Mathematical Modelling of Alternative Pathway of Complement System

Bulletin of Mathematical Biology, vol. 82, pp. 33

Abstract

The complement system (CS) is an integral part of innate immunity and can be activated via three different pathways. The alternative pathway (AP) has a central role in the function of the CS. The AP of complement system is implicated in several human disease pathologies. In the absence of triggers, the AP exists in a time-invariant resting state (physiological steady state). It is capable of rapid, potent and transient activation response upon challenge with a trigger. Previous models of AP have focused on the activation response. In order to understand the molecular machinery necessary for AP activation and regulation of a physiological steady state, we built parsimonious AP models using experimentally supported kinetic parameters. The models further allowed us to test quantitative roles played by negative and positive regulators of the pathway in order to test hypotheses regarding their mechanisms of action, thus providing more insight into the complex regulation of AP.

Authors 11

1. Suruchi Bakshi corresponding Aachen Division of Systems Biomedicine and Pharmacology

   Leiden University

   Affiliation as printed

   Certara QSP, 4818 SJ, Breda, The Netherlands. suruchi.bakshi@certara.com

   Division of Systems Biomedicine and Pharmacology, LACDR, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands. suruchi.bakshi@certara.com

   Division of Systems Biomedicine and Pharmacology, LACDR, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands

2. Fraser Cunningham

   GlaxoSmithKline (United Kingdom)

   Affiliation as printed

   Cytokine, Chemokine and Complement DPU, Immunoinflammation TA Unit, GSK, Stevenage, UK

3. Eva-Maria Nichols

   GlaxoSmithKline (United Kingdom)

   Affiliation as printed

   Cytokine, Chemokine and Complement DPU, Immunoinflammation TA Unit, GSK, Stevenage, UK

4. Marta Biedzka-Sarek

   GlaxoSmithKline (United Kingdom)

   Affiliation as printed

   Cytokine, Chemokine and Complement DPU, Immunoinflammation TA Unit, GSK, Stevenage, UK

5. Jessica Neisen

   GlaxoSmithKline (United Kingdom)

   Affiliation as printed

   Cytokine, Chemokine and Complement DPU, Immunoinflammation TA Unit, GSK, Stevenage, UK

6. Sebastien Petit-Frere

   GlaxoSmithKline (United Kingdom)

   Affiliation as printed

   Cytokine, Chemokine and Complement DPU, Immunoinflammation TA Unit, GSK, Stevenage, UK

7. Christina M. Bessant

   GlaxoSmithKline (United Kingdom)

   Affiliation as printed

   Cytokine, Chemokine and Complement DPU, Immunoinflammation TA Unit, GSK, Stevenage, UK

8. Loveleena Bansal

   GlaxoSmithKline (United States)

   Affiliation as printed

   Computational and Modelling Sciences, Platform Technology Sciences, GSK, Collegeville, Pennsylvania, USA

9. Lambertus A. Peletier Aachen Mathematical Institute

   Leiden University

   Affiliation as printed

   Mathematical Institute, Leiden University, P.O. Box 9512, 2300 RA, Leiden, The Netherlands

10. Stefano Zamuner

    GlaxoSmithKline (United Kingdom)

    Affiliation as printed

    Clinical Pharmacology, Modelling and Simulation, GSK, Stevenage, UK

11. Piet H. van der Graaf Aachen Division of Systems Biomedicine and Pharmacology

    Leiden University

    Affiliation as printed

    Certara QSP, Canterbury, CT2 7FG, UK

    Division of Systems Biomedicine and Pharmacology, LACDR, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands