- A field guide to human Fc-gamma receptors
- Genetics, cellular expression and interaction with immunoglobulins
T.K. van den Berg
- Award date
- 12 April 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
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.
Thesis (complete) (Embargo until 12 April 2019)
Chapter 2: Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis (Embargo until 12 April 2018)
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 (Embargo until 12 April 2019)
Chapter 4: The association and functional relevance of genetic variation in low-affinity Fc-gamma receptors with clinical platelet transfusion refractoriness (Embargo until 12 April 2019)
Chapter 8: Red pulp macrophages in the human spleen represent a distinct cell population with a unique expression pattern of Fc-gamma receptors (Embargo until 12 April 2019)
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