Glycosylation directs IgG affinity selection during immune response

Immunoglobulin (Ig) Fc region determines Antibody effector functionality. In humans, for example, there are four types of IgG molecules that differ in their Fc domain structure: IgG₁, IgG₂, IgG₃, IgG₄. In addition, glycolysation (sugarization) of Fc fragments by syalic acid and fucose influences their binding to inhibitory or activatory Fc receptors.

In this new paper published in journal Cell, Jeffrey Ravetch's lab suggested a mechanism how glycolysation would optimize IgG affinity. This is a hybrid study involving both human and mouse studies. 

The authors have used influenza antigen HA as a model antigen. First, the authors showed that following flu vaccinination in healthy volunteers, overall abundance of sialylated IgG₁ Fc molecules (sFc) correlates with vaccine efficacy as measured by HAI.    

Next, to understand mechanism for improved HAI titers, the authors treated human B cells with immune complexes (ICs) derived either from sialylated (sIC) or asialylated (aIC) antigen-IgG conjugates. This experiments reveal that sialylated ICs induced up-regulation of inhibitory FcRIIb on antigen-specific B cells in a CD23-dependent manner. This could instruct antigen-specific B cells to undergo more stringent affinity-selection in germinal centers.

Antigen-antibody binding studies confirmed that in vivo immunization with sICs could elicit IgG₁ with higher affinity in a CD23-dependent manner (this is a mouse study).

Finally the authors showed that unlike pure HA antigen immunization, immune sera derived from mice immunized with sICs displayed superior activity against flu virus expressing stalk region (this region is a target for universal anti-flu antibodies).

In summary, these results suggest that efficacy of vaccination protocols is influenced by overall abundance of sialylated IgG₁ molecules. However, it is not clear whether this optimization of IgG₁ response are physiologically happening following primary (naive) or secondary (memory) immune response. Another point is whether this particular strategy with sICs is feasible for human vaccination protocols. 

David Usharauli