(374d) A Computational ODE Model for the Evaluation of Complement System Activation, Function, and Regulation in Homeostasis and Disease

The complement system is an ancient form of innate immunity that eliminates invading pathogens and maintains host homeostasis. It is a very effective defense mechanism that is constantly on the “look out” but once activated unleashes a local inflammatory response capable of rapidly removing the stimulus. However, due to the potency of the complement system, regulators present in fluid phase and bound to membranes are also constantly on the “look out” for improper complement activation on host cells. Once the delicate balance between activation and regulation is compromised, a cascade of host cell damage follows leading to autoimmune diseases. Thus, understanding the dynamics involved in the biochemical reactions of the complement system is crucial. In light of this, we have a developed a comprehensive quantitative model of the complement system that incorporates all pathways (alternative, properdin, classical, lectin, and common) and their respective membrane bound and fluid phase components. Our model demonstrates the action of the complement system against invading pathogens, and the coordination of complement activators and regulators that shields host cells from improper complement attack. The insights obtained from this model may aid in the development of patient-specific diagnostic tool for pathological conditions that involve complement deficiencies, polymorphisms, deletions or mutations. Furthermore, the model makes it possible to determine points of intervention with drugs, and to evaluate the efficacies of single drugs or combinations of drugs targeting different complement proteins, protein fragments, or protein complexes. We will present a unified model that consists of a system of over 500 ordinary differential equations, which functions as a basis to derive autoimmune disease-specific models. We will also present basic mechanistic insights for selected complement-mediated diseases, and the effects of drugs under development in our lab for these diseases.