HighlightsComputational model describing dynamics of complement system activation pathwaysComplement dysregulation leads to deviation from homeostasis and to inflammatory diseasesModel identifies biomarkers to quantify the effects of complement dysregulationKnown drugs restore impaired dynamics of complement biomarkers under dysregulationDisease-specific models are suitable for diagnosis and patient-specific drug treatmentAbstractThe complement system is a part of innate immunity that rapidly removes invading pathogens and impaired host-cells. Activation of the complement system is balanced under homeostasis by regulators that protect healthy host-cells. Impairment of complement regulators tilts the balance, favoring activation and propagation that leads to inflammatory diseases. The most potent regulator of the complement system is Factor H (FH), and its impairment induces improper complement activation that leads to inflammatory diseases, such as atypical hemolytic uremic syndrome and age related macular degeneration. To understand the dynamics involved in the pivotal balance between activation and regulation, we have developed a comprehensive computational model of the alternative and classical pathways of the complement system. The model is composed of 290 ordinary differential equations with 142 kinetic parameters that describe the state of complement system under homeostasis and disorder through FH impairment. We have evaluated the state of the system by generating concentration-time profiles for the biomarkers C3, C3a-desArg, C5, C5a-desArg, Factor B (FB), Ba, Bb, and fC5b-9 that are influenced by complement dysregulation. We show that FH-mediated disorder induces substantial levels of complement activation compared to homeostasis, by generating reduced levels of C3 and FB, and to a lesser extent C5, and elevated levels of C3a-desArg, Ba, Bb, C5a-desArg, and fC5b-9. These trends are consistent with clinically observed biomarkers associated with complement-mediated diseases. Furthermore, we introduced therapy states by modeling known drugs of the complement system, a compstatin variant (C3 inhibitor) and eculizumab (a C5 inhibitor). Compstatin demonstrates strong restorative effects for early-stage biomarkers, such as C3a-desArg, FB, Ba, and Bb, and milder restorative effects for late-stage biomarkers, such as C5a-desArg and fC5b-9, whereas eculizumab has strong restorative effects on late-stage biomarkers, and negligible effects on early-stage biomarkers. These results highlight the need for patient-specific therapies that target early complement activation at the C3 level, or late-stage propagation of the terminal cascade at the C5 level, depending on the specific FH-mediated disease and the manifestations of a patient’s genetic profile in complement regulatory function.
A Computational Model for the Evaluation of Complement System Regulation under Homeostasis, Disease, and Drug Intervention