Characterization of neutrophil function in Papillon-Lefèvre syndrome

Abstract

Papillon-Lefévre syndrome is a rare, inherited, autosomal-recessive disease, characterized by palmoplantar keratosis and severe prepubertal periodontitis, leading to premature loss of all teeth. Papillon-Lefévre syndrome is caused by a mutation in the cathepsin C gene, resulting in complete loss of activity and subsequent failure to activate immune response proteins. Periodontitis in Papillon-Lefévre syndrome is thought to arise from failure to eliminate periodontal pathogens as a result of cathepsin C deficiency, although mechanistic pathways remain to be elucidated. The aim of this study was to characterize comprehensively neutrophil function in Papillon-Lefévre syndrome. Peripheral blood neutrophils were isolated from 5 patients with Papillon-Lefévre syndrome, alongside matched healthy control subjects. For directional chemotactic accuracy, neutrophils were exposed to the chemoattractants MIP-1α and fMLP and tracked by real-time videomicroscopy. Reactive oxygen species generation was measured by chemiluminescence. Neutrophil extracellular trap formation was assayed fluorometrically, and proinflammatory cytokine release was measured following overnight culture of neutrophils with relevant stimuli. Neutrophil serine protease deficiencies resulted in a reduced ability of neutrophils to chemotax efficiently and an inability to generate neutrophil extracellular traps. Neutrophil extracellular trap-bound proteins were also absent in Papillon-Lefévre syndrome, and Papillon-Lefévre syndrome neutrophils released higher levels of proinflammatory cytokines in unstimulated and stimulated conditions, and plasma cytokines were elevated. Notably, neutrophil chemoattractants MIP-1α and CXCL8 were elevated in Papillon-Lefévre syndrome neutrophils, as was reactive oxygen species formation. We propose that relentless recruitment and accumulation of hyperactive/reactive neutrophils (cytokines, reactive oxygen species) with increased tissue transit times into periodontal tissues, alongside a reduced antimicrobial capacity, create a locally destructive chronic inflammatory cycle in Papillon-Lefévre syndrome.

Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors

“…These off-targets were identified not only in human cancer cell lines, but also in liver tissue from mice treated with doses of osimertinib that match those used in the literature to block T790M-EGFR-driven tumor growth in xenograft models (Cross et al, 2014). Germline inactivating mutations in CTSC cause Papillon-Lefevre syndrome (Toomes et al, 1999), which manifests with severe periodontal disease and deregulated neutrophil function associated with increases in secreted and plasma proinflammatory cytokines (Roberts et al, 2016). That osimertinib and another covalent kinase inhibitor canertinib (Sun et al, 2016) cross-react with CTSC indicates a potentially complex effect of these oncology drugs on human immunology.…”

Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria

“…Neutrophils were isolated from the peripheral venous blood of periodontally and systemically healthy volunteers (University of Birmingham ethics reference ERN_13-0325) using discontinuous Percoll gradients (GE Healthcare, Amersham, UK) as previously described (67). The medical history was taken from each donor, and periodontal examinations were conducted to ensure periodontal and systemic health.…”

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…”