title: Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade.
abstract: 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.
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Stojanov
authors.forename: Sivia
authors.initials: S
authors.lastname: Lapidus
authors.forename: Puja
authors.initials: P
authors.lastname: Chitkara
authors.forename: Henry
authors.initials: H
authors.lastname: Feder
authors.forename: Juan C
authors.initials: JC
authors.lastname: Salazar
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Brown
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Edwards
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ward
authors.forename: Robert A
authors.initials: RA
authors.lastname: Colbert
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Sun
authors.forename: Geryl M
authors.initials: GM
authors.lastname: Wood
authors.forename: Beverly K
authors.initials: BK
authors.lastname: Barham
authors.forename: Anne
authors.initials: A
authors.lastname: Jones
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.forename: Balu
authors.initials: B
authors.lastname: Athreya
authors.forename: Karyl S
authors.initials: KS
authors.lastname: Barron
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D005334:Fever / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D008199:Lymphadenitis / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D010612:Pharyngitis / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D013281:Stomatitis, Aphthous / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D007375:Interleukin-1