- Influence of immunoglobulin G-glycan and subclass variation on antibody effector functions
C.E. van der Schoot
- Award date
- 1 December 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Antibodies signal to other parts of the immune system by binding of their constant domain (Fc) to receptors, such as Fc gamma receptors (FcγR) or C1q of the complement system in the case of immunoglobulin G (IgG). For these interactions the Fc-structure, influenced by subclasses or glycan-composition of the constant domain, is important. The research in this thesis aimed to further understand the effect IgG constant domain variation on the different effector functions.
A glyco-engineering toolset was developed to change every glycan end groups (galactose, sialic acid, fucose, bisection) of the IgG-Fc glycan. Using this, we show that C1q binding and classical complement activation were increased by addition of galactose and sialic acid.
Absence of fucose increases affinity of IgG for FcγRIII and was additionally enhanced by galactose addition. The composition of different FcγRs on effector cells is important for the effector function of IgG glycoforms. It was shown macrophages bearing all kinds of FcγR are unaffected, whilst NK cells bearing solely FcγRIIIa, are affected by changes in IgG-Fc glycan composition.
Affinity of all human IgG subclasses for the mouse FcγRs was determined and show that each subclass has a specific binding pattern. Mouse glycoforms are similarly affected by lack of fucose for binding to the mouse orthologue FcγRIII, where a single glycan in these orthologous receptors discriminates for fucosylated and afucosylated IgG.
Lastly we show presence of O-glycans in the hinge of IgG3 of which the function is yet unknown.
Thesis (complete) (Permanent embargo)
Chapter 5: Enhanced effector functions due to antibody defucosylation depend on the effector cell Fcγ receptor profile (Permanent embargo)
Chapter 7: Conserved FcγR-glycan discriminates between fucosylated and afucosylated IgG in humans and mice (Embargo up to and including 1 December 2019)
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