Thesis Sietse Nagelkerke

On 12 April 2017 Sietse Nagelkerke defended his thesis 'A field guide to human Fc-gamma receptors: genetics, cellular expression and interaction with immunoglobulins' at the University of Amsterdam.

Promotor: Prof TW Kuijpers MD PhD
Copromotor: TK van den Berg PhD
Venue: Agnietenkapel, Oudezijds Voorburgwal 231, Amsterdam

The research described in this thesis was performed at the Department of Blood Cell research of Sanquin Research (Amsterdam, The Netherlands).

Summary

In many autoimmune diseases, antibodies (immunoglobulins) play a central role in the pathophysiology. These auto-antibodies are often of the Immunoglobulin G (IgG) class and can cause damage to tissues in various ways. In many cases this process occurs via cellular receptors for IgG on immune cells, the Fc-gamma receptors (FcγRs). These receptors, upon binding IgG, instruct the cell to attack. For instance, auto-antibodies directed against a patient’s own blood cells cause destruction of these cells via FcγRs on macrophages in the spleen.

This thesis describes our research on human FcγRs and (patho)physiology of IgG–FcγR interactions in autoimmune diseases. We have thoroughly studied the complex genetics of the different FCGR genes, describing novel variants and a high degree of linkage disequilibrium and ethnic variation. These findings are crucial for genetic association studies, and we used this knowledge to show an association of FCGR genetic variation with various diseases (Systemic Lupus Erythematosus and Kawasaki Disease). Furthermore, we studied cellular expression of the FcγRs on immune cells in relation to FCGR genetic variation, including an analysis of human splenic macrophages, which had not been characterized in detail before. Finally, we investigated the poorly understood working mechanism of intravenous immunoglobulins (IVIg), a treatment for autoimmune diseases that consists of a multitude of normal IgG molecules, aiming for improvement of this therapy. We showed that sialylation of glycans in the IVIg is not important, whereas the binding avidity of the IgG to FcγRs seems to be very important for the efficacy of IVIg.

Chapters

Chapter 1
General introduction and scope of the thesis.
Front Immunol. 2015 Jan 21; 5: 674

Chapter 2
Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis.
Rheumatology (Oxford). 2016 May;55(5):939-48

Chapter 3
Comprehensive genotyping of the FCGR2/3 locus reveals a novel association of FCGR2C-ORF with susceptibility to Kawasaki Disease as well as extensive ethnic variation and linkage disequilibrium.

Chapter 4
The association and functional relevance of genetic variation in low-affinity Fc-gamma receptors with clinical platelet transfusion refractoriness.

Chapter 5
Nonallelic homologous recombination of the FCGR2/3 locus results in copy number variation and novel chimeric FCGR2 genes with aberrant functional expression.
Genes Immun. 2015 Sep;16(6):422-9

Chapter 6
Haplotypes of FcγRIIa and FcγRIIIb polymorphic variants influence IgG-mediated responses in neutrophils.
J Immunol. 2014 Mar 15;192(6):2715-21

Chapter 7 
Inhibition of FcγR-mediated phagocytosis by IVIg is independent of IgG-Fc sialylation and FcγRIIb in human macrophages.
Blood. 2014 Dec 11;124(25):3709-18

Chapter 8
Red pulp macrophages in the human spleen represent a distinct cell population with a unique expression pattern of Fc-gamma receptors

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Download PhD thesis (university repository).