Skip to main content

Advertisement

SpringerLink
Log in

Cytokine production by leukocytes of Papillon–Lefèvre syndrome patients in whole blood cultures

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Papillon–Lefèvre syndrome (PLS) is characterised by aggressively progressive periodontitis combined with palmo-plantar hyperkeratosis. It is caused by “loss of function” mutations in the cathepsin C gene. The hypothesis behind this study is that PLS patients’ polymorphonuclear leukocytes (PMNs) produce more proinflammatory cytokines to compensate for their reduced capacity to neutralize leukotoxin and to eliminate Aggregatibacter actinomycetemcomitans. Production of more interleukin (IL)-8 would result in the attraction of more PMNs. The aim of this study was to evaluate the cytokine profile in PLS patients’ blood cultures. Blood was sampled from eight PLS patients (one female) from six families (antiinfective therapy completed: six; edentulous: two) with confirmed cathepsin C mutations and deficient enzyme activity. Nine healthy males served as controls. Whole blood cultures were stimulated with highly pure lipopolysaccharide (LPS) from Escherichia coli R515 and IL-1β plus tumor necrosis factor (TNF)-α. Thereafter, release of IL-1β (stimulation: LPS and LPS plus adenosine triphosphate), IL-6, IL-8, interferon-inducible protein (IP)-10, and interferon (IFN)-γ (stimulation: LPS, IL-1β/TNFα) were detected by ELISA. Medians of cytokine release were, with the exception of IP-10, slightly higher for PLS than for controls’ cultures. None of these differences reached statistical significance. Increased production of IL-1β, IL-6, IL-8, IP-10, or IFNγ as a significant means to compensate for diminished activity and stability of polymorphonuclear leukocyte-derived proteases could not be confirmed in this study. Cytokine profiles in blood cultures may not be used to identify PLS patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Papillon M, Lefèvre P (1924) Dens cas de keratodermie palmaire et plantaire symetrique familale (maladie de meleda) chez le frere et al soeur: coexdistence dans les deux cas d’alterations dentaires groups. Soc Fr Dermatol Syphiligr 31:82–87

    Google Scholar 

  2. Gorlin RJ, Sedano H, Anderson VE (1964) The syndrome of palmar-plantar hyperkeratosis and premature periodontal destruction of the teeth. A clinical and genetic analysis of the Papillon-Lefèvre syndrome. J Pediatr 65:895–908

    Article  PubMed  Google Scholar 

  3. Haneke E (1979) The Papillon-Lefevre syndrome: keratosis palmoplantaris with periodontopathy—report of a case and review of the cases in the literature. Hum Genet 51:1–35

    Article  PubMed  Google Scholar 

  4. Almuneef M, Al Khenaizan S, Al Ajaji S, Al Anazi A (2003) Pyogenic liver abscess and Papillon-Lefevre syndrome: not a rare association. Pediatr 111:e85–e88

    Article  Google Scholar 

  5. Haneke E, Hornstein OP, Lex C (1975) Increased susceptibility to infections in the Papillon-Lefevre syndrome. Dermatologica 150:283–286

    Article  PubMed  Google Scholar 

  6. De Vree H, Steenackers K, De Boever JA (2000) Periodontal treatment of rapid progressive periodontitis in 2 siblings with Papillon-Lefevre syndrome: 15-year follow-up. J Clin Periodontol 27:354–360

    Article  PubMed  Google Scholar 

  7. Eickholz P, Kugel B, Pohl S, Näher H, Staehle HJ (2001) Combined mechanical and antibiotic periodontal therapy in a case of Papillon-Lefevre syndrome. J Periodontol 72:542–549

    Article  PubMed  Google Scholar 

  8. Rüdiger S, Petersilka G, Flemmig TF (1999) Combined systemic and local antimicrobial therapy of periodontal disease in Papillon-Lefevre syndrome. A report of 4 cases. J Clin Periodontol 26:847–854

    PubMed  Google Scholar 

  9. Schacher B, Baron F, Ludwig B, Valesky E, Noack B, Eickholz P (2006) Periodontal therapy in siblings with Papillon-Lefevre syndrome and tinea capitis: a report of two cases. J Clin Periodontol 33:829–836

