Quantitative Modeling of the Alternative Pathway of the Complement System

Abstract

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.

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

“…PMN also synthesize and secrete properdin (Fig. 5E), which, in combination with C3b membrane binding, amplifies convertase activity and C3a generation (54,56,57). Additionally, C3 can undergo direct cleavage by neutral and serine proteases, generating C3a (58,59).…”

Molecular crypsis by pathogenic fungi using human factor H. A numerical model

“…In the second part, we examine opsonization states of an individual infection scenario. This is done by adapting the quantitative model of human complement system described in Zewde et al (2016) to account for FH recruitment of pathogenic microbes. For the parameter values in the model, experiments were performed and complemented by data proposed in Zewde et al (2016) (Tables A1 and A2).…”

“…This is done by adapting the quantitative model of human complement system described in Zewde et al (2016) to account for FH recruitment of pathogenic microbes. For the parameter values in the model, experiments were performed and complemented by data proposed in Zewde et al (2016) (Tables A1 and A2). Our adapted model is used to predict physiological C3b opsonization states for the two microbial species Candida albicans and Escherichia coli, each in comparison to human erythrocytes.…”

“…To investigate C3b opsonization in a single infection scenario, we have adapted the models presented by Zewde et al (2016) and Korotaevskiy et al (2009) to account for FH surface acquisition of pathogens. Our adapted model focuses on the initial part of complement activation.…”

“…National Center for Health Statistics (NCHS), 2014). The remaining parameter values were taken from Zewde et al (2016). Altogether the parameter values were chosen so as to provide realistic estimates of the conditions encountered in the blood stream.…”