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A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System
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...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024260/ https://www.ncbi.nlm.nih.gov/pubmed/21283780 http://dx.doi.org/10.1371/journal.pcbi.1001059 |
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author | Liu, Bing Zhang, Jing Tan, Pei Yi Hsu, David Blom, Anna M. Leong, Benjamin Sethi, Sunil Ho, Bow Ding, Jeak Ling Thiagarajan, P. S. |
author_facet | Liu, Bing Zhang, Jing Tan, Pei Yi Hsu, David Blom, Anna M. Leong, Benjamin Sethi, Sunil Ho, Bow Ding, Jeak Ling Thiagarajan, P. S. |
author_sort | Liu, Bing |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-3024260 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30242602011-01-31 A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System Liu, Bing Zhang, Jing Tan, Pei Yi Hsu, David Blom, Anna M. Leong, Benjamin Sethi, Sunil Ho, Bow Ding, Jeak Ling Thiagarajan, P. S. PLoS Comput Biol Research Article 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. Public Library of Science 2011-01-20 /pmc/articles/PMC3024260/ /pubmed/21283780 http://dx.doi.org/10.1371/journal.pcbi.1001059 Text en Liu et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Liu, Bing Zhang, Jing Tan, Pei Yi Hsu, David Blom, Anna M. Leong, Benjamin Sethi, Sunil Ho, Bow Ding, Jeak Ling Thiagarajan, P. S. A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System |
title | A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System |
title_full | A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System |
title_fullStr | A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System |
title_full_unstemmed | A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System |
title_short | A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System |
title_sort | computational and experimental study of the regulatory mechanisms of the complement system |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024260/ https://www.ncbi.nlm.nih.gov/pubmed/21283780 http://dx.doi.org/10.1371/journal.pcbi.1001059 |
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