Abstract
BackgroundLoss-of-function point mutations in the cathepsin C gene are the underlying genetic event in patients with Papillon-Lefèvre syndrome (PLS). PLS neutrophils lack serine protease activity essential for cathelicidin LL-37 generation from hCAP18 precursor.AimWe hypothesized that a local deficiency of LL-37 in the infected periodontium is mainly responsible for one of the clinical hallmark of PLS: severe periodontitis already in early childhood.MethodsTo confirm this effect, we compared the level of neutrophil-derived enzymes and antimicrobial peptides in gingival crevicular fluid (GCF) and saliva from PLS, aggressive and chronic periodontitis patients.ResultsAlthough neutrophil numbers in GCF were present at the same level in all periodontitis groups, LL-37 was totally absent in GCF from PLS patients despite the large amounts of its precursor, hCAP18. The absence of LL-37 in PLS patients coincided with the deficiency of both cathepsin C and protease 3 activities. The presence of other neutrophilic anti-microbial peptides in GCF from PLS patients, such as alpha-defensins, were comparable to that found in chronic periodontitis. In PLS microbial analysis revealed a high prevalence of Aggregatibacter actinomycetemcomitans infection. Most strains were susceptible to killing by LL-37.ConclusionsCollectively, these findings imply that the lack of protease 3 activation by dysfunctional cathepsin C in PLS patients leads to the deficit of antimicrobial and immunomodulatory functions of LL-37 in the gingiva, allowing for infection with A. actinomycetemcomitans and the development of severe periodontal disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0148-y) contains supplementary material, which is available to authorized users.
Highlights
Loss-of-function point mutations in the cathepsin C gene are the underlying genetic event in patients with Papillon-Lefèvre syndrome (PLS)
Collectively, these findings imply that the lack of protease 3 activation by dysfunctional cathepsin C in PLS patients leads to the deficit of antimicrobial and immunomodulatory functions of LL-37 in the gingiva, allowing for infection with A. actinomycetemcomitans and the development of severe periodontal disease
PLS patients The characteristics, including year of birth, ethnicity, gender, phenotype, the presence of A. actinomycetemcomitans in subgingival plaque before treatment and mutation in the cathepsin C (CTSC) gene of the 11 PLS patients are summarized in Additional file 1: Table S1)
Summary
Loss-of-function point mutations in the cathepsin C gene are the underlying genetic event in patients with Papillon-Lefèvre syndrome (PLS). Papillon-Lefèvre syndrome (PLS), a rare autosomal recessive disease, with an incidence of 1–4 cases/million people is characterized by palmar and plantar hyperkeratosis and severe periodontitis affecting primary and permanent teeth leading to early loss of primary and permanent teeth [1,2]. This periodontitis is classified as a periodontitis as a manifestation of systemic diseases associated with genetic disorders [3]. A form starting normally in adolescence, Aggregatibacter actinomycetemcomitans is highly prevalent, its virulence was mainly equated to the production of a leukotoxin [11]
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