- Functional specialization and cooperation between the neonatal- and classical IgG receptors, FcRn and FcɣR
C.E. van der Schoot
- Award date
- 24 September 2014
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
The focus of this thesis is on the transport of maternal antibodies during pregnancy across the placenta but also on how subtle differences in the antibody structure can affect the downstream events following antibody-receptor ligation and thereby its function.
Overall our results do not indicate that either half-life extension or feto-maternal transport could be influenced by any other known Fc receptor than FcRn. We found that some individuals express H435 IgG3 variants which are more efficiently transported across the placenta than others due to stronger interaction with FcRn. We also discovered that FcRn, which is involved in both serum persistence and feto-maternal transport of IgG, has a higher affinity to IgG2ƛ than IgG2κ. However, this difference did not affect either process. We also found an opposite IgG2 light chain preference for FcɣRIIa, i.e. a preference for IgG2κ. As a result, IgG2κ antibody mediated more efficient in vitro phagocytosis than IgG2ƛ through FcɣRIIa, although this effect was somewhat diminished (but not negated) by the opposing FcRn preference. Thus these are the first reports showing that the effector function of IgG2, but not IgG1, is also encoded by its light chain, and not only the Fc portion.
Better understanding of the interactions between Fc-receptors and antibodies will help scientist design better therapeutic antibodies and more powerful vaccines, and can shed a light on the factors influencing the severity of various antibody mediated auto- and allo-immune diseases. For instance, people expressing the H435 IgG3 variants could theoretically be more susceptible to pregnancy-associated antibody-mediated alloimmune diseases (e.g. Rhesus incompatibility).
- Research conducted at: Sanquin Research and Landsteiner Laboratory
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