Atopic dermatitis and skin disease
Mathematical modeling of atopic dermatitis reveals “double-switch” mechanisms underlying 4 common disease phenotypes

https://doi.org/10.1016/j.jaci.2016.10.026Get rights and content
Under a Creative Commons license
open access

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.

Key words

Atopic dermatitis
mathematical models
double switch
disease progression
disease phenotypes
preventive treatment

Abbreviations used

AD
Atopic dermatitis
DC
Dendritic cell
Flg
Filaggrin gene
ft
Flaky tail
NF-κB
Nuclear factor κB
OVA
Ovalbumin
Stat3
Signal transducer and activator of transcription 3
TLR
Toll-like receptor
WT
Wild-type

Cited by (0)

Supported by the Engineering and Physical Sciences Research Council of the United Kingdom (EP/G007446/1 to R.J.T.), the Mexican Council for Science and Technology (PhD scholarship 212800 to E.D.-H.), and the National Autonomous University of Mexico (postdoctoral scholarship to E.D.-H.).

Disclosure of potential conflict of interest: E. Domínguez-Hüttinger's institution and she herself have received grants from the Mexican Council for Science and Technology (CONACyT, PhD scholarship 212800), and she has received the RISP travel grant from Riken. A. D. Irvine has received a grant from the National Children's Research Centre. R. J. Tanaka's institution has received a grant from the Engineering and Physical Sciences Research Council, United Kingdom (EG/G007446/1). The rest of the authors declare that they have no relevant conflicts of interest.