency in Papillon-Lefèvre syndrome patients resulted in reduced NSPs, negative PR3-ANCA tests, and diminished endothelial cell damage.
• Pharmacologic CatC inhibition in human stem cells recapitulated these findings, reducing NSPs and membrane PR3 without affecting differentiation.
• CatC inhibition, but not prednisolone, reduced neutrophil-induced damage to glomerular microvascular endothelial cells, the primary target in AAV.

Conclusions:

• Blocking CatC effectively reduces NSP levels and activity, mitigating endothelial cell injury relevant to AAV.
• Pharmacologic CatC inhibition shows potential as an adjunctive therapy for PR3-AAV.
• These findings support further clinical investigation of CatC inhibitors in PR3-AAV patients.