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

The biochemical reactions of the alternative pathway.Fluid state activation of the alternative pathway leads to C3b that can indiscriminately bind to host or pathogen surface. On the right (pathogen), complement activity propagates without the disruption of regulatory proteins. On the left (host), plasma proteins in conjunction with surface-bound regulators actively inhibit complement propagation by disrupting complement interaction at different points of the alternative pathway. Abbreviations: C3, complement component 3; C3(H2O), thioester-hydrolyzed form of C3; C3(H2O)Bb, initial C3 convertase of AP; C3a, anaphylatoxin fragment from C3; C3b, activated fragment from C3; iC3b, inactivated C3b; nfC3b, nascent fluid phase C3b; nhC3b, nascent host C3b; npC3b, nascent pathogen C3b; fC3b, fluid phase C3b; fC3bBb, fluid phase C3 convertase, C3bBb, C3 convertase; C3bBbP, C3 convertase with properdin; C3bBbP*, C3 convertase with properdin* released from neutrophils; C5, complement component 5; C5a anaphylatoxin fragment from C5; C5b, activated fragment from C5; C3bBbC3b, C5 convertase; FB, Factor B; FD, Factor D; FI, Factor I; CR1, Complement Receptor 1; DAF, Decay Accelerating Factor; Vn, vitronectin; Cn, clusterin; CD59, Protectin. Lines and colors: solid lines with an arrow tip denote activation and dashed lines with a straight tip denote inhibition. Red line color denotes inhibition. The rest of line colors denote clusters of reactions involving different C3b molecules, i.e. nhC3b (orange), nfC3b (light blue), npC3b (purple), fC3b (dark blue).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0152337.g001: The biochemical reactions of the alternative pathway.Fluid state activation of the alternative pathway leads to C3b that can indiscriminately bind to host or pathogen surface. On the right (pathogen), complement activity propagates without the disruption of regulatory proteins. On the left (host), plasma proteins in conjunction with surface-bound regulators actively inhibit complement propagation by disrupting complement interaction at different points of the alternative pathway. Abbreviations: C3, complement component 3; C3(H2O), thioester-hydrolyzed form of C3; C3(H2O)Bb, initial C3 convertase of AP; C3a, anaphylatoxin fragment from C3; C3b, activated fragment from C3; iC3b, inactivated C3b; nfC3b, nascent fluid phase C3b; nhC3b, nascent host C3b; npC3b, nascent pathogen C3b; fC3b, fluid phase C3b; fC3bBb, fluid phase C3 convertase, C3bBb, C3 convertase; C3bBbP, C3 convertase with properdin; C3bBbP*, C3 convertase with properdin* released from neutrophils; C5, complement component 5; C5a anaphylatoxin fragment from C5; C5b, activated fragment from C5; C3bBbC3b, C5 convertase; FB, Factor B; FD, Factor D; FI, Factor I; CR1, Complement Receptor 1; DAF, Decay Accelerating Factor; Vn, vitronectin; Cn, clusterin; CD59, Protectin. Lines and colors: solid lines with an arrow tip denote activation and dashed lines with a straight tip denote inhibition. Red line color denotes inhibition. The rest of line colors denote clusters of reactions involving different C3b molecules, i.e. nhC3b (orange), nfC3b (light blue), npC3b (purple), fC3b (dark blue).

Mentions: The complement system is one of our primary defense mechanisms that plays a vital role in coordinating immune responses. Complement function and regulation are induced by more than 30 distinct proteins present in plasma and on cell surfaces. The soluble proteins normally circulate as inactive precursors but once stimulated initiate cascades of biochemical reactions that propagate the activation of the complement system through three distinct pathways, the classical (CP), lectin (LP), and alternative (AP) pathways. The activation of these pathways leads to recognition and elimination of invading pathogens, recruitment of adaptive immunity, and facilitation of the removal of apoptotic cells [1–4]. Despite having similar roles, all three pathways have different sources for activation. The classical pathway is triggered by C1q binding to antigen-bound antibody complexes and also by direct attachment of C1q to pathogen surfaces. This leads to the production of C4b and C2a, which together form the C3 cleaving enzyme of the classical pathway, C4bC2a, called C3 convertase. Upon enzymatic cleavage, C3 is converted to the anaphylactic peptide C3a and opsonin C3b, which covalently attaches to cell surfaces via a thioester bond. The lectin pathway is activated by binding of mannose-binding lectin (MBL) with carbohydrate structures on bacterial and viral surfaces. This pathway is homologous to the classical pathway since the lectin pathway initiates complement cascade using MBL, a protein that is similar to C1q. The lectin pathway also forms the C3 convertase C4bC2a. Finally, the alternative pathway activation starts in the fluid phase by the spontaneous hydrolysis of the internal thioester bond of C3 to form a molecule known as hydrolyzed C3, C3(H2O). This molecule follows a cascade of reactions that involves complement proteins Factor B and Factor D to form the initial C3 convertase of the alternative pathway, C3(H2O)Bb. This protease complex like its counterparts in the classical and lectin pathway also generates C3a and C3b fragments by cleaving C3. Once C3b attaches to the surface of the pathogen it plays a crucial role in initiating a robust AP activation that results in an amplification loop. The cleavage of C3 is the convergence point of all three activation pathways and the initiation point of the common pathway towards the formation of the membrane attack complex that produces a pore on the surface of pathogens to cause lysis. Fig 1 shows the set of biochemical reactions involved in the alternative pathway through its initiation in the fluid phase, continued propagation on pathogen surface, and regulation on host cell.


