Thesis Evelien Sprenkeler

Summary

This thesis highlights the importance of the most abundant leukocyte in the human blood circulation, the neutrophil. These highly motile cells (the fast) are the first immune cells recruited to sites of infection, and when they encounter disease-causing microbes, they are capable of eliminating these pathogens with an impressive arsenal of host defense mechanisms (the furious), namely phagocytosis, production of reactive oxygen species (ROS), degranulation, and the formation of neutrophil extracellular traps (NETs). In this thesis we investigated neutrophils from patients with rare inherited immune deficiencies in order to increase our understanding of neutrophil defense mechanisms. These patients with so-called ‘inborn errors of immunity’ often have mutations in a single-gene (monogenic gene defect), allowing to deduce the role of the translated protein for neutrophil function. The first part of this thesis highlights a relatively new category of innate immune deficiencies, the ‘immuno-actinopathies’. These actinopathies are caused by deleterious mutations present in genes that encode for proteins that are important for actin cytoskeleton regulation. The cytoskeleton provides structural support to our cells and is essential for a variety of biological processes, including cell division, intracellular protein transport, and cell migration. The second part of this thesis describes inborn errors of immunity in which the development of neutrophils is impaired. By better understanding the biology behind a disease, we hope to support clinical management regarding patients with these rare congenital disorders.