Mathematical modeling of atopic dermatitis reveals "double switch" mechanisms underlying 4 common disease phenotypes
File(s)
Published version
Accepted version
Author(s)
Type
Journal Article
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: To develop a multi-scale 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 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 two concatenated bistable switches, as a key network motif that dictates AD pathogenesis: The first switch is responsible for the reversible onset of inflammation; The second switch is triggered by long-lasting or frequent activation of the first switch, causing the irreversible onset of systemic Th2 sensitization and worsening of AD symptoms.
Conclusions: Our mathematical analysis of the bistable switch predicts that genetic risk factors lower the threshold of environmental stressors to trigger systemic Th2 sensitization. This analysis predicts and explains four 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.
Objective: To develop a multi-scale 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 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 two concatenated bistable switches, as a key network motif that dictates AD pathogenesis: The first switch is responsible for the reversible onset of inflammation; The second switch is triggered by long-lasting or frequent activation of the first switch, causing the irreversible onset of systemic Th2 sensitization and worsening of AD symptoms.
Conclusions: Our mathematical analysis of the bistable switch predicts that genetic risk factors lower the threshold of environmental stressors to trigger systemic Th2 sensitization. This analysis predicts and explains four 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.
Date Issued
2017-06-01
Date Acceptance
2016-10-26
Citation
Journal of Allergy and Clinical Immunology, 2017, 139 (6), pp.1861-1872.e7
ISSN
0091-6749
Publisher
Elsevier
Start Page
1861
End Page
1872.e7
Journal / Book Title
Journal of Allergy and Clinical Immunology
Volume
139
Issue
6
Copyright Statement
© 2016 The Authors. Published by Elsevier Inc. on behalf of the American Academy
of Allergy, Asthma & Immunology. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).
of Allergy, Asthma & Immunology. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).
License URL
Sponsor
Engineering & Physical Science Research Council (EPSRC)
Riken
Identifier
https://www.jacionline.org/article/S0091-6749(16)31433-6/fulltext
Grant Number
EP/G007446/1
BMPF_P50964
Subjects
Science & Technology
Life Sciences & Biomedicine
Allergy
Immunology
Atopic dermatitis
mathematical models
double switch
disease progression
disease phenotypes
preventive treatment
PERMEABILITY BARRIER HOMEOSTASIS
STRATUM-CORNEUM
SKIN BARRIER
EPIDERMAL PERMEABILITY
MURINE MODEL
FILAGGRIN
EXPRESSION
GENE
CELLS
GATA-3
Atopic dermatitis
disease phenotypes
disease progression
double switch
mathematical models
preventive treatment
Allergens
Animals
Dermatitis, Atopic
Emollients
Humans
Immunoglobulin E
Lipopolysaccharides
Mice, Knockout
Models, Biological
Ovalbumin
Phenotype
Risk Factors
STAT3 Transcription Factor
Skin
Skin
Animals
Mice, Knockout
Humans
Dermatitis, Atopic
Lipopolysaccharides
Ovalbumin
Immunoglobulin E
Emollients
Allergens
Risk Factors
Phenotype
Models, Biological
STAT3 Transcription Factor
1107 Immunology
Allergy
Publication Status
Published
Date Publish Online
2016-12-05