Zewde Nehemiah, Gorham Ronald D, Dorado Angel, Morikis Dimitrios
Department of Bioengineering, University of California Riverside, Riverside, California, United States of America.
Department of Mechanical Engineering, University of California Riverside, Riverside, California, United States of America.
PLoS One. 2016 Mar 31;11(3):e0152337. doi: 10.1371/journal.pone.0152337. eCollection 2016.
The complement system is an integral part of innate immunity that detects and eliminates invading pathogens through a cascade of reactions. The destructive effects of the complement activation on host cells are inhibited through versatile regulators that are present in plasma and bound to membranes. Impairment in the capacity of these regulators to function in the proper manner results in autoimmune diseases. To better understand the delicate balance between complement activation and regulation, we have developed a comprehensive quantitative model of the alternative pathway. Our model incorporates a system of ordinary differential equations that describes the dynamics of the four steps of the alternative pathway under physiological conditions: (i) initiation (fluid phase), (ii) amplification (surfaces), (iii) termination (pathogen), and (iv) regulation (host cell and fluid phase). We have examined complement activation and regulation on different surfaces, using the cellular dimensions of a characteristic bacterium (E. coli) and host cell (human erythrocyte). In addition, we have incorporated neutrophil-secreted properdin into the model highlighting the cross talk of neutrophils with the alternative pathway in coordinating innate immunity. Our study yields a series of time-dependent response data for all alternative pathway proteins, fragments, and complexes. We demonstrate the robustness of alternative pathway on the surface of pathogens in which complement components were able to saturate the entire region in about 54 minutes, while occupying less than one percent on host cells at the same time period. Our model reveals that tight regulation of complement starts in fluid phase in which propagation of the alternative pathway was inhibited through the dismantlement of fluid phase convertases. Our model also depicts the intricate role that properdin released from neutrophils plays in initiating and propagating the alternative pathway during bacterial infection.
补体系统是固有免疫的一个组成部分，通过一系列反应来检测和清除入侵的病原体。补体激活对宿主细胞的破坏作用通过血浆中存在的和与膜结合的多种调节因子来抑制。这些调节因子正常发挥功能的能力受损会导致自身免疫性疾病。为了更好地理解补体激活与调节之间的微妙平衡，我们建立了一个替代途径的综合定量模型。我们的模型包含一个常微分方程组，描述了生理条件下替代途径四个步骤的动态过程：(i) 起始（液相），(ii) 放大（表面），(iii) 终止（病原体），以及 (iv) 调节（宿主细胞和液相）。我们使用特征性细菌（大肠杆菌）和宿主细胞（人红细胞）的细胞尺寸，研究了不同表面上的补体激活和调节。此外，我们将中性粒细胞分泌的备解素纳入模型，突出了中性粒细胞与替代途径在协调固有免疫中的相互作用。我们的研究得出了所有替代途径蛋白质、片段和复合物的一系列时间依赖性反应数据。我们证明了替代途径在病原体表面的稳健性，其中补体成分能够在约54分钟内饱和整个区域，而在同一时间段内在宿主细胞上的占有率不到1%。我们的模型表明，补体的严格调节始于液相，在液相中替代途径的传播通过液相转化酶的拆解而受到抑制。我们的模型还描绘了中性粒细胞释放的备解素在细菌感染期间启动和传播替代途径中所起的复杂作用。
