Project Abstract: The association between decreased plasma IgG sialylation and a variety of inflammatory diseases has been known for decades. The downstream effects of changes in IgG sialylation have been studied in depth, and it is now believed that decreases in sialylation increase the affinity of IgG for activating Fc receptors, thereby driving immune activation throughout the body. Although the downstream effects of dysregulated IgG sialylation have been well documented, the regulatory mechanisms controlling IgG sialylation remain unknown. If these mechanisms are elucidated, they may serve as novel therapeutic targets to manipulate IgG function to either enhance or suppress IgG-based inflammation, depending on the circumstances. Previous research has suggested that, unlike many other glycoproteins, IgG is not sialylated efficiently during the secretory process, pointing to a B cell-extrinsic mechanism in which IgG sialylation is dynamically regulated following its release into the bloodstream. Therefore, the goals of the proposed studies are (1) to identify key regulatory mechanisms underlying IgG sialylation and (2) to elucidate how inflammatory signals are translated into changes in the IgG glycan. The success of this study will be characterized by revealing a novel and dynamic mechanism regulating IgG function through regulated changes in glycan sialylation, while providing cutting-edge scientific and professional training that blends both glycobiology and immunology to facilitate a career trajectory focused upon leadership in IgG-based therapies and translational science.