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A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System

Liu, Bing; Zhang, Jing; Tan, Pei Yi; Hsu, David; Blom, Anna LU ; Leong, Benjamin; Sethi, Sunil; Ho, Bow; Ding, Jeak Ling and Thiagarajan, P. S. (2011) In PLoS Computational Biology 70(1).
Abstract
The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down-regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying... (More)
The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down-regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio-pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Computational Biology
volume
70
issue
1
publisher
Public Library of Science
external identifiers
  • wos:000286652100017
  • scopus:79551555770
ISSN
1553-7358
DOI
10.1371/journal.pcbi.1001059
language
English
LU publication?
yes
id
060fb9b5-dbd4-41b5-8a30-7b0a3ee3213e (old id 1878271)
date added to LUP
2011-04-27 09:53:13
date last changed
2017-09-17 03:44:40
@article{060fb9b5-dbd4-41b5-8a30-7b0a3ee3213e,
  abstract     = {The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down-regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio-pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system.},
  author       = {Liu, Bing and Zhang, Jing and Tan, Pei Yi and Hsu, David and Blom, Anna and Leong, Benjamin and Sethi, Sunil and Ho, Bow and Ding, Jeak Ling and Thiagarajan, P. S.},
  issn         = {1553-7358},
  language     = {eng},
  number       = {1},
  publisher    = {Public Library of Science},
  series       = {PLoS Computational Biology},
  title        = {A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System},
  url          = {http://dx.doi.org/10.1371/journal.pcbi.1001059},
  volume       = {70},
  year         = {2011},
}