    Article  PubMed  Google Scholar 

  10. Toygar HU, Kircelli C, Firat E, Guzeldemir E (2007) Combined therapy in a patient with Papillon-Lefèvre syndrome: a 13-year follow-up. J Periodontol 78:1819–1824

    Article  PubMed  Google Scholar 

  11. Ullbro C, Brown A, Twetman S (2005) Preventive periodontal regimen in Papillon-Lefevre syndrome. Pediatr Dent 27:226–232

    PubMed  Google Scholar 

  12. Hart PS, Bowden DW, Michalec MD, Callison SA, Walker SJ, Zhang Y, Firatli E (1999) Mutations of the cathepsin C gene are responsible for Papillon-Lefevre syndrome. J Med Genet 36:881–887

    PubMed  Google Scholar 

  13. Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N, Hewitt C, Moynihan L, Roberts E, Woods CG, Markham A, Wong M, Widmer R, Ghaffar KA, Pemberton M, Hussein IR, Temtamy SA, Davies R, Read AP, Sloan P, Dixon MJ, Thakker NS (1999) Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 23:421–424

    Article  PubMed  Google Scholar 

  14. Noack B, Görgens H, Schacher B, Puklo M, Eickholz P, Hoffmann T, Schackert HK (2008) Functional cathepsin C mutations cause different Papillon-Lefèvre syndrome phenotypes. J Clin Periodontol 35:311–316

    Article  PubMed  Google Scholar 

  15. Adkison AM, Raptis SZ, Kelley DG, Pham CTN (2002) Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J Clin Invest 109:363–371

    PubMed  Google Scholar 

  16. de Haar SF, Jansen DC, Schoenmaker T, De Vree H, Everts V, Beertsen W (2004) Loss-of-function mutations in cathepsin C in two families with Papillon-Lefevre syndrome are associated with deficiency of serine proteinases in PMNs. Hum Mutat 23:524

    Article  PubMed  Google Scholar 

  17. Pham CT, Ivanovich JL, Raptis SZ, Zehnbauer B, Ley TJ (2004) Papillon-Lefevre syndrome: correlating the molecular, cellular, and clinical consequences of cathepsin C/dipeptidyl peptidase I deficiency in humans. J Immunol 173:7277–7281

    PubMed  Google Scholar 

  18. Pham CT, Ley TJ (1999) Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc Natl Acad Sci U S A 96:8627–8632

    Article  PubMed  Google Scholar 

  19. de Haar SF, Hiemstra PS, van Steenbergen MT, Everts V, Beertsen W (2006) Role of polymorphonuclear leukocyte-derived serine proteinases in defense against Actinobacillus actinomycetemcomitans. Infect Immun 74:5284–5291

    Article  PubMed  Google Scholar 

  20. Nuckolls GH, Slavkin HC (1999) Paths of glorious proteases. Nat Genet 23:378–380

    Article  PubMed  Google Scholar 

  21. Lundgren T, Parhar RS, Renvert S, Tatakis DN (2005) Impaired cytotoxicity in Papillon-Lefevre syndrome. J Dent Res 84:414–417

    Article  PubMed  Google Scholar 

  22. Meade JL, de Wynter EA, Brett P, Sharif SM, Woods CG, Markham AF, Cook GP (2006) A family with Papillon-Lefevre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity. Blood 107:3665–3668

    Article  PubMed  Google Scholar 

  23. Liu YC, Lerner UH, Teng YT (2010) Cytokine responses against periodontal infection: protective and destructive roles. Periodontol 2000 52:163–206

    Article  Google Scholar 

  24. Angiolillo AL, Cecilia Sgadari C, Taub DD, Liao F, Joshua M, Farber JF, Maheshwari S, Kleinman HK, Keaman GH, Tosato G (1995) Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 182:155–162

    Article  PubMed  Google Scholar 

  25. Garlet GP (2010) Destructive and protective roles of cytokines in periodontitis: a re-appraisal from host defense and tissue destruction viewpoints. J Dent Res 89:1349–1363

