title: 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.
  
  
  OBJECTIVE
  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.forename: Sigrun
authors.initials: S
authors.lastname: Eick
authors.forename: Magdalena
authors.initials: M
authors.lastname: Puklo
authors.forename: Karina
authors.initials: K
authors.lastname: Adamowicz
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kantyka
authors.forename: Pieter
authors.initials: P
authors.lastname: Hiemstra
authors.forename: Henning
authors.initials: H
authors.lastname: Stennicke
authors.forename: Arndt
authors.initials: A
authors.lastname: Guentsch
authors.forename: Beate
authors.initials: B
authors.lastname: Schacher
authors.forename: Peter
authors.initials: P
authors.lastname: Eickholz
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
mesh_terms: D016976:Aggregatibacter actinomycetemcomitans / Q000187:drug effects; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism* / Q000494:pharmacology*; D015153:Blotting, Western; D020789:Cathepsin C / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006706:Homeostasis; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D053146:Myeloblastin / Q000378:metabolism; D010214:Papillon-Lefevre Disease / Q000378:metabolism* / Q000503:physiopathology; D010519:Periodontium / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D009195:Peroxidase / Q000378:metabolism; D017354:Point Mutation; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D009195:Peroxidase; D020789:Cathepsin C; D019272:Leukocyte Elastase; D053146:Myeloblastin; D054804:Cathelicidins