Limits...
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.

Show MeSH

Related in: MedlinePlus

Time profile for the production of C3a and C5a.(A) The response generated for C3a shows a lag phase that is followed by an accelerated production phase. In 60 minutes, the amount of C3a produced is 108 times greater than that of C5a. (B) Zoom-in of panel (A) to show the time profile of C5a.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4816337&req=5

pone.0152337.g005: Time profile for the production of C3a and C5a.(A) The response generated for C3a shows a lag phase that is followed by an accelerated production phase. In 60 minutes, the amount of C3a produced is 108 times greater than that of C5a. (B) Zoom-in of panel (A) to show the time profile of C5a.

Mentions: As concentrations of the surface bound convertases decreases over time due to the Bb subunit dissociating and C3 convertase enzymes becoming C5 convertases (C3bBbC3b), the formation of C3bBbC3b initiates the cleavage process of C5a from C5. The total amount of anaphylatoxins C3a and C5a produced from C3 and C5 convertases are shown in Fig 5. Within 60 minutes, C3a reaches a concentration of 7.6×10−8 M while C5a reaches 8.4×10−16 M (Fig 5). We can see from the response generated that the amount of C3a produced in 1 hour is 108 times greater than C5a. However, C3a does plateau in 105 minutes with a concentration of 11.5×10−8 M while that of C5a reaches a concentration of 2.4×10−16 M within the same time frame (S4 Fig).


Quantitative Modeling of the Alternative Pathway of the Complement System.

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

Time profile for the production of C3a and C5a.(A) The response generated for C3a shows a lag phase that is followed by an accelerated production phase. In 60 minutes, the amount of C3a produced is 108 times greater than that of C5a. (B) Zoom-in of panel (A) to show the time profile of C5a.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0152337.g005: Time profile for the production of C3a and C5a.(A) The response generated for C3a shows a lag phase that is followed by an accelerated production phase. In 60 minutes, the amount of C3a produced is 108 times greater than that of C5a. (B) Zoom-in of panel (A) to show the time profile of C5a.
Mentions: As concentrations of the surface bound convertases decreases over time due to the Bb subunit dissociating and C3 convertase enzymes becoming C5 convertases (C3bBbC3b), the formation of C3bBbC3b initiates the cleavage process of C5a from C5. The total amount of anaphylatoxins C3a and C5a produced from C3 and C5 convertases are shown in Fig 5. Within 60 minutes, C3a reaches a concentration of 7.6×10−8 M while C5a reaches 8.4×10−16 M (Fig 5). We can see from the response generated that the amount of C3a produced in 1 hour is 108 times greater than C5a. However, C3a does plateau in 105 minutes with a concentration of 11.5×10−8 M while that of C5a reaches a concentration of 2.4×10−16 M within the same time frame (S4 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