101. Asthma-associated IgE mechanisms are regulated by the beta-2-adrenergic receptor on human B cells

Abstract

Asthma affects 300 million people worldwide. Treatment involves the use of inhalers containing agonists that stimulate the beta-2-adrenergic receptor (b2AR) on lung smooth muscle cells. Norepinephrine, which is released in elevated amounts during a stress response, also stimulates the b2AR. Stimulation of the b2AR on a B cell responding to allergen results in an increase in IgE, which exacerbates bronchoconstriction and counteracts therapeutic benefit and worsens stress-related asthma effects. Our goal is to block the negative b2AR-induced effect on the B cell while retaining the positive effect on bronchodilation. Previously, we showed that when the B cell-associated b2AR is stimulated during antigen activation, hematopoietic protein tyrosine phosphatase (HePTP) is phosphorylated in a PKA-dependent manner to release bound p38 MAPK for phosphorylation, and to subsequently increase IgE transcription. Deletion of either b2AR or norepinephrine in mice results in a decrease in antigen-induced IgE and lung inflammation. It is unknown if HePTP functions similarly in human B cells. We found that anti-CD40/IL-4-primed human B cells exposed to a b2AR agonist expressed higher levels of HePTP/p38 MAPK phosphorylation and IgE as compared to primed B cells alone, suggesting that b2AR stimulation causes a similar response in human and murine B cells. Our studies suggest that HePTP represents a potential novel target for blocking the adverse b2AR-induced increase in IgE, while maintaining the beneficial effects on bronchodilation.