Mathematical modeling of atopic dermatitis reveals "double-switch" mechanisms underlying 4 common disease phenotypes
Mathematical modeling of atopic dermatitis reveals "double-switch" mechanisms underlying 4 common disease phenotypes
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DOI：
10.1016/j.jaci.2016.10.026
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发表时间：
2017-06-01
影响因子：
14.2
通讯作者：
Tanaka, Reiko J.
中科院分区：
文献类型：
--
作者：
Dominguez-Huttinger, Elisa;Christodoulides, Panayiotis;Tanaka, Reiko J.
背景资料：皮肤屏障是抵御持续暴露于生物、微生物、物理和化学环境应激源的第一道防线。皮肤屏障缺陷、免疫应答功能障碍和环境应激因素之间的动态相互作用是特应性皮炎（AD）发展的主要因素。系统生物学建模方法可以通过整合先前的生物学数据来深入了解这些复杂的动态过程。目的：我们试图建立一个AD发病机制的多尺度数学模型，该模型描述了皮肤屏障、环境应激和免疫失调之间的动态相互作用，并使用它来实现对AD发病、进展和预防的连贯机制理解。方法：我们在数学上研究了已知的遗传和环境风险因素对AD表型的动态发病和进展的协同效应，从大多数无症状的轻度表型到严重的治疗抵抗形式。结果：我们的模型分析确定了一个“双开关”，具有2个串联的双开关，作为决定AD发病机制的关键网络基序：第一个开关负责炎症的可逆性发作，第二个开关由第一个开关的长期或频繁激活触发，导致全身T（H）2致敏的不可逆性发作和AD症状的恶化。我们对T（H）2开关的数学分析预测，遗传风险因素降低了环境应激触发系统性T（H）2致敏的阈值。该分析预测并解释了4种常见的临床AD表型，从轻度和可逆表型到重度和难治性疾病，并为临床证明的软化治疗对AD发展的预防作用提供了机制解释。
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, froma 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 T(H)2 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 T(H)2 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.