The symptoms of an allergic response are associated with the level of IgE. However, the exact role of IgE in an allergic response is not well defined. Therefore, understanding how the IgE response is regulated will hasten the development of therapeutic interventions to keep an allergic response manageable. While immune factors that regulate the number of B cells that produce IgE through class switch recombination are well-characterized, little is known about the intrinsic and extrinsic factors that regulate the amount of IgE produced by a B cell at the level of mature IgE transcription. The goal of this research project is two-fold. First, we propose to identify the mechanism by which stimulation of the ?AR on a B cell by the neurotransmitter norepinephrine (NE) participates in an IgE response. And second, we propose to use the modulatory effect induced by ?AR stimulation on a B cell to help identify new, and clarify accepted, mechanisms by which the IgE response is regulated intrinsically in the absence of ?AR stimulation. Our laboratory showed that 22AR stimulation on a B cell participates in a normal IgE response in vivo, and that the addition of NE or a ?AR agonist to a culture of activated B cells increases the level of IgE produced, without affecting class switch recombination (CSR), through a mechanism that appears to inactivate Hematopoetic protein tyrosine phosphatase (HePTP) and enhance p38 MAPK phosphorylation to mediate an increase in ADAM10, which cleaves membrane CD23 to a soluble form. Thus far, ?AR mediated regulation of HePTP to control p38 MAPK phosphorylation has not been studied in a B cell and appears to be unique to IgE regulation. Also, the basic immunological mechanism that links p38 MAPK activation to ADAM10 expression and regulation of its cleavage of sCD23, which mediates regulation of IgE, remains unknown. We propose to test the hypothesis that ?AR stimulation on an activated B cell regulates a protein tyrosine phosphatase to augment the level of activation- induced signaling pathways to promote an increase in the rate of mature IgE transcription. The relevance of testing our hypothesis is that the findings will define novel signaling intermediates unique to IgE production, which may then be targeted by therapeutics to diminish an IgE-mediated allergic response, and may possibly explain why long-term conventional ?AR agonist therapy and/or stress exacerbate an allergic episode.
IgE is associated with an allergic response. Stress is known to increase the severity of an allergic response. We propose to study how a neurotransmitter released by the nervous system during stress affects the production of IgE, so that we can develop drugs to help individuals that respond adversely.
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