title: Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity.
abstract: BACKGROUND
  Atopic dermatitis (AD) is an inflammatory skin condition that can occur in early life, predisposing to asthma development in a phenomenon known as the atopic march. Although genetic and environmental factors are known to contribute to AD and asthma, the mechanisms underlying the atopic march remain poorly understood. Filaggrin loss-of-function mutations are a major genetic predisposer for the development of AD and progression to AD-associated asthma.
  
  
  OBJECTIVE
  We sought to experimentally address whether filaggrin mutations in mice lead to the development of spontaneous eczematous inflammation and address the aberrant immunologic milieu arising in a mouse model of filaggrin deficiency.
  
  
  METHODS
  Filaggrin mutant mice were generated on the proallergic BALB/c background, creating a novel model for the assessment of spontaneous AD-like inflammation. Independently recruited AD case collections were analyzed to define associations between filaggrin mutations and immunologic phenotypes.
  
  
  RESULTS
  Filaggrin-deficient mice on a BALB/c background had profound spontaneous AD-like inflammation with progression to compromised pulmonary function with age, reflecting the atopic march in patients with AD. Strikingly, skin inflammation occurs independently of adaptive immunity and is associated with cutaneous expansion of IL-5-producing type 2 innate lymphoid cells. Furthermore, subjects with filaggrin mutations have an increased frequency of type 2 innate lymphoid cells in the skin in comparison with control subjects.
  
  
  CONCLUSIONS
  This study provides new insights into our understanding of the atopic march, with innate immunity initiating dermatitis and the adaptive immunity required for subsequent development of compromised lung function.
authors: Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland.
authors: Sean P
authors: SP
authors: Saunders
authors: Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland.
authors: Tara
authors: T
authors: Moran
authors: Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland.
authors: Achilleas
authors: A
authors: Floudas
authors: Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland.
authors: Felicity
authors: F
authors: Wurlod
authors: Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland.
authors: Agnieszka
authors: A
authors: Kaszlikowska
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors: Maryam
authors: M
authors: Salimi
authors: Institute of Molecular Medicine, St James's Hospital, Dublin, Ireland.
authors: Emma M
authors: EM
authors: Quinn
authors: MRC Laboratory of Molecular Biology, Cambridge, United Kingdom; Biosceptre, Babraham Research Campus, Babraham, Cambridge, United Kingdom.
authors: Christopher J
authors: CJ
authors: Oliphant
authors: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Mich.
authors: Gabriel
authors: G
authors: Núñez
authors: Institute of Molecular Medicine, St James's Hospital, Dublin, Ireland.
authors: Ross
authors: R
authors: McManus
authors: Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland.
authors: Emily
authors: E
authors: Hams
authors: National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland; Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin, Ireland.
authors: Alan D
authors: AD
authors: Irvine
authors: MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors: Andrew N J
authors: AN
authors: McKenzie
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors: Graham S
authors: GS
authors: Ogg
authors: Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland; Institute of Molecular Medicine, St James's Hospital, Dublin, Ireland. Electronic address: pfallon@tcd.ie.
authors: Padraic G
authors: PG
authors: Fallon
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D003876:Dermatitis, Atopic / Q000150:complications* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D000091344:Filaggrin Proteins; D007113:Immunity, Innate; D007381:Intermediate Filament Proteins / Q000172:deficiency / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D011014:Pneumonia / Q000209:etiology* / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins
keywords: Allergy; asthma; atopic dermatitis; atopy; eczema; filaggrin; flaky tail; innate immunity; mouse; mutation; type 2 innate lymphoid cells