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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2018)

ABSTRACT OF THE THESIS

Tonsil-Specific Inflammation is Present in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) Syndrome

by

Irene M. Luu

Master of Science in Biology

University of California San Diego, 2018

Lori Broderick, Chair

Stephen M. Hedrick, Co-Chair

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a pediatric immune disorder with unknown pathogenesis that is characterized by recurrent fevers of fixed periodicity, without evidence of infection. Tonsillectomy has been shown to be curative. We hypothesize that PFAPA patients have a dysregulated innate immune system that results in the predictable flares. To characterize the innate immune mechanisms underlying PFAPA syndrome, we evaluated patient-derived tonsillar cells ex vivo and in vitro. Ex vivo analysis demonstrated increased IL-1 receptor antagonist (IL1RN) and tumor necrosis factor (TNF) gene expression in PFAPA tonsils, with persistent phosphorylation of IRF and NF-κB pathways. Febrile effects in vitro suggest an autoinflammatory feedback loop contributes to the pathogenesis behind PFAPA. Our results suggest that PFAPA patients experience ongoing subclinical inflammation in the tonsillar microenvironment, even during asymptomatic periods, and provide a mechanism for the success of tonsillectomy in this disease. The unique cytokine signature detected in the tonsil samples supports our recognition of PFAPA as an autoinflammatory disorder, but suggests the underlying pathology is of greater complexity than the previously described monogenic disorders. In addition, the distinct expression of cytokines in PFAPA tonsils compared to controls suggests that measurement of IL1RN and TNF expression, as performed in this study or in saliva may be a novel biomarker for the diagnosis of PFAPA.

    Cover page: Tonsil-Specific Inflammation is Present in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) syndrome
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2021)
    Autoinflammatory disorders of the innate immune system present with recurrent episodes of inflammation often beginning in early childhood. While there are now more than 30 genetically-defined hereditary fever disorders, many patients lack a clear diagnosis. Many pediatric patients are often grouped with patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome despite failing to meet diagnostic criteria. Here, we categorize these patients as syndrome of undifferentiated recurrent fever (SURF), and identify the unique features which distinguish them from the PFAPA syndrome. SURF patients were more likely to report gastrointestinal symptoms of nausea, vomiting and abdominal pain, and experienced inconsistent responses to on-demand steroid therapy compared to PFAPA patients. For this previously undefined cohort, an optimal course of therapy remains uncertain, with medical and surgical therapies largely driven by parental preference. A subset of patients with SURF underwent tonsillectomy with complete resolution. Flow cytometric evaluation demonstrates leukocytic populations distinct from PFAPA patients, with reduced CD3+ T cell numbers. SURF patient tonsils were predominantly characterized by an IL-1 signature compared to PFAPA, even during the afebrile period. Peripheral blood signatures were similar between groups suggesting that PFAPA and SURF patient tonsils have localized, persistent inflammation, without clinical symptoms. These data suggest that SURF is a heterogenous syndrome on the autoinflammatory disease spectrum.
      Cover page: Undifferentiated recurrent fevers in pediatrics are clinically distinct from PFAPA syndrome but retain an IL-1 signature
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2020)
      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.
        Cover page: Immune Dysregulation in the Tonsillar Microenvironment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome.
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