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  • Clinical Research Article
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The first proteomics analysis of tonsils in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome (PFAPA)

Pediatric Research volume 98, pages 629–635 (2025)Cite this article

Abstract

Background

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a recurrent fever syndrome. The exact etiopathogenesis of PFAPA syndrome remains unknown. Biological fluids or tissues may provide disease-specific biomarkers that may help clinicians to find new pathogenic pathways.

Methods

Tonsil tissues of seven patients with PFAPA were collected during the tonsillectomy. Seven patients who underwent tonsillectomy for reasons other than chronic tonsillitis were enrolled as a control group. The nHPLC LC-MS/MS system was used for protein identification and label-free quantification. Bioinformatics analysis was carried out using the UniProt accession numbers of the identified proteins.

Results

Proteomics analysis revealed to identity of proteins of which at least 23 were up and 57 were downregulated. Bioinformatics analysis of differentially regulated proteins by STRING indicated that protein folding and clearance machinery were interrupted in PFAPA patients compared to the controls. The affected pathways underlined the importance of the mitochondrial electron transport chain and ATP biosynthesis process.

Conclusion

Although it is not clear that changes in tonsil protein expression whether directly related to pathogenesis or simply result of chronic inflammation, the identification of tonsil biomarkers for PFAPA may provide clinicians an opportunity to understand disease pathogenesis or develop new molecular targets for treatments.

Impact

  • Proteomics analyses of tonsils revealed the identity of 80 proteins of which at least 23 were up and 57 were downregulated.

  • Bioinformatics analysis underlined the importance of mitochondrial ETC and regulation of ATP biosynthetic process.

  • This is the first study evaluating the proteomics of the tonsils of PFAPA patients.

  • The identification of tonsil biomarkers for PFAPA may provide clinicians an opportunity to understand disease pathogenesis or develop new molecular targets for treatments.

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Fig. 1: Histopathological examination of tonsil tissue samples.
Fig. 2: PFAPA-associated differentially regulated proteins and a possible interaction network, as predicted by STRING.
Fig. 3: Western Blot analysis of protein pools prepared from cell-free extracts of the control and patient tonsil tissues.
Fig. 4: The changes in PDHC and Complex V of ETC were probed by Western Blot analysis to ensure that implications of STRING analysis regarding Krebs cycle were verifiable.
Fig. 5

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Data availability

Data available on request.

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Acknowledgements

This study was supported by Kocael University BAP Unit (Project number: TSA-2023-3441).

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Authors and Affiliations

  1. Department of Otorhinolaryngology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey

    Fatih Mutlu & Alperen Önal

  2. Department of Basic Medical Sciences, Medical Biology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey

    Murat Kasap, Mehmet Sarıhan & Gürler Akpınar

  3. Department of Pathology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey

    Busra Yaprak Bayrak

  4. Department of Pediatrics, Division of Pediatric Rheumatology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey

    Nihal Şahin, Yunus Emre Bayrak & Hafize Emine Sönmez

Authors
  1. Fatih Mutlu
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  2. Murat Kasap
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  3. Busra Yaprak Bayrak
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  4. Mehmet Sarıhan
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  5. Nihal Şahin
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  6. Alperen Önal
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  7. Gürler Akpınar
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  8. Yunus Emre Bayrak
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  9. Hafize Emine Sönmez
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Contributions

Conceptualization: F.M., M.K., B.Y.Y., M.S., N.Ş., A.Ö., G.A., Y.E.B., H.E.S.; Methodology: F.M., M.K., B.Y.Y., M.S., N.Ş., A.Ö., G.A., Y.E.B., H.E.S.; Formal analysis and investigation: F.M., M.K., B.Y.Y., M.S., N.Ş., A.Ö., G.A., Y.E.B., H.E.S.; Writing—original draft preparation: F.M., M.K., B.Y.Y., M.S., N.Ş., A.Ö., G.A., Y.E.B., H.E.S.; Writing—review and editing: F.M., M.K., B.Y.Y., M.S., N.Ş., A.Ö., G.A., Y.E.B., H.E.S.; Funding acquisition: F.M., M.K., B.Y.Y., M.S., N.Ş., A.Ö., G.A., Y.E.B., H.E.S.; Supervision: F.M., M.K., B.Y.Y., M.S., N.Ş., A.Ö., G.A., Y.E.B., H.E.S. All authors reviewed and revised the manuscript and approved the final version of the manuscript.

Corresponding author

Correspondence to Hafize Emine Sönmez.

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The authors declare no competing interests.

Ethical approval

The protocol of the study was approved by the Ethical Commission for Research from Kocaeli University School of Medicine.

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Mutlu, F., Kasap, M., Yaprak Bayrak, B. et al. The first proteomics analysis of tonsils in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome (PFAPA). Pediatr Res 98, 629–635 (2025). https://doi.org/10.1038/s41390-024-03741-z

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