    Article  PubMed  Google Scholar 

  26. Hewitt C, McCormick D, Linden G, Turk D, Stern I, Wallace I, Southern L, Zhang L, Howard R, Bullon P, Wong M, Widmer R, Gaffar KA, Awawdeh L, Briggs J, Yaghmai R, Jabs EW, Hoeger P, Bleck O, Rüdiger SG, Petersilka G, Battino M, Brett P, Hattab F, Al Hamed M, Sloan P, Toomes C, Dixon M, James J, Read AP, Thakker N (2004) The role of cathepsin C in Papillon-Lefevre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum Mutat 23:222–228

    Article  PubMed  Google Scholar 

  27. Noack B, Görgens H, Hoffmann T, Fanghänel J, Kocher T, Eickholz P, Schackert HK (2004) Novel mutations in the cathepsin C gene in patients with pre-pubertal aggressive periodontitis and Papillon-Lefevre syndrome. J Dent Res 83:368–370

    Article  PubMed  Google Scholar 

  28. Dinorello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095–2147

    Google Scholar 

  29. Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756

    Article  PubMed  Google Scholar 

  30. Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–14

    Article  PubMed  Google Scholar 

  31. Rubartelli A (2005) Control of IL-1β secretion in inflammation and immune response. Curr Med Chem AntiInflammatory AntiAllergy Agents 4:133–140

    Article  Google Scholar 

  32. Lux CJ, Kugel B, Komposch G, Pohl S, Eickholz P (2005) Orthodontic treatment in a patient with Papillon-Lefèvre syndrome. J Periodontol 76:149–157

    Article  Google Scholar 

  33. Bullon P, Pascual A, Fernandez-Novoa MC, Borobio MV, Muniain MA, Camacho F (1993) Late onset Papillon-Lefevre syndrome? A chromosomic, neutrophil function and microbiological study. J Clin Periodontol 20:662–667

    Article  PubMed  Google Scholar 

  34. Hattab FN, Rawashdeh MR, Yassin OM, Al-Momani AS, Al-Ubosi MM (1995) Papillon-Lefèvre syndrome: a review of the literature and a report of 4 cases. J Periodontol 66:413–420

    PubMed  Google Scholar 

  35. Baer PN, McDonald RE (1981) Suggested mode of periodontal therapy for patients with Papillon-Lefèvre syndrome. Periodontal Case Rep 1:10

    Google Scholar 

  36. Preus HR, Gjermo P (1987) Clinical management of prepubertal periodontitis in 2 siblings with Papillon-Lefèvre syndrome. J Clin Periodontol 14:156–160

    Article  PubMed  Google Scholar 

  37. Tinanoff N, Tempro P, Maderazo EG (1995) Dental treatment of Papillon-Lefèvre syndrome: 15 year follow-up. J Clin Periodontol 22:609–612

    Article  PubMed  Google Scholar 

  38. Ishikawa I, Umeda M, Laosrisin N (1994) Clinical, bacteriological, and immunological examination and the treatment process of two Papillon-Lefèvre syndrome patients. J Periodontol 65:364–371

    PubMed  Google Scholar 

  39. Pacheco JJ, Coelho C, Salazar F, Contreras A, Slots J, Velazco CH (2002) Treatment of Papillon-Lefèvre syndrome periodontitis. J Clin Periodontol 29:370–374

    Article  PubMed  Google Scholar 

  40. Brown RS, Hays GL, Flaitz CM, O’Neill PA, Abramovitch K, White RR (1993) A possible late onset variation of Papillon-Lefevre syndrome: report of 3 cases. J Periodontol 64:379–386

    PubMed  Google Scholar 

  41. Fardal O, Drangsholt E, Olsen I (1998) Palmar plantar keratosis and unusual periodontal findings. Observations from a family of 4 members. J Clin Periodontol 25:181–184

    Article  PubMed  Google Scholar 

  42. Nakano A, Nomura K, Nakano H, Ono Y, LaForgia S, Pulkkinen L, Hashimoto I, Uitto J (2001) Papillon-Lefevre syndrome: mutations and polymorphisms in the cathepsin C gene. J Invest Dermatol 116:339–343

