title: A computational and experimental study of the regulatory mechanisms of the complement system.
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.
authors.affiliation: School of Computing, National University of Singapore, Singapore.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Pei Yi
authors.initials: PY
authors.lastname: Tan
authors.forename: David
authors.initials: D
authors.lastname: Hsu
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leong
authors.forename: Sunil
authors.initials: S
authors.lastname: Sethi
authors.forename: Bow
authors.initials: B
authors.lastname: Ho
authors.forename: Jeak Ling
authors.initials: JL
authors.lastname: Ding
authors.forename: P S
authors.initials: PS
authors.lastname: Thiagarajan
mesh_terms: D001499:Bayes Theorem; D003165:Complement System Proteins / Q000502:physiology*; D008962:Models, Theoretical
chemical_list: D003165:Complement System Proteins