School of Computing, National University of Singapore, Singapore.
PLoS Comput Biol. 2011 Jan 20;7(1):e1001059. doi: 10.1371/journal.pcbi.1001059.
The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down- regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio-pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system.
补体系统是先天免疫的关键，其激活对于清除细菌和凋亡细胞是必要的。然而，补体激活不足或过度会导致免疫相关疾病。目前尚不清楚补体活性是如何被上调或下调的，以及相关的病理生理机制是什么。为了定量理解补体系统的调节机制，我们构建了一个涉及增强和抑制机制的计算模型，以调节补体活性。我们的模型由一个包含大量常微分方程（ODE）的系统组成，以及一个动态贝叶斯网络作为 ODE 动力学的概率逼近。应用贝叶斯推断技术，该逼近用于执行参数估计和敏感性分析。我们的计算和实验综合研究表明，抗菌反应对 pH 值和钙水平的变化敏感，这决定了 CRP 和 L-岩藻糖结合蛋白之间串扰的强度。我们的研究还揭示了 C4BP 的差异调节作用。虽然 C4BP 会延迟但不会降低经典补体激活，但它会减弱但不会显著延迟凝集素途径的激活。我们还发现 C4BP 的主要抑制作用是促进 C3 转化酶的衰减。总之，本工作阐明了补体系统的调节机制，并展示了生物途径机制如何在激活和抑制之间维持平衡。我们获得的见解可能有助于开发针对补体系统的治疗方法。
