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Quantitative Modeling of the Alternative Pathway of the Complement System.

Zewde N, Gorham RD, Dorado A, Morikis D - PLoS ONE (2016)

Bottom Line: 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.Our model also depicts the intricate role that properdin released from neutrophils plays in initiating and propagating the alternative pathway during bacterial infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of California Riverside, Riverside, California, United States of America.

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.

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Formation of MAC pores is characterized by three phases: lag phase, production phase, and a steady state phase.The first 22 minutes present a lag phase that is followed by a rapid production of MAC pores, which plateaus in 54 minutes and occupies 3.3 percent of the pathogen surface. However, on host cells the MAC pores take significantly less than 1 percent.
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pone.0152337.g007: Formation of MAC pores is characterized by three phases: lag phase, production phase, and a steady state phase.The first 22 minutes present a lag phase that is followed by a rapid production of MAC pores, which plateaus in 54 minutes and occupies 3.3 percent of the pathogen surface. However, on host cells the MAC pores take significantly less than 1 percent.

Mentions: After the formation of the C5 convertase, a cascade of reactions is initiated that forms MAC. This complex produces pores that render the pathogen/host cell amenable to lysis. In Fig 7, the amount of formed MAC pores occupies 3.3 percent of total pathogen surface, while taking significantly less than 1 percent on the surface of a host cell. The MAC pore production on pathogens is characterized by three phases: lag phase, production phase, and a steady state phase. The lag phase is 22 minutes long and is followed by a pronounced production of MAC pores that plateaus in 54 minutes. It is worth noting the time frame for MAC pore production to plateau is the same as the time frame for covering the entire pathogen surface (Fig 7) by complement components (Fig 2). Furthermore, this process highlights the rapidity of complement cascade that leaves no more than 3.3 percent of the pathogen surface for MAC pores to take root, also shown at extended time frames of 180 minutes in S5 Fig.


Quantitative Modeling of the Alternative Pathway of the Complement System.

Zewde N, Gorham RD, Dorado A, Morikis D - PLoS ONE (2016)

Formation of MAC pores is characterized by three phases: lag phase, production phase, and a steady state phase.The first 22 minutes present a lag phase that is followed by a rapid production of MAC pores, which plateaus in 54 minutes and occupies 3.3 percent of the pathogen surface. However, on host cells the MAC pores take significantly less than 1 percent.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4816337&req=5

pone.0152337.g007: Formation of MAC pores is characterized by three phases: lag phase, production phase, and a steady state phase.The first 22 minutes present a lag phase that is followed by a rapid production of MAC pores, which plateaus in 54 minutes and occupies 3.3 percent of the pathogen surface. However, on host cells the MAC pores take significantly less than 1 percent.
Mentions: After the formation of the C5 convertase, a cascade of reactions is initiated that forms MAC. This complex produces pores that render the pathogen/host cell amenable to lysis. In Fig 7, the amount of formed MAC pores occupies 3.3 percent of total pathogen surface, while taking significantly less than 1 percent on the surface of a host cell. The MAC pore production on pathogens is characterized by three phases: lag phase, production phase, and a steady state phase. The lag phase is 22 minutes long and is followed by a pronounced production of MAC pores that plateaus in 54 minutes. It is worth noting the time frame for MAC pore production to plateau is the same as the time frame for covering the entire pathogen surface (Fig 7) by complement components (Fig 2). Furthermore, this process highlights the rapidity of complement cascade that leaves no more than 3.3 percent of the pathogen surface for MAC pores to take root, also shown at extended time frames of 180 minutes in S5 Fig.

Bottom Line: 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.Our model also depicts the intricate role that properdin released from neutrophils plays in initiating and propagating the alternative pathway during bacterial infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of California Riverside, Riverside, California, United States of America.

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.

Show MeSH
Related in: MedlinePlus