Lack of cathelicidin processing in Papillon-Lefèvre syndrome patients reveals essential role of LL-37 in periodontal homeostasis.

Abstract

BACKGROUND:

Loss-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.

AIM:

We 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.

METHODS:

To 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.

RESULTS:

Although 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.

CONCLUSIONS:

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.

• Authors: Sigrun Eick, Magdalena Puklo, Karina Adamowicz, Tomasz Kantyka, Pieter Hiemstra, Henning Stennicke, Arndt Guentsch, Beate Schacher, Peter Eickholz, Jan Potempa
• Journal: Orphanet journal of rare diseases (Orphanet J Rare Dis) Vol. 9 Pg. 148 (Sep 27 2014) ISSN: 1750-1172 [Electronic] England
• PMID: 25260376 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimicrobial Cationic Peptides
• Peroxidase
• Cathepsin C
• Leukocyte Elastase
• Myeloblastin
• Cathelicidins

Topics

• Aggregatibacter actinomycetemcomitans (drug effects)
• Antimicrobial Cationic Peptides (metabolism, pharmacology)
• Blotting, Western
• Cathepsin C (genetics, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Homeostasis
• Humans
• Leukocyte Elastase (metabolism)
• Myeloblastin (metabolism)
• Papillon-Lefevre Disease (metabolism, physiopathology)
• Periodontium (metabolism, microbiology, physiopathology)
• Peroxidase (metabolism)
• Point Mutation
• Cathelicidins