51. Targeting Cathepsin C in PR3-ANCA Vasculitis
- Author
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Jerke, Uwe, Eulenberg-Gustavus, Claudia, Rousselle, Anthony, Nicklin, Paul, Kreideweiss, Stefan, Grundl, Marc A., Eickholz, Peter, Nickles, Katrin, Schreiber, Adrian, Korkmaz, Brice, and Kettritz, Ralph
- Abstract
In ANCA?associated vasculitis (AAV), the autoantigens proteinase 3 (PR3) and myeloperoxidase (MPO) are exclusively expressed by neutrophils and monocytes. Cathepsin C (CatC), which activates the proteolytic function of neutrophil serine proteases (NSPs), provides a potential novel treatment target by controlling NSPs in both human neutrophils and monocytes. The authors show that genetic deficiency of CatC in humans and pharmacologic inhibition of CatC in a human stem cell model effectively downregulate NSPs, including PR3. Consequently, these neutrophils showed a diminished activation response to PR3-ANCA but not to MPO-ANCA. Moreover, both genetic and pharmacologic NSP depletion resulted in less neutrophil-induced injury of glomerular microvascular endothelial cells. These findings may offer encouragement for pursuing clinical studies with adjunctive CatC inhibitor administration in patients with PR3-AAV.
- Published
- 2022
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