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Immune Dysregulation in the Tonsillar Microenvironment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome

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Abstract

Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an inflammatory disorder of childhood classically characterized by recurrent fevers, pharyngitis, stomatitis, cervical adenitis, and leukocytosis. While the mechanism is unclear, previous studies have shown that tonsillectomy can be a therapeutic option with improvement in quality of life in many patients with PFAPA, but the mechanisms behind surgical success remain unknown. In addition, long-term clinical follow-up is lacking. In our tertiary care center cohort, 62 patients with PFAPA syndrome had complete resolution of symptoms after surgery (95.3%). Flow cytometric evaluation demonstrates an inflammatory cell population, distinct from patients with infectious pharyngitis, with increased numbers of CD8+ T cells (5.9% vs. 3.8%, p < 0.01), CD19+ B cells (51% vs. 35%, p < 0.05), and CD19+CD20+CD27+CD38-memory B cells (14% vs. 7.7%, p < 0.01). Cells are primed at baseline with increased percentage of IL-1β positive cells compared to control tonsil-derived cells, which require exogenous LPS stimulation. Gene expression analysis demonstrates a fivefold upregulation in IL1RN and TNF expression in whole tonsil compared to control tonsils, with persistent activation of the NF-κB signaling pathway, and differential microbial signatures, even in the afebrile period. Our data indicates that PFAPA patient tonsils have localized, persistent inflammation, in the absence of clinical symptoms, which may explain the success of tonsillectomy as an effective surgical treatment option. The differential expression of several genes and microbial signatures suggests the potential for a diagnostic biomarker for PFAPA syndrome.

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Abbreviations

CpG-ODN:

CpG-oligodeoxynucleotide

FBS:

Fetal bovine serum

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HRP:

Horseradish peroxidase

IFN:

Interferon

IKK:

Inhibitor of kappa B kinase

IL-1:

Interleukin-1

IL-1Ra:

Interleukin-1 receptor antagonist (protein)

IL1RN:

Interleukin-1 receptor antagonist (gene)

LPS:

Lipopolysaccharide

NF-κB:

Nuclear factor kappa-light-chain enhancer of activated B cells

NK:

Natural killer

OSA:

Obstructive sleep apnea

PFAPA:

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis

PSG:

Penicillin-streptomycin-glutamine

PVDF:

Polyvinylidene fluoride

RP:

Recurrent pharyngitis

RT-qPCR:

Reverse transcription quantitative polymerase chain reaction

SEM:

Standard error of mean

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

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Acknowledgments

The authors would like to acknowledge Dr. Hal M. Hoffman (University of California, San Diego) for helpful discussion, and the patients and families who participated.

Funding

This work was supported by National Institutes of Health 1K08HD075830-01A1 (L.B.), Thrasher Research Fund (L.B.), The Hartwell Foundation (L.B), and A.P. Giannini (L.B.).

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Author notes

  1. Irene Luu and Anukriti Sharma contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Division of Allergy, Immunology and Kawasaki Disease, University of California San Diego, La Jolla, CA, USA

    Irene Luu, Marisela Guaderrama, Michelle Peru & Lori Broderick

  2. Department of Pediatrics and Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA

    Anukriti Sharma & Jack A. Gilbert

  3. Rady Children’s Foundation, Rady Children’s Hospital, San Diego, San Diego, CA, 92123, USA

    Javan Nation, Nathan Page, Daniela Carvalho, Anthony Magit, Wen Jiang, Shelby Leuin, Morgan Bliss, Marcella Bothwell, Matthew Brigger, Donald Kearns, Seth Pransky & Lori Broderick

  4. Department of Surgery, Division of Otolaryngology, University of California San Diego, La Jolla, CA, USA

    Javan Nation, Nathan Page, Daniela Carvalho, Anthony Magit, Wen Jiang, Shelby Leuin, Morgan Bliss, Marcella Bothwell, Matthew Brigger, Donald Kearns & Seth Pransky

  5. Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA

    Robert Newbury

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  1. Irene Luu
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Contributions

All authors contributed to the study conception, design, and execution. Patient recruitment and securing of clinical material were performed by Javan Nation, Nathan Page, Daniela Carvalho, Anthony Magit, Wen Jiang, Shelby Leuin, Morgan Bliss, Marcella Bothwell, Matthew Brigger, Donald Kearns, Robert Newbury, Seth Pransky, and Lori Broderick. Ex vivo and in vitro experiments were performed by Lori Broderick, Irene Luu, and Marisela Guaderrama. Data collection and analysis were performed by Lori Broderick, Irene Luu, and Michelle Peru. Microbiome analysis was performed by Anukriti Sharma and Jack Gilbert. The first draft of the manuscript was written by Lori Broderick and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Lori Broderick.

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Conflict of Interest

L.B. is a speaker for Novartis, Inc., and has an ongoing research collaboration with Regeneron, Inc. The other authors declare no conflicts of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the UCSD Institutional Review Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Dr. Pransky is now affiliated with Pediatric Specialty Partners, La Jolla, CA

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Luu, I., Sharma, A., Guaderrama, M. et al. Immune Dysregulation in the Tonsillar Microenvironment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome. J Clin Immunol 40, 179–190 (2020). https://doi.org/10.1007/s10875-019-00724-2

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