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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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Complement deposition on pathogen and host surfaces.Saturation of pathogen surface is reached in 54 minutes with complement proteins such as C3b, iC3b, iC3bP (pathogen), C3dg, C3/C5 convertases, properdin (P*), MAC, and intermediates such as C3bB, C3bBP, C5b6-7, C5b6-8, and others. Propagation of the alternative pathway is inhibited on host cells resulting in complement proteins occupying significantly less than 1 percent.
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pone.0152337.g002: Complement deposition on pathogen and host surfaces.Saturation of pathogen surface is reached in 54 minutes with complement proteins such as C3b, iC3b, iC3bP (pathogen), C3dg, C3/C5 convertases, properdin (P*), MAC, and intermediates such as C3bB, C3bBP, C5b6-7, C5b6-8, and others. Propagation of the alternative pathway is inhibited on host cells resulting in complement proteins occupying significantly less than 1 percent.

Mentions: Our model incorporates a set of rate equations that describes the biochemical reactions shown in Fig 1. The alternative pathway is activated by the tick-over reaction of C3 and leads to a C3b molecule that indiscriminately binds to host cells/pathogens and initiates a set of cascade reactions. Fig 2 shows the percentage of host and pathogenic cell surfaces occupied by complement components, including C3/C5 convertases, C3b, iC3b, iC3bP, C3dg, P*, MAC, and all intermediate species like C3bB, C3bBP, C5b6-7, C5b6-8, and others. A sigmoidal response is generated on the surface of pathogens that plateaus in 54 minutes. Preceding the robust activation, there was a lag phase of 11 minutes. Complement components occupy half of the available space on the pathogen surface in 24 minutes during the exponential phase of the sigmoidal response. However, due to the presence of complement regulators on host cells, significantly less than 1 percent of their surface is covered by complement components, as shown in Fig 2. Extended time profiles to 180 minutes are shown in S1 Fig. One of the main catalysts for the amplification loop in the alternative pathway is the production of C3 convertases that rapidly cleave C3 into C3a and C3b. Fig 3 shows the response generated for the initial (fluid phase) convertase, C3(H2O)Bb, and fluid phase convertase, fC3bBb. In 35 minutes, fC3bBb reaches a peak concentration of 4.6×10−13 M and starts declining to reach a concentration of 2.7×10−13 M in 60 minutes while C3(H2O)Bb reaches a concentration of 2.9×10−11 M in 35 minutes and continues to reach a concentration of 3.8×10−11 M in 60 minutes. Thus, C3(H2O)Bb seems to be the primary fluid phase convertase responsible for C3 cleavage, with significantly higher concentration than fC3bBb, despite possibly minor differences in their enzymatic activity against C3. Extended time frames to 180 minutes (S2 Fig), show that the concentration profile of both C3(H2O)Bb and fC3bBb flattens in 105 and 75 minutes, respectively, owed to the dissociation of Bb subunit and the regulatory action of Factor H that degrades formed convertases.


Quantitative Modeling of the Alternative Pathway of the Complement System.

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

Complement deposition on pathogen and host surfaces.Saturation of pathogen surface is reached in 54 minutes with complement proteins such as C3b, iC3b, iC3bP (pathogen), C3dg, C3/C5 convertases, properdin (P*), MAC, and intermediates such as C3bB, C3bBP, C5b6-7, C5b6-8, and others. Propagation of the alternative pathway is inhibited on host cells resulting in complement proteins occupying significantly less than 1 percent.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0152337.g002: Complement deposition on pathogen and host surfaces.Saturation of pathogen surface is reached in 54 minutes with complement proteins such as C3b, iC3b, iC3bP (pathogen), C3dg, C3/C5 convertases, properdin (P*), MAC, and intermediates such as C3bB, C3bBP, C5b6-7, C5b6-8, and others. Propagation of the alternative pathway is inhibited on host cells resulting in complement proteins occupying significantly less than 1 percent.
Mentions: Our model incorporates a set of rate equations that describes the biochemical reactions shown in Fig 1. The alternative pathway is activated by the tick-over reaction of C3 and leads to a C3b molecule that indiscriminately binds to host cells/pathogens and initiates a set of cascade reactions. Fig 2 shows the percentage of host and pathogenic cell surfaces occupied by complement components, including C3/C5 convertases, C3b, iC3b, iC3bP, C3dg, P*, MAC, and all intermediate species like C3bB, C3bBP, C5b6-7, C5b6-8, and others. A sigmoidal response is generated on the surface of pathogens that plateaus in 54 minutes. Preceding the robust activation, there was a lag phase of 11 minutes. Complement components occupy half of the available space on the pathogen surface in 24 minutes during the exponential phase of the sigmoidal response. However, due to the presence of complement regulators on host cells, significantly less than 1 percent of their surface is covered by complement components, as shown in Fig 2. Extended time profiles to 180 minutes are shown in S1 Fig. One of the main catalysts for the amplification loop in the alternative pathway is the production of C3 convertases that rapidly cleave C3 into C3a and C3b. Fig 3 shows the response generated for the initial (fluid phase) convertase, C3(H2O)Bb, and fluid phase convertase, fC3bBb. In 35 minutes, fC3bBb reaches a peak concentration of 4.6×10−13 M and starts declining to reach a concentration of 2.7×10−13 M in 60 minutes while C3(H2O)Bb reaches a concentration of 2.9×10−11 M in 35 minutes and continues to reach a concentration of 3.8×10−11 M in 60 minutes. Thus, C3(H2O)Bb seems to be the primary fluid phase convertase responsible for C3 cleavage, with significantly higher concentration than fC3bBb, despite possibly minor differences in their enzymatic activity against C3. Extended time frames to 180 minutes (S2 Fig), show that the concentration profile of both C3(H2O)Bb and fC3bBb flattens in 105 and 75 minutes, respectively, owed to the dissociation of Bb subunit and the regulatory action of Factor H that degrades formed convertases.

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