Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1? production - 30/05/13
Abstract |
Background |
The exact pathogenesis of the pediatric disorder periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome is unknown.
Objectives |
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.
Conclusion |
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.
Le texte complet de cet article est disponible en PDF.Key words : Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome, recurrent fever, autoinflammatory disease, interleukine-1β, inflammasome
Abbreviations used : AID, CAPS, IL-1Ra, IP-10, MCP, MRP, PFAPA, PFAPA-IN, PFAPA-OUT, SoJIA
Plan
| Supported by a grant from the Swiss National Science Foundation (FN 310030-130085/1), the Novartis Foundation, the Jean and Linette Warnery Foundation, and the German Ministry of Education and Research (BMBF project AID-NET). |
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| Disclosure of potential conflict of interest: N. Busso has received grants from the Swiss National Science Foundation. I. Moix has received grants from Novartis. D. Holzinger has received grants from Bundesministerium für Bildung und Forschung. G. Guarda is employed by and has received grants from the University of Lausanne. A. So serves on advisory boards for Novartis AG and Menarini, has received grants from the Swiss National Foundation, has received payment for lectures/service on speakers' bureaus from Menarini, and has received payment for development of educational presentations from Novartis. M. A. Morris has received grants from Novartis. M. Hofer has received grants from the Novartis Foundation, has board membership with Novartis and Bristol-Myers-Squibb, and has received travel expenses from Pfizer. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 6
P. 1635-1643 - juin 2013 Retour au numéro
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