Imperial College London
Portrait Picture

Professor Reiko J. Tanaka

Faculty of Engineering, Department of Bioengineering

Professor of Computational Systems Biology & Medicine
 
 
 
//

Contact

 

+44 (0)20 7594 6374r.tanaka Website

 
 
//

Location

 

RSM 3.10Royal School of MinesSouth Kensington Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Domínguez-Hüttinger:2017:10.1016/j.jaci.2016.10.026,
author = {Domínguez-Hüttinger, E and Christodoulides, P and Miyauchi, K and Irvine, AD and Okada-Hatakeyama, M and Kubo, M and Tanaka, RJ},
doi = {10.1016/j.jaci.2016.10.026},
journal = {Journal of Allergy and Clinical Immunology},
pages = {1861--1872.e7},
title = {Mathematical modeling of atopic dermatitis reveals "double switch" mechanisms underlying 4 common disease phenotypes},
url = {http://dx.doi.org/10.1016/j.jaci.2016.10.026},
volume = {139},
year = {2017}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Domínguez-Hüttinger,E
AU  - Christodoulides,P
AU  - Miyauchi,K
AU  - Irvine,AD
AU  - Okada-Hatakeyama,M
AU  - Kubo,M
AU  - Tanaka,RJ
DO  - 10.1016/j.jaci.2016.10.026
EP  - 1872
PY  - 2017///
SN  - 0091-6749
SP  - 1861
TI  - Mathematical modeling of atopic dermatitis reveals "double switch" mechanisms underlying 4 common disease phenotypes
T2  - Journal of Allergy and Clinical Immunology
UR  - http://dx.doi.org/10.1016/j.jaci.2016.10.026
UR  - https://www.jacionline.org/article/S0091-6749(16)31433-6/fulltext
UR  - http://hdl.handle.net/10044/1/42181
VL  - 139
ER  -
Download