Thesis defense Mads Delbo Larsen
The power of a few – on the origin and regulation of afucosylated IgG responses
On 15 January 2025 Sanquin researcher Mads Delbo Larsen defended his PhD thesis 'The power of a few – on the origin and regulation of afucosylated IgG responses' at Utrecht University. He was awarded the doctoral degree Cum Laude.
Promotores
Prof G Vidarsson PhD, Prof CE van der Schoot MD PhD, Prof M Wuhrer PhD
Venue
Academy Building, Utrecht University
Abstract
Antibodies are soluble proteins reactive with so called antigens that protect the host from recurrent infections. However, responses elicited by antibodies can cause disease if they are too powerful or if the antibodies bind inappropriate targets. An example of both, is when a pregnant woman develops antibodies against antigens on blood cells of her fetus that are inherited from the father of the fetus. Not only are these antibodies directed towards an unfortunate target, they can also be extra potent due to the lack of the sugar residue fucose on the antibodies (afucosylated IgG). Afucosylated IgG is rare but is found to be enriched in certain responses, including the responses described above.
During infections with malaria parasites and certain viruses, microbial proteins can be found on the surface of infected cells, a situation similar to antigens found on fetal blood cells inherited from the father. We hypothesized that afucosylated IgG have evolved to eliminate parasites and viruses hiding within cells but are sometimes formed against fetal blood cells due to the similar appearance of the targets.
This hypothesis was assessed by measuring the fucosylation degrees of antibodies in multiple immune responses as well as deciphering the regulation of afucosylated IgG in antibody-producing B cells. We found that afucosylated IgG are formed against targets in the context of a surface of the host’s own cells and seems to be produced by mildly activated B cells independent of the fucosylation degree of related B cell clones. The results of this thesis influence our general understanding of antibody responses and could be utilized for improved vaccine design.
