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

In English

Författare

  • Bing Liu
  • Jing Zhang
  • Pei Yi Tan
  • David Hsu
  • Anna Blom
  • Benjamin Leong
  • Sunil Sethi
  • Bow Ho
  • Jeak Ling Ding
  • P. S. Thiagarajan

Summary, in English

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.

Publiceringsår

2011

Språk

Engelska

Publikation/Tidskrift/Serie

PLoS Computational Biology

Volym

70

Issue

1

Dokumenttyp

Artikel i tidskrift

Förlag

Public Library of Science (PLoS)

Ämne

  • Bioinformatics and Systems Biology

Status

Published

Forskningsgrupp

  • Protein Chemistry, Malmö

ISBN/ISSN/Övrigt

  • ISSN: 1553-7358