    Article  PubMed  Google Scholar 

  43. Inalöz HS, Harman M, Akdeniz S, Inalöz SS, Isik AG (2001) Atypical familial Papillon-Lefevre syndrome. J Eur Acad Dermatol Venereol 15:48–50

    Article  PubMed  Google Scholar 

  44. Soskolne WA, Stabholz A, Dyke TE, Hart TC, Meyle J (1996) Partial expression of the Papillon-Lefevre syndrome in 2 unrelated families. J Clin Periodontol 23:764–769

    Article  PubMed  Google Scholar 

  45. Allende LM, Garcia-Perez MA, Moreno A, Corell A, Carasol M, Martinez-Canut P, Arnaiz-Villena A (2001) Cathepsin C gene: first compound heterozygous patient with Papillon-Lefevre syndrome and a novel symptomless mutation. Hum Mutat 17:152–153

    Article  PubMed  Google Scholar 

  46. Cury VF, Costa JE, Gomez RS, Boson WL, Loures CG, De ML (2002) A novel mutation of the cathepsin C gene in Papillon-Lefevre syndrome. J Periodontol 73:307–312

    Article  PubMed  Google Scholar 

  47. Cury VF, Gomez RS, Costa JE, Friedman E, Boson W, De Marco L (2005) A homozygous cathepsin C mutation associated with Haim-Munk syndrome. Brit J Dermatol 152:353–356

    Article  Google Scholar 

  48. Hart TC, Hart PS, Michalec MD, Zhang Y, Marazita ML, Cooper M, Yassin OM, Nusier M, Walker S (2000) Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation. J Med Genet 37:95–101

    Article  PubMed  Google Scholar 

  49. Hart PS, Zhang Y, Firatli E, Uygur C, Lotfazar M, Michalec MD, Marks JJ, Lu X, Coates BJ, Seow WK, Marshall R, Williams D, Reed JB, Wright JT, Hart TC (2000) Identification of cathepsin C mutations in ethnically diverse Papillon-Lefevre syndrome patients. J Med Genet 37:927–932

    Article  PubMed  Google Scholar 

  50. Lefevre C, Blanchet-Bardon C, Jobard F, Bouadjar B, Stalder JF, Cure S, Hoffmann A, Prud’Homme JF, Fischer J (2001) Novel point mutations, deletions, and polymorphisms in the cathepsin C gene in nine families from Europe and North Africa with Papillon-Lefevre syndrome. J Invest Dermatol 117:1657–1661

    Article  PubMed  Google Scholar 

  51. Ullbro C, El-Samadi S, Boumah C, Boumah C, Al-Yousef N, Wakil S, Twetman S, Alfadley A, Thestrup-Pedersen K, Meyer B (2006) Phenotypic variation and allelic heterogeneity in young patients with Papillon-Lefèvre syndrome. Acta Derm Venereol 86:3–7

    PubMed  Google Scholar 

Download references

Conflicts of interest

The authors declare that they have no conflicts of interest. This study was funded by the authors and their institutions.

Author information

Authors and Affiliations

  1. Institute of General Pharmacology and Toxicology, Center for Pharmacology, Johann Wolfgang Goethe-University Frankfurt am Main, Frankfurt am Main, Germany

    Christian D. Sadik, Josef Pfeilschifter & Heiko Mühl

  2. Department of Periodontology, University Hospital Carl Gustav Carus, TU Dresden, Germany

    Barbara Noack

  3. Department of Periodontology, Center for Dental, Oral, and Maxillofacial Medicine (Carolinum), Johann Wolfgang Goethe-University Frankfurt am Main, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Beate Schacher & Peter Eickholz

Authors
  1. Christian D. Sadik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Noack
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beate Schacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Josef Pfeilschifter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Heiko Mühl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Eickholz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Eickholz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sadik, C.D., Noack, B., Schacher, B. et al. Cytokine production by leukocytes of Papillon–Lefèvre syndrome patients in whole blood cultures. Clin Oral Invest 16, 591–597 (2012). https://doi.org/10.1007/s00784-011-0532-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-011-0532-0

Keywords

Search

Navigation