Friday, May 3, 2024
5/3/2024
Project Summary/Abstract It is not clear why some individuals with allergen-specific IgE suffer from allergies, while others do not. It is likely that multiple factors contribute, including differences in IgE affinity or epitope diversity for allergens, mast cell numbers, FceRI expression levels, Syk signaling, allergen-specific IgG antibodies, and anti-IgE antibodies. An addition factor that has not been considered is the contribution of differences in IgE constant chains, and specific its glycosylation. We recently compared the N-linked glycans on IgE from peanut allergic and non-allergic adults and found reduced sialic acid on complex biantennary glycans of non-allergic IgE. Further, removal of sialic acid from IgE resulted in markedly reduced anaphylaxis in both human and murine models. Our long-term goal is to understand how glycosylation of antibodies regulates, and is regulated, by immune responses. Our central hypothesis is that specific glycan on IgE lacking sialic acid engage an inhibitory receptor that attenuates mast cell and basophil degranulation. Indeed, this is supported by preliminary data shown in this application. The rationale for our studies is that determining how IgE lacking sialic acid is attenuated will identify novel pathways that regulate allergic disease, identify novel therapeutic targets for atopic diseases, establish IgE glycosylation patterns as biomarkers for disease, and rewriting the dogma of IgE biology. We will test our central hypothesis and, thereby, attain the objective of this application by pursuing the following two specific aims: 1) Define the inhibitory glycan structure on IgE that is exposed following sialic acid removal; 2) Determine how removing sialic acid from IgE leads to its attenuation. Using an approach that combines biophysics, biochemistry cellular and molecular immunology, and glycobiology, we will determine how IgE lacking sialic acid is attenuated, define a novel anti-anaphylactic pathway, establish pathogenic IgE glycosylation patterns, and attenuate anaphylaxis by modulating IgE glycans. In addition to enabling discovery of biomarkers marking allergy-causing IgE, the studies here will potentially result in identification of novel therapeutic targets for allergic disease. Finally, these studies will have impact beyond allergy in diseases in which IgE is involved, including systemic lupus erythematosus (SLE) and helminth infection.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
