The molecular pathways of IgG oligomerization and classical complement activation on antigenic surfaces

Strasser, J. (Speaker)

Activity: Talk or presentationOral presentation

Description

The human immune system consists of powerful defense mechanisms that recognize and eliminate pathogens from our bodies. Immunoglobulin G (IgG) antibodies play a central role in this protection by alerting and activating components of the innate immune system, such as the classical complement pathway, which is triggered by IgG-hexamer formation on cells. The dynamic assembly of these IgG hexamers on surfaces represents a recently recognized, yet poorly understood, effector function of IgGs. We employed high-speed atomic force microscopy to visualize the dynamic process of IgG binding and hexamer formation on antigenic lipid membranes. With single-molecule force spectroscopy and quartz crystal microbalance we further characterized the molecular interactions by determining chemical rate constants and energies. Functional assays on cells allowed us to directly correlate IgG hexamerization and efficient complement activation via the classical pathway.We show that antigen recognition by IgGs nucleate subsequent oligomerization through IgG recruitment from solution and, depending on the valency of its binding state, through lateral collisions, leading to stable IgG hexamers which recruit and tightly bind C1q. Complement dependent cytotoxicity (CDC)-enhancing mutations increase the abundance of higher-order oligomers, while certain mutations that were shown to decrease CDC also hinder the hexamerization process. The low affinity of Fc-Fc interactions prevents IgG oligomerization and thus unwanted complement activation at physiological concentrations in solution. Upon surface-epitope binding, however, oligomerization may proceed via two different pathways: recruitment from solution, or diffusion-driven lateral collisions. We present a dynamic IgG oligomerization model, which provides a framework for immunotherapy optimization and for exploiting the macromolecular assembly of IgGs on antigenic surfaces.
Period20 Nov 2019
Event title5th Kepler Science Day: null
Event typeConference
LocationLinz, Austria