title: Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production.
abstract: BACKGROUND
  The exact pathogenesis of the pediatric disorder periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome is unknown.
  
  
  OBJECTIVE
  We hypothesized that PFAPA might be due to dysregulated monocyte IL-1β production linked to genetic variants in proinflammatory genes.
  
  
  METHODS
  Fifteen patients with PFAPA syndrome were studied during and outside a febrile episode. Hematologic profile, inflammatory markers, and cytokine levels were measured in the blood. The capacity of LPS-stimulated PBMCs and monocytes to secrete IL-1β was assessed by using ELISA, and active IL-1β secretion was visualized by means of Western blotting. Real-time quantitative PCR was performed to assess cytokine gene expression. DNA was screened for variants of the MEFV, TNFRSF1A, MVK, and NLRP3 genes in a total of 57 patients with PFAPA syndrome.
  
  
  RESULTS
  During a febrile attack, patients with PFAPA syndrome revealed significantly increased neutrophil counts, erythrocyte sedimentation rates, and C-reactive protein, serum amyloid A, myeloid-related protein 8/14, and S100A12 levels compared with those seen outside attacks. Stimulated PBMCs secreted significantly more IL-1β during an attack (during a febrile episode, 575 ± 88 pg/mL; outside a febrile episode, 235 ± 56 pg/mL; P < .001), and this was in the mature active p17 form. IL-1β secretion was inhibited by ZYVAD, a caspase inhibitor. Similar results were found for stimulated monocytes (during a febrile episode, 743 ± 183 pg/mL; outside a febrile episode, 227 ± 92 pg/mL; P < .05). Genotyping identified variants in 15 of 57 patients, with 12 NLRP3 variants, 1 TNFRSF1A variant, 4 MEFV variants, and 1 MVK variant.
  
  
  CONCLUSIONS
  Our data strongly suggest that IL-1β monocyte production is dysregulated in patients with PFAPA syndrome. Approximately 20% of them were found to have NLRP3 variants, suggesting that inflammasome-related genes might be involved in this autoinflammatory syndrome.
authors.affiliation: Rheumatology Service, DAL, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Laeticia
authors.initials: L
authors.lastname: Kolly
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busso
authors.forename: Annette
authors.initials: A
authors.lastname: von Scheven-Gete
authors.forename: Nathaliane
authors.initials: N
authors.lastname: Bagnoud
authors.forename: Isabelle
authors.initials: I
authors.lastname: Moix
authors.forename: Dirk
authors.initials: D
authors.lastname: Holzinger
authors.forename: Gregoire
authors.initials: G
authors.lastname: Simon
authors.forename: Annette
authors.initials: A
authors.lastname: Ives
authors.forename: Greta
authors.initials: G
authors.lastname: Guarda
authors.forename: Alexander
authors.initials: A
authors.lastname: So
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morris
authors.forename: Michaël
authors.initials: M
authors.lastname: Hofer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D005334:Fever / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis*; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008199:Lymphadenitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils; D010612:Pharyngitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013281:Stomatitis, Aphthous / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013577:Syndrome; D055815:Young Adult
chemical_list: D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides