The Ig-glycan code: a third level of regulation controlling effector function of immunoglobulins in health and disease LSBR 1721
Project leader: Dr. Gestur Vidarsson (Dept Immunopathology Sanquin Research)
PhD student: Mads Larsen (December 2018 – December 2022)
Research technician: Arthur Bentlage (July 2019 – February 2020)
Partly outsourced technical resources for RNAseq work
In this project we set out to understand why the human immune system reacts with a unique antibody signature to foreign blood cells with an enhanced inflammatory nature. The properties that are altered in these immune responses, are sugar structures found in IgG antibodies, in particular the omittance of fucose. Normal immune responses exclusively include this fucose in IgG. Without it, the IgG gains up to 40 fold enhanced binding to receptors on immune cells, with even greater changes observed in function of the immune cells when triggered by these antibodies. Afucosylated IgG antibodies can be formed after blood transfusion, transplantation, and in pregnancy, but in this project we also identified that the nature of these responses are similar as found in responses to enveloped viruses (that included SARS-CoV-2, HIV and more). Furthermore, we identified that the red-blood cell stage of the malaria parasite also triggers these afucosylated IgG responses very efficiently. Although these antibodies are in principle protective in infectious diseases (as in malaria and HIV), these can also exacerbate the immune responses and cause pathologies. Such seems to be the case in SARS-CoV- 2, as the majority of hospitalized individuals seem to generate more of these proinflammatory afucosylated antibodies, but only transiently as these antibodies eventually take on fucose that quenches the responses in a matter of weeks. We also identified that vaccination with recombinant proteins generally induces fully fucosylated antibodies, including experimental vaccines against the malaria parasite, which may explain why these are not inducing protection. In future work we hope to identify the exact molecular pathways triggered in the immune system that leads to afucosylated IgG responses, which can be used for diagnostic and treatment purposes, to either prevent (transfusion/pregnancy/transplantation) or induce these responses (cancer/vaccination against difficult targets).