Papillon-Lefèvre syndrome patient reveals species-dependent requirements for neutrophil defenses

Abstract

Papillon-Lefèvre syndrome (PLS) results from mutations that inactivate cysteine protease cathepsin C (CTSC), which processes a variety of serine proteases considered essential for antimicrobial defense. Despite serine protease-deficient immune cell populations, PLS patients do not exhibit marked immunodeficiency. Here, we characterized a 24-year-old woman who had suffered from severe juvenile periodontal disease, but was otherwise healthy, and identified a homozygous missense mutation in CTSC indicative of PLS. Proteome analysis of patient neutrophil granules revealed that several proteins that normally localize to azurophil granules, including the major serine proteases, elastase, cathepsin G, and proteinase 3, were absent. Accordingly, neutrophils from this patient were incapable of producing neutrophil extracellular traps (NETs) in response to ROS and were unable to process endogenous cathelicidin hCAP-18 into the antibacterial peptide LL-37 in response to ionomycin. In immature myeloid cells from patient bone marrow, biosynthesis of CTSC and neutrophil serine proteases appeared normal along with initial processing and sorting to cellular storage. In contrast, these proteins were completely absent in mature neutrophils, indicating that CTSC mutation promotes protease degradation in more mature hematopoietic subsets, but does not affect protease production in progenitor cells. Together, these data indicate CTSC protects serine proteases from degradation in mature immune cells and suggest that neutrophil serine proteases are dispensable for human immunoprotection.

A novel mechanism for NETosis provides antimicrobial defense at the oral mucosa

“…PLS neutrophils lack elastase and are incapable of forming NETs, both in response to PMA or glucose oxidase. 18 In contrast, saliva induced robust NETosis in PLS neutrophils ( Figure 3B). …”

Histones as Mediators of Host Defense, Inflammation and Thrombosis

“…In contrast, these mice had similar response to sepsis induced by cecal ligation and puncture and were partially protected from endotoxin-induced shock [68]. An interesting recent report raised some question about the importance of NETs in human defense against infection [69,70]. Sorensen et al described a patient with Papillon-Lefevre syndrome resulting from lack of neutrophil serine proteases.…”

Anti-Microbial Peptides and Their Speculative Role in Periodontitis

“…Thus, a dual approach is mandatory to comprehend the task of hosts' immunity in response to, against periodontitis [37]. This involves more comprehensive statistics about HNP and hBD, LL-37, and other oral antimicrobial peptides and proteins, along with their mode of action and clinical significance [38][39][40][41][42][43][44][45][46][47][48][49][50]. These peptides are peculiar in keeping the level of bacteria in control, having distinctive as well as dual roles in maintaining oral health.…”

“…Normal Lactoferrin levels Papillon-Lefe`vre syndrome [48,49] Haim-Munk syndrome [50] Palm plantar keratoderma and severe periodontitis Allelic mutations of the cathepsin C(CTSC) gene…”