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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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Time profiles for complement regulators Factor H, CR1, DAF, vitronectin, clusterin, and CD59.(A, B) The concentrations of Factor H and CR1 decrease, with Factor H showing initially a linear like response. The initial response of Factor H signifies the regulation taking root at the start of the AP by inhibiting C3(H2O) and C3(H2O)Bb. (C) The concentration of DAF remains constant and does not change, which highlights the rapid deactivation of any C3b by FH and CR1. (D,E) Vitronectin and clusterin experience a long delay of 52 and 51 minutes respectively before their concentration starts decreasing. Their regulatory component takes root at the formation of fluid C5b-7, which comes at a later stage of complement activation. (F) The response generated for CD59 is the same as that of DAF (no change in concentration). This is expected since DAF remains the same (inhibition of C3 convertase formation), the terminal cascade for MAC pore formation will not take root because formation C5 convertases will also be inhibited.
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pone.0152337.g009: Time profiles for complement regulators Factor H, CR1, DAF, vitronectin, clusterin, and CD59.(A, B) The concentrations of Factor H and CR1 decrease, with Factor H showing initially a linear like response. The initial response of Factor H signifies the regulation taking root at the start of the AP by inhibiting C3(H2O) and C3(H2O)Bb. (C) The concentration of DAF remains constant and does not change, which highlights the rapid deactivation of any C3b by FH and CR1. (D,E) Vitronectin and clusterin experience a long delay of 52 and 51 minutes respectively before their concentration starts decreasing. Their regulatory component takes root at the formation of fluid C5b-7, which comes at a later stage of complement activation. (F) The response generated for CD59 is the same as that of DAF (no change in concentration). This is expected since DAF remains the same (inhibition of C3 convertase formation), the terminal cascade for MAC pore formation will not take root because formation C5 convertases will also be inhibited.

Mentions: Due to the destructive effects of the complement system on pathogens, the body has implemented several mechanisms to prevent its uncontrolled activation on host cells by using complement control proteins that are present in plasma and bound on host cell membranes. Fig 9 presents the results generated for fluid phase (Factor H, vitronectin, clusterin) and surface-bound (CR1, DAF, CD59) complement regulators. The time profile of the concentration of Factor H rapidly decreases (Fig 9A), while that of CR1 also decreases, but the decrease is not as rapid as Factor H. (Fig 9B). This is expected because despite the fact that both Factor H and CR1 regulate the initial complement protein of the alternative pathway, C3(H2O), Factor H has a higher binding affinity. In addition to regulating the hydrolyzed C3 (C3H2O), Factor H can also bind to C3bBb and C3(H2O)Bb to promote their rapid decay. Regulatory proteins on host cell membranes, such as CR1 and DAF also inhibit the formation and/or promote rapid dissociation of convertases [23–25]. While the concentration of CR1 decreases (Fig 9B), that of DAF does not change (Fig 9C). This highlights how rapidly CR1 and Factor H inactivate C3b to inhibit the formation of the C3 convertases on host cells and also their continued complement regulation in the fluid state. The time profiles of Factor H, CR1, and DAF at extended timeframes are shown in S6A–S6C Fig. If the formation of the C3 convertase is tightly controlled, one can conclude that the terminal cascade will be effectively shut down because the formation of the C5 convertase will also be inhibited.


Quantitative Modeling of the Alternative Pathway of the Complement System.

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

Time profiles for complement regulators Factor H, CR1, DAF, vitronectin, clusterin, and CD59.(A, B) The concentrations of Factor H and CR1 decrease, with Factor H showing initially a linear like response. The initial response of Factor H signifies the regulation taking root at the start of the AP by inhibiting C3(H2O) and C3(H2O)Bb. (C) The concentration of DAF remains constant and does not change, which highlights the rapid deactivation of any C3b by FH and CR1. (D,E) Vitronectin and clusterin experience a long delay of 52 and 51 minutes respectively before their concentration starts decreasing. Their regulatory component takes root at the formation of fluid C5b-7, which comes at a later stage of complement activation. (F) The response generated for CD59 is the same as that of DAF (no change in concentration). This is expected since DAF remains the same (inhibition of C3 convertase formation), the terminal cascade for MAC pore formation will not take root because formation C5 convertases will also be inhibited.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0152337.g009: Time profiles for complement regulators Factor H, CR1, DAF, vitronectin, clusterin, and CD59.(A, B) The concentrations of Factor H and CR1 decrease, with Factor H showing initially a linear like response. The initial response of Factor H signifies the regulation taking root at the start of the AP by inhibiting C3(H2O) and C3(H2O)Bb. (C) The concentration of DAF remains constant and does not change, which highlights the rapid deactivation of any C3b by FH and CR1. (D,E) Vitronectin and clusterin experience a long delay of 52 and 51 minutes respectively before their concentration starts decreasing. Their regulatory component takes root at the formation of fluid C5b-7, which comes at a later stage of complement activation. (F) The response generated for CD59 is the same as that of DAF (no change in concentration). This is expected since DAF remains the same (inhibition of C3 convertase formation), the terminal cascade for MAC pore formation will not take root because formation C5 convertases will also be inhibited.
Mentions: Due to the destructive effects of the complement system on pathogens, the body has implemented several mechanisms to prevent its uncontrolled activation on host cells by using complement control proteins that are present in plasma and bound on host cell membranes. Fig 9 presents the results generated for fluid phase (Factor H, vitronectin, clusterin) and surface-bound (CR1, DAF, CD59) complement regulators. The time profile of the concentration of Factor H rapidly decreases (Fig 9A), while that of CR1 also decreases, but the decrease is not as rapid as Factor H. (Fig 9B). This is expected because despite the fact that both Factor H and CR1 regulate the initial complement protein of the alternative pathway, C3(H2O), Factor H has a higher binding affinity. In addition to regulating the hydrolyzed C3 (C3H2O), Factor H can also bind to C3bBb and C3(H2O)Bb to promote their rapid decay. Regulatory proteins on host cell membranes, such as CR1 and DAF also inhibit the formation and/or promote rapid dissociation of convertases [23–25]. While the concentration of CR1 decreases (Fig 9B), that of DAF does not change (Fig 9C). This highlights how rapidly CR1 and Factor H inactivate C3b to inhibit the formation of the C3 convertases on host cells and also their continued complement regulation in the fluid state. The time profiles of Factor H, CR1, and DAF at extended timeframes are shown in S6A–S6C Fig. If the formation of the C3 convertase is tightly controlled, one can conclude that the terminal cascade will be effectively shut down because the formation of the C5 convertase will also be inhibited.

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