Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade

National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2011; 108(17):7148-53. DOI: 10.1073/pnas.1103681108
Source: PubMed


The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.

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Available from: Ivona Aksentijevich
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    • "It has been shown that AIM2 gene is overexpressed in PFAPA patients during flare compared to PFAPA patients in remission and healthy controls [5]. Given that IL-1í µí»½ pathway is involved in the PFAPA pathogenesis, it is likely that AIM2 gene could also play an important role in this syndrome. "
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    ABSTRACT: PFAPA syndrome is the most common autoinflammatory disorder in childhood with unknown etiology. The aim of our study was clinical evaluation of PFAPA patients from a single tertiary care center and to determine whether variations of AIM2, MEFV, NLRP3, and MVK genes are involved in PFAPA pathogenesis. Clinical and laboratory data of consecutive patients with PFAPA syndrome followed up at the University Children’s Hospital, Ljubljana, were collected from 2008 to 2014. All four genes were PCR amplified and directly sequenced. Eighty-one patients fulfilled criteria for PFAPA syndrome, 50 (63%) boys and 31 (37%) girls, with mean age at disease onset of 2.1 ± 1.5 years. Adenitis, pharyngitis, and aphthae were present in 94%, 98%, and 56%, respectively. Family history of recurrent fevers in childhood was positive in 78%.Nineteen variantswere found in 17/62 (27%) patients, 4 different variants in NLRP3 gene in 13 patients, and 6 different variants in MEFV gene in 5 patients, and 2 patients had 2 different variants.No variants of clinical significance were found in MVK and AIM2 genes. Our data suggest that PFAPA could be the result of multiple low-penetrant variants in different genes in combination with epigenetic and environmental factors leading to uniform clinical picture.
    Full-text · Article · Dec 2014 · Mediators of Inflammation
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    • "Like IL-1β, IL-6 induces the production of acute phase proteins, pyrexia and sickness behaviour [21,22]. The increased levels of CRP and serum amoyloid A, high fever and malaise following febrile attacks of PFAPA [4,8,9,12] may be attributed to the increase of IL-6. "
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    ABSTRACT: The Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis syndrome (PFAPA) is the most common periodic fever syndrome in childhood. Clinically, PFAPA may resemble autoinflammatory diseases, but the etiology is not fully understood. We measured inflammatory proteins in plasma and hematologic parameters in children with PFAPA during and between febrile episodes, and in a control group with suspected bacterial pneumonia. In children with PFAPA, a first blood sample was taken within 24 hours of a febrile episode and a second sample between episodes. In children with pneumonia, the first sample was taken shortly after admission and a second sample after full recovery. A total of 22 children with PFAPA and 14 children with pneumonia were included. In children with PFAPA, levels of interleukin (IL) 6, CXCL10 and CCL4 were significantly increased during febrile episodes. The levels of IL-6 and CXCL10 were higher in children with PFAPA during febrile episodes than in children with pneumonia. The levels of CXCL10 remained higher in children with PFAPA between febrile episodes compared to children with pneumonia after recovery. Children with PFAPA had a relative eosinopenia and lymphocytopenia with reduced numbers of both CD4+ and CD8+ T cells during febrile episodes. This pattern was not observed in the children with pneumonia. The results indicate an innate immune response as the initial step in PFAPA, and a subsequent adaptive response with activation and redistribution of T cells. Moreover, an activation of the innate immune system involving CXCL10 may persist between febrile episodes. CXCL10 may be a possibly clinical marker in children with PFAPA.
    Full-text · Article · Oct 2013 · Pediatric Rheumatology
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    • "Because of consequent abnormal control of an immune response to antigenic stimulation, the levels of pro-inflammatory cytokines, such as IL-6, IFN-γ, and IL-1β, increase markedly during episodes of fever, with smaller increases persisting between episodes [7], as was observed in our patient. In PFAPA syndrome, expression of complement-related genes, such as C1QB and IL-1-related genes, and genes induced by IFN-γ also increase during episodes of fever [6]. Serum concentrations of T cell-derived chemokine proteins also increase in relation to febrile responses [6]. "
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    ABSTRACT: Background A syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA), as well as immunoglobulin A nephropathy (IgAN), may be caused by autoimmune reactivity nephropathy. Case-diagnosis/treatment A 10-year-old boy presented with periodic fever, exudative tonsillitis, oral aphthous ulcer, and cervical lymph node inflammation. These conditions had occurred at intervals of about 2–6 weeks since the age of 3 years. Microscopic hematuria, first detected at age 8 years, worsened during episodes of PFAPA-related fever; since 10 years of age, the hematuria was accompanied by sustained proteinuria. Examination of a kidney biopsy specimen led to a diagnosis of IgAN. In the kidney specimen, fractalkine immunoreactivity and heavy macrophage infiltration were prominent. Multi-drug cocktail therapy improved the urinalysis findings, and subsequent tonsillectomy succeeded in controlling recurrences of PFAPA and IgAN. In a post-treatment renal biopsy specimen, mesangial proliferation was decreased, and fractalkine immunoreactivity was absent. Conclusion Immunologic reactions against certain antigens in local mucosa, including tonsils, may be impaired in PFAPA and IgAN, as evidenced by the suppression of both diseases in our patient by tonsillectomy. Accordingly, the concurrence of PFAPA and IgAN in our patient appeared to be a consequence of shared autoimmune mechanisms and systemic and local increases in cytokine concentrations, rather than coincidence.
    Full-text · Article · Sep 2012 · Pediatric Nephrology
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