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.
Highlights
The complement system (CS) is a part of the innate immune system and bridges innate and adaptive immunity
A Value of k13 is calculated using the reported k14 value (Hourcade 2006) in combination with affinity of properdin to C3b (DiScipio 1981) assuming a standard 1:1 binding model. b Value of k7 is available from computational estimations (Korotaevskiy et al 2009). c The minimum value of k15 was estimated by Pangburn and Mueller-Eberhard (1983), which we have used in the model. d Value of k21 was estimated using graphical data available in Harder et al (2016) under the assumption of exponential decay. e Value of synthesis rate of FH was calculated using its reported degradation rate d3 and serum concentration in Dopler et al (2019)
It can be seen that a steady state is attained in which the concentrations of C3, factor B (FB) and FH match the physiological concentrations observed experimentally (Table 3 in the “Appendix”) (Alper and Rosen 1984; Scholl et al 2008)
Summary
The complement system (CS) is a part of the innate immune system and bridges innate and adaptive immunity. It is required for clearance of apoptotic cells and immune complexes. Several soluble and cell-surface proteins are involved in function and regulation of the CS. This research was carried out at the Leiden University and was supported in part by the GSK Early career postdoctoral scheme.
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