Impact of serum IgG levels on antibody effector functions

Human blood is a complex fluid consisting of plasma, red and white blood cells, platelets and various soluble components. Serum, the liquid part of blood that remains after coagulation, in turn, consists of water, electrolytes, proteins, hormones, nutrients, and waste products. It is the interplay of immune cells and serum proteins that protects the body from infection and maintains immune tolerance, with antibodies and the complement system playing a central role. The classical complement pathway is an essential component of the immune system, which is activated by specially arranged IgG antibodies, known as IgG oligomers, on the surface of pathogens, infected cells or cancer cells, leading to their destruction. Crucial to this process are highly specific interactions between the antibodies and specific molecules on the surfaces of the target cells (the antigens), between the antibodies themselves, and between the antibodies and the proteins of the complement system. Healthy human blood contains a very high concentration (approximately 40 billion billion IgG antibodies per liter) of endogenous IgG antibodies that target a variety of different antigens, while only a subset, either acquired naturally or administered as part of immunotherapy, is able to recognize a specific antigen and thus activate the complement system in response to a specific threat. Preliminary work suggests that the overwhelming majority of IgGs outside the subgroup relevant to a specific threat, i.e. IgGs unspecific and thus long thought irrelevant to the threat at hand, must have a significant inhibitory effect on these interactions. Total IgG levels could therefore play a crucial role in autoimmune diseases with disease-related sharply elevated/depleted antibody concentrations irrespective of their specificities. This project uses a combination of several state-of-the-art biophysical methods, including high-speed atomic force microscopy, 3D single-molecule fluorescence microscopy, and quartz crystal microbalance, to investigate this mechanism in detail. Based on the experimental results, we will further develop a mechanistic model of the underlying molecular interactions, thereby laying the foundation for optimizing IgG antibody development and pharmacokinetic/pharmacodynamic modelling in connection with future immunotherapies. The project is being carried out by Dr. Johannes Preiner (PI) and Dr. Jaroslaw Jacak at the University of Applied Sciences Upper Austria in close collaboration with Dr. Suzan Rooijakkers, UMC Utrecht.