title: Mathematical modeling of atopic dermatitis reveals "double-switch" mechanisms underlying 4 common disease phenotypes.
abstract: BACKGROUND
  The skin barrier acts as the first line of defense against constant exposure to biological, microbial, physical, and chemical environmental stressors. Dynamic interplay between defects in the skin barrier, dysfunctional immune responses, and environmental stressors are major factors in the development of atopic dermatitis (AD). A systems biology modeling approach can yield significant insights into these complex and dynamic processes through integration of prior biological data.
  
  
  OBJECTIVE
  We sought to develop a multiscale mathematical model of AD pathogenesis that describes the dynamic interplay between the skin barrier, environmental stress, and immune dysregulation and use it to achieve a coherent mechanistic understanding of the onset, progression, and prevention of AD.
  
  
  METHODS
  We mathematically investigated synergistic effects of known genetic and environmental risk factors on the dynamic onset and progression of the AD phenotype, from a mostly asymptomatic mild phenotype to a severe treatment-resistant form.
  
  
  RESULTS
  Our model analysis identified a "double switch," with 2 concatenated bistable switches, as a key network motif that dictates AD pathogenesis: the first switch is responsible for the reversible onset of inflammation, and the second switch is triggered by long-lasting or frequent activation of the first switch, causing irreversible onset of systemic TH2 sensitization and worsening of AD symptoms.
  
  
  CONCLUSIONS
  Our mathematical analysis of the bistable switch predicts that genetic risk factors decrease the threshold of environmental stressors to trigger systemic TH2 sensitization. This analysis predicts and explains 4 common clinical AD phenotypes from a mild and reversible phenotype through to severe and recalcitrant disease and provides a mechanistic explanation for clinically demonstrated preventive effects of emollient treatments against development of AD.
authors.affiliation: Department of Bioengineering, Imperial College London, London, United Kingdom; Instituto de Ecología, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: Elisa
authors.initials: E
authors.lastname: Domínguez-Hüttinger
authors.affiliation: Department of Bioengineering, Imperial College London, London, United Kingdom.
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Christodoulides
authors.affiliation: Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Miyauchi
authors.affiliation: National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland; Paediatric Dermatology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland; Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
authors.affiliation: Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Okada-Hatakeyama
authors.affiliation: Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan; Research Institute for Biomedical Science, Tokyo University of Science, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Bioengineering, Imperial College London, London, United Kingdom. Electronic address: r.tanaka@imperial.ac.uk.
authors.forename: Reiko J
authors.initials: RJ
authors.lastname: Tanaka
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D003876:Dermatitis, Atopic / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D004643:Emollients / Q000627:therapeutic use; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides; D018345:Mice, Knockout; D008954:Models, Biological; D010047:Ovalbumin / Q000276:immunology; D010641:Phenotype; D012307:Risk Factors; D050796:STAT3 Transcription Factor / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000485:Allergens; D004643:Emollients; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D007073:Immunoglobulin E; D010047:Ovalbumin
keywords: Atopic dermatitis; disease phenotypes; disease progression; double switch; mathematical models; preventive treatment