Immune Determinants of Dengue Disease Severity
IgG antibodies are central mediators of adaptive immunity. Effector functions mediated by IgGs can be proinflammatory or anti-inflammatory, modulatory or inhibitory. The activity of IgGs depends on the antigen specificity of Fab domains along with the structure of Fc domains. Fc domain structure is critical to IgG activity because it determines which Fc gamma receptors and, in turn, which effector cells and functions will be recruited during immune activation. Recent studies have revealed a striking amount of heterogeneity among humans in structural repertoires of IgG Fc domains. Studies in the Wang laboratory are driven by the hypothesis that this heterogeneity is a central driver of diversity in human immune functioning. Our projects are aimed at defining cellular mechanisms by which specific Fc domain repertoires confer enhanced protection or susceptibility to infectious diseases. We have recently found that susceptibility to dengue disease is associated with production of antibodies that have an activating Fc domain repertoire, defined here by abundant afucosylated glycoforms. Ongoing studies are determining how this repertoire modulates dengue infections and disease. Additional projects aim to identify regulators of the Fc domain repertoire. Through this work, we hope to define cellular pathways that can be targeted to optimize antibody-mediated immunity in humans.