Highlights from a live keynote by Gestur Vidarsson, Head of Immunoglobulin Research/PI, Experimental Immunohematology at Sanquin Research
Gestur Vidarsson, Head of Immunoglobulin Research/PI, Experimental Immunohematology at Sanquin Research presented a session on sugar switches and antibody responses in humans. Candace Kastanis revisits.
It was suggested by Dr. Vidarrsson that memory through B cells is etched within the memory banks of our DNA.
The various subclasses of IgG and how they relate to glycan (polysaccharides) were discussed.
Visual representations were provided to show how the glycan and the Fc interact with one another. Both complement one another and are mediated through diverse types of synapses.
Afucosylation Enhances NK (natural killer cells) Cell Mediated ADCC
Afucosylated IgG has elevated binding and activity for the human FCIII Family Antibody glycans and sugar switches Fucosylsation as a molecular switch.
Different antibodies are a key distinction between afucosylated molecules and fucosylated molecules as it relates to their individualized biochemical activity.
Antibodies low in fucose bind equally well to the antigen and not affected by the Fc portion. Only the Afucoylsated antibodies do something. Fc is invariably present in plasma IgG.
Key Experiment Takeaway: 6% of ig1 antibodies in serum sample are afucoslyated making it a small minority. We may better be able to make better antibodies that have better ADCC to for use in tumor therapy.
Human Responses: Glycosylation of IgG Blood Cells in Pregnancy
Using pregnancy to analyze these responses is a preferred biological setting because there is IgG antibodies due to antigenic mismatch between mother and fetus. IgG can cross the placenta where a breakdown occurs.
Affinity to this antigen is not predictive and it is very life threatening.
Alarmingly, there is no screening for antiplatelet antibodies in pregnancy, and it is particularly important.
If you have these antibodies, it can lead anemia or severe bleeding events due to a lack of platelets.
Glycosylation Profiles in IgG
A summary of information was referenced to frame a study that analyzed 166 pregnancies. Fucolysation antiplatelet and anti RBC IgG glycosylation.
An evolutionary prospective was introduced as it presents that strong evolutionary selection is unlikely to exist making antibodies with enhanced ADCC against newborns.
Yet, mechanisms are in place to make afucosylated IgG Recognize and respond strongly to afucosylated IgG.
Vidarsson introduced an evolutionary perspective. It was relative to answer the question as to why their research team chose to use pregnant women as study models.
Keeping true to the evolutionary based hypotheses, the idea behind the decision was that these type of afucosylated igG response would only be tolerated in nature if it were important in another context.
He indicated that while you don’t need to be pregnant to produce the antibodies, but since pregnancy is such a strong evolutionary biological event, it may highlight a different response to avoid killing off a fetus.
Consequently, the proof of concept was provided in this study using pregnancy as a template to study precise MOA (mechanism of action).
Known Hypofucosylated Response IgG Fc Responses
What Does this mean for Covid-19 patients?
Afucosylated IgG create proinflammatory environment through FcYR on Microphages.
We begin life with a high amount of afucosylated antibodies;about 94% on average.
Those responses are those that stay and are remembered through some sort of memory that we don’t quite understand as of this presentation.
The hypothesis is centered around that they are making B cells with different profile and push out antibodies that are fucosylated.
B cells MOA
B cells work together with something unknown and glycans are being added to antibodies. Genetic snips may also play a role and influence slight changes.
By sorting B cells and cultivating, and then looking at the products they make; all of those antibodies are fucosylated.
What is known is that Afucosylated IgG becomes much stronger with increasing immunization events.
Covid-19 Patients Show High AFucosylation
Covid-19 patients tend to present with iincreased production of IgG1 antibodies with significantly reduced Fc fucosylation (high afucosylation) and elevated IgG3 .
However, in patients who were treated in the intensive care unit (ICU), both of these antibody forms being proinflammatory in nature.
Within SARS-CoV-2 immune complexes, afucosylated Fc structures triggered activation of natural killer (NK) cells and production of inflammatory cytokines.
The responses may be steerable but are not really understood at this point. After testing glycan-engineered antibodies, the research team found that IgG fucosylation is very stable.
Conclusion
Following the presentation, certain questions were raised such as:
Dr. Vidarsson helped us to understand that these are questions that cannot yet be answered without more research. He did respond favorably to the fact that this research holds high promise in this area.
He also confirmed that the connection between sugar and viral load responses in COVID-19 patients is a subject of little knowledge at this point.
We are just at the beginning stages of experimentation due to laboratory lockdowns.