Quantitative Modeling of the Alternative Pathway of the Complement System.

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

The biochemical reactions of the alternative pathway.Fluid state activation of the alternative pathway leads to C3b that can indiscriminately bind to host or pathogen surface. On the right (pathogen), complement activity propagates without the disruption of regulatory proteins. On the left (host), plasma proteins in conjunction with surface-bound regulators actively inhibit complement propagation by disrupting complement interaction at different points of the alternative pathway. Abbreviations: C3, complement component 3; C3(H2O), thioester-hydrolyzed form of C3; C3(H2O)Bb, initial C3 convertase of AP; C3a, anaphylatoxin fragment from C3; C3b, activated fragment from C3; iC3b, inactivated C3b; nfC3b, nascent fluid phase C3b; nhC3b, nascent host C3b; npC3b, nascent pathogen C3b; fC3b, fluid phase C3b; fC3bBb, fluid phase C3 convertase, C3bBb, C3 convertase; C3bBbP, C3 convertase with properdin; C3bBbP*, C3 convertase with properdin* released from neutrophils; C5, complement component 5; C5a anaphylatoxin fragment from C5; C5b, activated fragment from C5; C3bBbC3b, C5 convertase; FB, Factor B; FD, Factor D; FI, Factor I; CR1, Complement Receptor 1; DAF, Decay Accelerating Factor; Vn, vitronectin; Cn, clusterin; CD59, Protectin. Lines and colors: solid lines with an arrow tip denote activation and dashed lines with a straight tip denote inhibition. Red line color denotes inhibition. The rest of line colors denote clusters of reactions involving different C3b molecules, i.e. nhC3b (orange), nfC3b (light blue), npC3b (purple), fC3b (dark blue).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0152337.g001: The biochemical reactions of the alternative pathway.Fluid state activation of the alternative pathway leads to C3b that can indiscriminately bind to host or pathogen surface. On the right (pathogen), complement activity propagates without the disruption of regulatory proteins. On the left (host), plasma proteins in conjunction with surface-bound regulators actively inhibit complement propagation by disrupting complement interaction at different points of the alternative pathway. Abbreviations: C3, complement component 3; C3(H2O), thioester-hydrolyzed form of C3; C3(H2O)Bb, initial C3 convertase of AP; C3a, anaphylatoxin fragment from C3; C3b, activated fragment from C3; iC3b, inactivated C3b; nfC3b, nascent fluid phase C3b; nhC3b, nascent host C3b; npC3b, nascent pathogen C3b; fC3b, fluid phase C3b; fC3bBb, fluid phase C3 convertase, C3bBb, C3 convertase; C3bBbP, C3 convertase with properdin; C3bBbP*, C3 convertase with properdin* released from neutrophils; C5, complement component 5; C5a anaphylatoxin fragment from C5; C5b, activated fragment from C5; C3bBbC3b, C5 convertase; FB, Factor B; FD, Factor D; FI, Factor I; CR1, Complement Receptor 1; DAF, Decay Accelerating Factor; Vn, vitronectin; Cn, clusterin; CD59, Protectin. Lines and colors: solid lines with an arrow tip denote activation and dashed lines with a straight tip denote inhibition. Red line color denotes inhibition. The rest of line colors denote clusters of reactions involving different C3b molecules, i.e. nhC3b (orange), nfC3b (light blue), npC3b (purple), fC3b (dark blue).
Mentions: The complement system is one of our primary defense mechanisms that plays a vital role in coordinating immune responses. Complement function and regulation are induced by more than 30 distinct proteins present in plasma and on cell surfaces. The soluble proteins normally circulate as inactive precursors but once stimulated initiate cascades of biochemical reactions that propagate the activation of the complement system through three distinct pathways, the classical (CP), lectin (LP), and alternative (AP) pathways. The activation of these pathways leads to recognition and elimination of invading pathogens, recruitment of adaptive immunity, and facilitation of the removal of apoptotic cells [1–4]. Despite having similar roles, all three pathways have different sources for activation. The classical pathway is triggered by C1q binding to antigen-bound antibody complexes and also by direct attachment of C1q to pathogen surfaces. This leads to the production of C4b and C2a, which together form the C3 cleaving enzyme of the classical pathway, C4bC2a, called C3 convertase. Upon enzymatic cleavage, C3 is converted to the anaphylactic peptide C3a and opsonin C3b, which covalently attaches to cell surfaces via a thioester bond. The lectin pathway is activated by binding of mannose-binding lectin (MBL) with carbohydrate structures on bacterial and viral surfaces. This pathway is homologous to the classical pathway since the lectin pathway initiates complement cascade using MBL, a protein that is similar to C1q. The lectin pathway also forms the C3 convertase C4bC2a. Finally, the alternative pathway activation starts in the fluid phase by the spontaneous hydrolysis of the internal thioester bond of C3 to form a molecule known as hydrolyzed C3, C3(H2O). This molecule follows a cascade of reactions that involves complement proteins Factor B and Factor D to form the initial C3 convertase of the alternative pathway, C3(H2O)Bb. This protease complex like its counterparts in the classical and lectin pathway also generates C3a and C3b fragments by cleaving C3. Once C3b attaches to the surface of the pathogen it plays a crucial role in initiating a robust AP activation that results in an amplification loop. The cleavage of C3 is the convergence point of all three activation pathways and the initiation point of the common pathway towards the formation of the membrane attack complex that produces a pore on the surface of pathogens to cause lysis. Fig 1 shows the set of biochemical reactions involved in the alternative pathway through its initiation in the fluid phase, continued propagation on pathogen surface, and regulation on host cell.

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