Structural and synthetic biology of the human complement system

Abstract

A key part of the innate immune system is the complement system, which helps eliminate pathogens and clear apoptotic cells and debris. However, complement activation is also involved in various autoimmune diseases.

The complement system can be activated through three pathways: the classical, lectin, and alternative pathways. This thesis focuses on the classical pathway, which is activated when antibodies bind to antigens on surfaces and oligomerize, forming platforms that recruit the C1 complex (C1q, C1r, and C1s). This initiates a cascade that can lead to opsonization or cell lysis. The switch between silent clearance and inflammation, however, remains poorly understood.

This thesis explores complement activation using structural, biochemical, and synthetic biology approaches. Special attention is given to Immunoglobulin G (IgG), particularly IgG3, the strongest complement activator among IgG subclasses, distinguished by its extended, flexible hinge region. Cryo-electron microscopy reveals new structural insights into antigen-bound IgG3 and uncovers previously unknown mechanisms, such as C4b deposition on Fab regions.

Additionally, DNA nanotechnology is used to precisely pattern antigens and antibodies, enabling the first complement activation via DNA nanostructure templates and allowing spatial studies of immune activation.