title: Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells.
abstract: Mutations in the gene encoding filaggrin (FLG), an epidermal structural protein, are the strongest risk factor identified for the development of atopic dermatitis (AD). Up to 50% of patients with moderate-to-severe AD in European populations have FLG-null alleles compared with a general population frequency of 7% to 10%.
  
  
  
  This study aimed to investigate the relationship between FLG-null mutations and epidermal antigen-presenting cell (APC) maturation in subjects with and without AD. Additionally, we investigated whether the cis isomer of urocanic acid (UCA), a filaggrin breakdown product, exerts immunomodulatory effects on dendritic cells.
  
  
  
  Epidermal APCs from nonlesional skin were assessed by using flow cytometry (n = 27) and confocal microscopy (n = 16). Monocyte-derived dendritic cells from healthy volunteers were used to assess the effects of cis- and trans-UCA on dendritic cell phenotype by using flow cytometry (n = 11).
  
  
  
  Epidermal APCs from FLG-null subjects had increased CD11c expression. Confocal microscopy confirmed this and additionally revealed an increased number of epidermal CD83(+) Langerhans cells in FLG-null subjects. In vitro differentiation in the presence of cis-UCA significantly reduced costimulatory molecule expression on monocyte-derived dendritic cells from healthy volunteers and increased their ability to induce a regulatory T-cell phenotype in mixed lymphocyte reactions.
  
  
  
  We show that subjects with FLG-null mutations have more mature Langerhans cells in nonlesional skin irrespective of whether they have AD. We also demonstrate that cis-UCA reduces maturation of dendritic cells and increases their capacity to induce regulatory T cells, suggesting a novel link between filaggrin deficiency and immune dysregulation.
authors.affiliation: Department of Dermatology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Leitch
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Eenass
authors.initials: E
authors.lastname: Natafji
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Cunjing
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Dermatology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Sharizan
authors.initials: S
authors.lastname: Abdul-Ghaffar
authors.affiliation: Department of Dermatology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Nayani
authors.initials: N
authors.lastname: Madarasingha
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Zoë C
authors.initials: ZC
authors.lastname: Venables
authors.affiliation: Department of Dermatology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Roland
authors.initials: R
authors.lastname: Chu
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Fitch
authors.affiliation: Alan Lyell Centre for Dermatology, Southern General Hospital, Glasgow, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Muinonen-Martin
authors.affiliation: Centre for Dermatology and Genetic Medicine, University of Dundee, Dundee, United Kingdom.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Campbell
authors.affiliation: Centre for Dermatology and Genetic Medicine, University of Dundee, Dundee, United Kingdom.
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schwarze
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Howie
authors.affiliation: Department of Dermatology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: r.weller@ed.ac.uk.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Weller
mesh_terms: D000328:Adult; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers; D039521:CD11c Antigen / Q000378:metabolism; D002450:Cell Communication; D002454:Cell Differentiation / Q000235:genetics*; D018920:Coculture Techniques; D003876:Dermatitis, Atopic / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004817:Epidermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D000091344:Filaggrin Proteins; D005434:Flow Cytometry; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007381:Intermediate Filament Proteins / Q000235:genetics*; D007801:Langerhans Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D039521:CD11c Antigen; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D007073:Immunoglobulin E
keywords: Filaggrin; Langerhans cells; atopic dermatitis; costimulatory molecules; urocanic acid