Mathematical Modeling of the Circadian Rhythm of Key Neuroendocrine-Immune System Players in Rheumatoid Arthritis A Systems Biology Approach
Mathematical Modeling of the Circadian Rhythm of Key Neuroendocrine-Immune System Players in Rheumatoid Arthritis A Systems Biology Approach
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DOI：
10.1002/art.24797
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发表时间：
2009-09-01
影响因子：
--
通讯作者：
Straub, Rainer H.
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文献类型：
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作者：
Meyer-Hermann, Michael;Figge, Marc Thilo;Straub, Rainer H.
objective.健康受试者和类风湿性关节炎（RA）患者表现出神经内分泌免疫系统的昼夜节律。由于神经内分泌免疫网络的非线性行为，理解昼夜节律动力学是复杂的。本研究进行了寻求和测试的数学模型，研究这个网络。我们建立了一个定量计算模型来模拟神经内分泌-免疫系统中的关键因素，如血浆肿瘤坏死因子（TNF）、血浆皮质醇（和肾上腺胆固醇储备）和血浆去甲肾上腺素（NA）（和突触前NA储备）之间的非线性相互作用。该模型与健康受试者和RA患者的测量参考数据很好地拟合。虽然个人的昼夜节律起搏器的皮质醇，NA和TNF的安装没有相移，这些因素之间的相对相移演变的结果建模的网络相互作用。结合长期和短期的TNF增加（“RA模型”）增加皮质醇血浆水平只有几天，胆固醇储存开始变得明显耗尽。这很好地证明了皮质醇分泌相对于血浆TNF水平不足的现象，这是肾上腺缺乏的结果。使用RA模型，发现在午夜至凌晨2：00之间用糖皮质激素治疗对TNF分泌具有最强的抑制作用，这支持了最近关于RA治疗的研究。通过模拟抗TNF治疗长期降低TNF水平使"RA"条件下胆固醇储存正常化。这些首次在计算机上研究神经内分泌免疫系统在风湿病学证明，计算生物学在医学上，利用大量的实验数据，支持复杂的非线性系统的病理生理学的理解。
Objective. Healthy subjects and patients with rheumatoid arthritis (RA) exhibit circadian rhythms of the neuroendocrine-immune system. Understanding circadian dynamics is complex due to the nonlinear behavior of the neuroendocrine-immune network. This study was undertaken to seek and test a mathematical model for studying this network.Methods. We established a quantitative computational model to simulate nonlinear interactions between key factors in the neuroendocrine-immune system, such as plasma tumor necrosis factor (TNF), plasma cortisol (and adrenal cholesterol store), and plasma noradrenaline (NA) (and presynaptic NA store).Results. The model was nicely fitted with measured reference data on healthy subjects and RA patients. Although the individual circadian pacemakers of cortisol, NA, and TNF were installed without a phase shift, the relative phase shift between these factors evolved as a consequence of the modeled network interactions. Combined long-term and short-term TNF increase (the "RA model") increased cortisol plasma levels for only a few days, and cholesterol stores started to become markedly depleted. This nicely demonstrated the phenomenon of inadequate cortisol secretion relative to plasma TNF levels, as a consequence of adrenal deficiency. Using the RA model, treatment with glucocorticoids between midnight and 2:00 AM was found to have the strongest inhibitory effect on TNF secretion, which supports recent studies on RA therapy. Longterm reduction of TNF levels by simulation of anti-TNF therapy normalized cholesterol stores under "RA" conditions.Conclusion. These first in silico studies of the neuroendocrine-immune system in rheumatology demonstrate that computational biology in medicine, making use of large collections of experimental data, supports understanding of the pathophysiology of complex nonlinear systems.