Mathematical Modeling of Atopic Dermatitis Reveals “Double switch” Mechanisms Underlying Four Common Disease Phenotypes

Publication date: Available online 5 December 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Elisa Domínguez-Hüttinger, Panayiotis Christodoulides, Kosuke Miyauchi, Alan D. Irvine, Mariko Okada-Hatakeyama, Masato Kubo, Reiko J. Tanaka
BackgroundThe 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.ObjectiveTo 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.MethodsWe 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.ResultsOur 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.ConclusionsOur 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.

Graphical abstract

Teaser

Mathematical models that integrate biological data can help explain complex pathogenic processes in AD, offering a coherent explanation of mechanisms behind four common AD phenotypes and the dynamic onset, progression, and prevention of AD.


http://ift.tt/2gyBROa