Asthmatic inflammation requires neuronal upregulation of B-cells - Project Summary Asthma and asthmatic symptoms continue to persist and are a growing health burden demonstrating the need to understand how the main asthmatic effector molecule, immunoglobulin (Ig) E (IgE), is produced. Asthmatic pathology occurs by IgE being produced in response to what are typically innocuous substances. While IgE production can lead to protective immunity in response to venoms and multicellular pathogens, its overproduction in response to benign substances underlies its role in asthmatic and allergic inflammation. IgE is secreted from B lineage cells in the presence of cognate antigen and activates mast cells and basophils to release potent inflammatory molecules which act directly on the airway wall and attract inflammatory cells to the lungs. Emerging evidence demonstrates that allergic inflammation sensitizes another cell type- neurons. Once sensitized, neurons release a host of neurotransmitters which enhance allergic inflammation, and recent data indicate the neuronal ability to enhance B-cell mediated IgE overproduction. However, what sensitizes these neurons and what effect sensitized neurons have on asthmatic pathology, in particular the overproduction of IgE, requires further investigation. The overall objective of this application is to investigate the role of the sensory and autonomic neurons in IgE overproduction in allergic asthma. Our preliminary data has led us to hypothesize that sensory neurons stimulate sympathetic neurons to stimulate B-cell overproduction to increase IgE release. We show that sensory neurons can sense antigen alongside antigen-sensing immune cells. This stimulation of sensory neurons by antigen then increases B-cell production by eliciting sympathetic reflex activation. Once the surplus B-cell reservoir reaches the allergic lung, stimulated sensory neurons then release their neurotransmitters during antigen recognition which stimulates the overproduction of IgE. We will investigate this novel neuronal circuit of IgE overproduction in two aims. Studies in AIM 1 will use robust electrophysiological recording and calcium imaging techniques to assess a novel signaling pathway of sensory neuron antigen recognition, excitation, and hypersensitization. Subsequent molecular assays will delineate the exact downstream molecule effector with the hopes to identify potential drug targets for future study. Studies in AIM 2 will use neural tracer technology to learn which brain regions are involved in this novel neuronal circuit. Further studies in this aim will test the necessity and sufficiency of sensory neurons and autonomic neurons in regulating B-cell production using state- of-the-art chemogenetic tools. Isolated cell experiments will delineate which neuronal molecules affect B-cell IgE production. These data will drive further experiments to identify how the entire pathway works in a mouse model of fungal allergic asthma. This contribution is significant because it is expected to elucidate a complete picture of how IgE is produced and dysregulated in asthma. Such knowledge has the potential to inform the development of new strategies that will help to reduce the growing problem of allergic asthma.
