title: Filaggrin breakdown products determine corneocyte conformation in patients with atopic dermatitis.
abstract: BACKGROUND
  Loss-of-function (LOF) mutations in the filaggrin gene (FLG) are a well-replicated risk factor for atopic dermatitis (AD) and are known to cause an epidermal barrier defect. The nature of this barrier defect is not fully understood. Patients with AD with FLG LOF mutations are known to have more persistent disease, more severe disease, and greater risk of food allergies and eczema herpeticum. Abnormalities in corneocyte morphology have been observed in patients with AD, including prominent villus-like projections (VP); however, these ultrastructural features have not been systematically studied in patients with AD in relation to FLG genotype and acute and convalescent status.
  
  
  OBJECTIVE
  We sought to quantitatively explore the relationship between FLG genotype, filaggrin breakdown products (natural moisturizing factor [NMF]), and corneocyte morphology in patients with AD.
  
  
  METHODS
  We studied 15 children at first presentation of AD and after 6 weeks of standard therapy. We applied atomic force microscopy to study corneocyte conformation in patients with AD stratified by FLG status and NMF level. By using a new quantitative methodology, the number of VPs per investigated corneocyte area was assessed and expressed as the Dermal Texture Index score. Corneocytes were also labeled with an anti-corneodesmosin antibody and visualized with scanning electron microscopy.
  
  
  RESULTS
  We found a strong correlation between NMF levels and Dermal Texture Index scores in both acute and convalescent states (respective r = -0.80 and -0.75, P < .001 and P = .002). Most, but not all, VPs showed the presence of corneodesmosin abundantly all over the cell surface in homozygous/compound heterozygous FLG patients and, to a lesser extent, in heterozygous and wild-type patients.
  
  
  CONCLUSIONS
  NMF levels are highly correlated with corneocyte morphology in patients with AD. These corneocyte conformational changes shed further insight into the filaggrin-deficient phenotype and help explain the barrier defect in patients with AD with FLG LOF mutations.
authors.affiliation: Serend-ip GmbH, Munster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Riethmuller
authors.affiliation: Department of Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
authors.forename: Maeve A
authors.initials: MA
authors.lastname: McAleer
authors.affiliation: Coronel Institute of Occupational Health, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Sjors A
authors.initials: SA
authors.lastname: Koppes
authors.affiliation: University of Lyon 1, EA4169 "Fundamental, clinical and therapeutic aspects of the skin barrier function", Lyon, France.
authors.forename: Rawad
authors.initials: R
authors.lastname: Abdayem
authors.affiliation: Serend-ip GmbH, Munster, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Franz
authors.affiliation: University of Lyon 1, EA4169 "Fundamental, clinical and therapeutic aspects of the skin barrier function", Lyon, France.
authors.forename: Marek
authors.initials: M
authors.lastname: Haftek
authors.affiliation: Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee, United Kingdom.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Campbell
authors.affiliation: Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee, United Kingdom.
authors.forename: Stephanie F
authors.initials: SF
authors.lastname: MacCallum
authors.affiliation: Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee, United Kingdom.
authors.forename: W H Irwin
authors.initials: WHI
authors.lastname: McLean
authors.affiliation: Department of Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland; Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee, United Kingdom; Clinical Medicine, Trinity College Dublin, Dublin, Ireland. Electronic address: irvinea@tcd.ie.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
authors.affiliation: Coronel Institute of Occupational Health, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: s.kezic@amc.uva.nl.
authors.forename: Sanja
authors.initials: S
authors.lastname: Kezic
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003315:Cornea / Q000002:abnormalities* / Q000166:cytology / Q000648:ultrastructure; D003876:Dermatitis, Atopic / Q000235:genetics*; D005260:Female; D000091344:Filaggrin Proteins; D005838:Genotype; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018625:Microscopy, Atomic Force; D008855:Microscopy, Electron, Scanning; D009154:Mutation; D055815:Young Adult
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins
keywords: Skin barrier; atopic dermatitis; corneocyte; filaggrin; transepidermal water loss