title: Epidermal filaggrin deficiency mediates increased systemic T-helper 17 immune response.
abstract: BACKGROUND
  Cellular T-helper (Th)17 infiltrates dominate skin inflammation in filaggrin-deficient flaky tail (ft/ft) mice, and Th17 cells are found in both the skin and blood of patients with acute atopic dermatitis. However, the potential role of loss-of-function mutations in the filaggrin gene (FLG) for increased peripheral Th17 cells is unclear.
  
  
  OBJECTIVE
  To study whether mutations in FLG influence the frequency of peripheral Th17 cells.
  
  
  METHODS
  We studied blood samples from six adults with mutations in FLG and five controls without mutations for frequencies of cytokine-producing CD4(+) T cells. We evaluated ft/ft mice and wild-type (WT) control mice for interleukin (IL)-17-producing CD4(+) T cells in naive mice and following 2,4-dinitrofluorobenzene (DNFB) challenge. In addition, the T-cell receptor (TCR) Vβ-chain repertoire was analysed by flow cytometry.
  
  
  RESULTS
  Human studies showed increased frequency of peripheral Th17 cells in FLG mutation carriers when compared with WT individuals. Mouse studies showed increased frequency of peripheral Th17 cells in adult ft/ft mice but not in 2-week-old ft/ft mice. Moreover, altered TCR Vβ-chain repertoire was found in ft/ft mice when compared with WT mice. An increased frequency of CD4(+) Vβ10(+) T cells producing IL-17 was found in the spleen of adult ft/ft mice when compared with WT mice. Finally, DNFB challenge induced an increased number of Th17 cells in ft/ft mice compared with WT mice.
  
  
  CONCLUSIONS
  Deficiency of filaggrin appeared to be a driver of increased peripheral levels of Th17 cells. This increase must be acquired as peripheral Th17 cells were found in adult ft/ft mice but not in 2-week-old ft/ft mice indicating involvement of exogenous factors.
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. cmenne@sund.ku.dk.
authors.forename: C M
authors.initials: CM
authors.lastname: Bonefeld
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: T H
authors.initials: TH
authors.lastname: Petersen
authors.affiliation: National Allergy Research Centre, Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Bandier
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Agerbeck
authors.affiliation: Research Centre for Prevention and Health, the Capital Region of Denmark, Copenhagen, Denmark.|Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Linneberg
authors.affiliation: National Allergy Research Centre, Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Ross-Hansen
authors.affiliation: Department of Clinical Biochemistry, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Stender
authors.affiliation: Department of Clinical Biochemistry, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: P B
authors.initials: PB
authors.lastname: Szecsi
authors.affiliation: National Allergy Research Centre, Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: J D
authors.initials: JD
authors.lastname: Johansen
authors.affiliation: Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Geisler
authors.affiliation: National Allergy Research Centre, Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: J P
authors.initials: JP
authors.lastname: Thyssen
mesh_terms: D000328:Adult; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives / Q000494:pharmacology; D000091344:Filaggrin Proteins; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000235:genetics / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics* / Q000276:immunology; D007381:Intermediate Filament Proteins / Q000172:deficiency* / Q000235:genetics; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics* / Q000276:immunology; D013154:Spleen / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; C045305:2,4-dinitrofluorobenzene sulfonic acid; D004139:Dinitrofluorobenzene