A novel mechanism responsible for IgE regulation involves beta2-adrenergic receptor-mediated regulation of CD23 and ADAM10 localization to B cell-derived exosomes. (125.11)

Abstract

Abstract Allergic asthma severity positively correlates with plasma IgE, but physiological mechanisms responsible for regulating IgE production by B cells are unknown. We have shown that beta-2 adrenergic receptor (β2AR) engagement on a CD40L/IL-4-primed B cell increases the level of IgE produced per cell, without affecting class switch recombination. Asthma therapy involves stimulation of the β2AR on bronchiolar smooth muscle cells to relieve bronchoconstriction. This therapy also targets the β2AR expressed on primed B cells to increase IgE production, potentially intensifying symptoms. In this study we show that surface CD23 remained constant on primed B cells exposed to a β2AR agonist, while CD23 expression and soluble CD23 (sCD23), which is a positive regulator of IgE production, increased. We hypothesized that the primary sheddase of CD23, ADAM10, is regulated by β2AR engagement on a primed B cell. We found that CD23 and ADAM10 are expressed on B cell-derived exosomes over time and that blockade of exosome release allows for CD23 and ADAM10 retention, with β2AR engagement augmenting CD23 and ADAM10 retention. Localization of ADAM10 and CD23 to non-lipid raft fractions where CD23 is cleaved by ADAM10 was also increased by β2AR engagement. Thus, ADAM10 may serve as a molecular target that can be blocked during β2AR drug therapy to prevent increased sCD23 and IgE production, while maintaining the therapeutic effect of bronchorelaxation.