Role of IgE in Homeostasis and Disease

PROJECT SUMMARY Mammals have evolved several antibody isotypes capable of engaging distinct response pathways upon subsequent recognition of antigen. Immunoglobulin E (IgE) is an antibody isotype highly specialized to rapidly and potently activate Type II effector cells. The deleterious role of IgE in allergic disease has been well- described in the literature extending back to the early 20th century. However, the roles of IgE in homeostasis and in host protection from disease remain poorly understood. One approach to understanding the functional role(s) of antibody isotypes is through identifying targeted antigens. Reactivity profiling has been performed for all antibody isotypes except for IgE and has been informative in establishing the tissue sites, effector pathways, and functional consequences of antigen recognition by specific antibody isotypes. The antigenic targets of IgE have not been broadly characterized to date largely due to the difficulty in obtaining sufficient antibody quantities for testing. We created a genetic tool to both extend the half-life of IgE and to facilitate IgE purification, enabling high-throughput reactivity screening. Preliminary data for this proposal showed that during homeostasis and after infectious challenge, IgE and IgG recognized distinct sets of antigens. Some reactivities unique to the IgE antibody pool were conserved under all tested conditions, suggesting that these antigen:antibody interactions are an important component of fundamental IgE biology. Additional data demonstrated that homeostatic IgE had a profound influence on the host response to acute inflammatory challenge, and that this influence was antigen- dependent. We propose to fully resolve IgE reactivities in homeostasis (Aim 1), in relevant genetic and environmental contexts (Aim 2), and ultimately to contextualize IgE effector function(s) within the host response to acute inflammatory perturbation (Aim 3).