Targeting Cathepsin C in PR3-ANCA Vasculitis

Abstract

BackgroundThe ANCA autoantigens proteinase 3 (PR3) and myeloperoxidase (MPO) are exclusively expressed by neutrophils and monocytes. ANCA-mediated activation of these cells is the key driver of the vascular injury process in ANCA-associated vasculitis (AAV), and neutrophil serine proteases (NSPs) are disease mediators. Cathepsin C (CatC) from zymogens activates the proteolytic function of NSPs, including PR3. Lack of NSP zymogen activation results in neutrophils with strongly reduced NSP proteins.MethodsTo explore AAV-relevant consequences of blocking NSP zymogen activation by CatC, we used myeloid cells from patients with Papillon-Lefèvre syndrome, a genetic deficiency of CatC, to assess NSPs and NSP-mediated endothelial cell injury. We also examined pharmacologic CatC inhibition in neutrophil-differentiated human hematopoietic stem cells, primary human umbilical vein cells, and primary glomerular microvascular endothelial cells.ResultsPatients with Papillon-Lefèvre syndrome showed strongly reduced NSPs in neutrophils and monocytes. Neutrophils from these patients produced a negative PR3-ANCA test, presented less PR3 on the surface of viable and apoptotic cells, and caused significantly less damage in human umbilical vein cells. These findings were recapitulated in human stem cells, in which a highly specific CatC inhibitor, but not prednisolone, reduced NSPs without affecting neutrophil differentiation, reduced membrane PR3, and diminished neutrophil activation upon PR3-ANCA but not MPO-ANCA stimulation. Compared with healthy controls, neutrophils from patients with Papillon-Lefèvre syndrome transferred less proteolytically active NSPs to glomerular microvascular endothelial cells, the cell type targeted in ANCA-induced necrotizing crescentic glomerulonephritis. Finally, both genetic CatC deficiency and pharmacologic inhibition, but not prednisolone, reduced neutrophil-induced glomerular microvascular endothelial cell damage.ConclusionsThese findings may offer encouragement for clinical studies of adjunctive CatC inhibitor in patients with PR3-AAV.

A View on Cathepsin C as a Target for Therapy in AAV

“…Indeed, early studies of targeted-release formulation (TRF) budesonide (the first US Food and Drug Administration-approved treatment for IgAN that specifically targets gut-associated lymphoid tissue), BION-1301 (an anti-APRIL mAb), and atacicept (a recombinant fusion protein containing the binding portion of transmembrane activator and CAML interactor (TACI) that inhibits both BAFF and APRIL) have each been demonstrated to reduce GdIgA1 levels in IgAN. [7][8][9] In contrast, depletion of peripheral CD20 1 B cells with rituximab did not affect GdIgA1 levels, which is likely due to GdIgA1-secreting plasma cells not being targeted by this approach. 10 Further characterization of circulating GdIgA1 1 B-cell populations, as well as improving our understanding of the pathogenesis, could eventually lead to their use as a biomarker to assess response to therapy or to the identification of new therapeutic targets.…”

“…In a model adjusted for age, sex, and baseline eGFR, patients with CHIP were at an approximately two-fold greater risk of a sustained 50% decline in eGFR or ESKD over 5 years. The authors also applied the internationally validated Kidney Failure Risk Equation (KFRE) to their cohort to determine if the presence of CHIP alters the risk of progression to ESKD 7 ; the KFRE score estimates the risk of ESKD using a model that adjusts for age, sex, eGFR, and urine albumin-creatinine ratio. The KFREestimated risk of ESKD was increased in patients with CHIP.…”

“…Altogether, Vlasschaert et al 7 add a new and provocative dataset to the growing corpus on the association of CHIP with nonmalignant diseases. In line with the findings presented here, a recent analysis of the UK Biobank also reported lower eGFR among individuals with CHIP and an association between CHIP and adverse outcomes in CKD.…”

“…In this issue, Jerke et al 7 use a rare “experiment of nature” to investigate involvement of CatC in microvascular injury, as in AAV. Papillon–Lefèvre syndrome (PLS) is an autosomal recessive disease, first described in 1924, that is caused by loss of function of CTCS , the gene coding for CatC 8 .…”

The neutrophil: A key resourceful agent in immune‐mediated vasculitis

“…Accordingly, cathepsin C inhibition has been shown to reduce NSP expression and proteolytic activity in mice 403,404 and to reduce glomerular microvascular endothelial cell damage in vitro. 405 Finally, stimulation of innate immunity by the defective clearance of PR3-expressing neutrophils may also be harnessed in future therapies targeting macrophage activation or plasmacytoid dendritic cells. 200 Nanoparticles are also under investigation to target neutrophils and macrophages in inflammatory diseases.…”