The human complement system : a mathematical analysis of its regulation

The complement system is part of the innate immune system and plays an important role in the host defense against infectious pathogens. One of the main effects is the opsonization of foreign invaders and subsequent uptake by phagocytosis. The central molecule of the complement system is the molecule C3. Proteolysis gives rise to its active forms: the opsonin C3b and the anaphylatoxin C3a. The opsonin C3b can only exert its effect in close proximity to cell surfaces before it becomes inactive, so it is crucial where C3 is activated. Due to rapid and massive activation mechanisms, a tight regulation of the complement system is required to protect the body’s own cells (self cells) from opsonization and from complement damage. A major complement regulator is Factor H, which circulates and regulates the complement system in the blood. Additionally Factor H can be recruited from the fluid phase and attaches to self cell surfaces where it effectively controls complement activation. Besides self cells, pathogens also have acquired the ability to bind Factor H; they can thus escape opsonization and phagocytosis causing severe infections. Understanding how these pathogens escape opsonization is thus essential for the development of new diagnostic and therapeutic approaches. In this thesis, these opsonization mechanisms and immune evasion processes of selected pathogens have been investigated according to the concept of systems biology. In order to advance our understanding of the opsonization process at a quantitative level, a mathematical model for the dynamics of the complement system - termed DynaCoSys model - has been developed. The model is based on ordinary differential equations for the dynamics of cell surface-bound molecules and on partial differential equations for concentration profiles of the dynamics of fluid phase molecules in the environment of cells.