Thesis defense Mads Larsen

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IgG antibodies protect the host from recurrent infections by neutralizing targets or by stimulating effector functions such as complement, phagocytosis, and antibody-dependent cellular cytotoxicity. However, unwanted effects may arise from immune overactivation and/or as a consequence of inappropriate targets, e.g., during auto- and alloimmune responses. The effector functions of IgG are governed by a glycan at a conserved site in the CH2 region. IgG containing glycans without fucose (afucosylated IgG) have an augmented potency due to an increased affinity to members of the IgG-Fc receptor III family compared to fucosylated IgG. Afucosylated IgG is rare but is enriched in IgG specific for certain antigens, including blood group alloantigens, such as RhD and HPA-1a.

We hypothesized the context of the antigen to be of importance for triggering afucosylated IgG responses, as all afucosylated IgG responses known at the commencement of this thesis were specific for antigens located in a self-membrane. This hypothesis was assessed by measuring the fucosylation degrees of IgG from immune responses against both malaria parasites and viruses, and through in vitro studies of single B cell clones. The serological studies confirmed the necessity of self-membrane association of antigens to elicit afucosylated IgG responses. Furthermore, we found IgG-Fc fucosylation to be regulated at the level of the single B cell clones and correlate positively with the overall activation of the secreting B cell clones. These results add an additional layer to the understanding of the regulation of IgG responses, which can be used prognostically in natural responses and in the design of vaccines.