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A Study of the Distal Molecular Mechanism by which Beta-2 Adrenergic Receptor Stimulation on a B Cell Regulates IgE Production

Padro, Caroline Jeannette
http://rave.ohiolink.edu/etdc/view?acc_num=osu1384763500

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
The goal of this dissertation was to determine the mechanism by which beta-2 adrenergic receptor (ß2AR) stimulation on a CD40L/IL-4-primed B cell regulates the level of IgE produced. IgE is the mediator of allergic asthma, an inflammatory condition treated with ß2AR agonists to relieve bronchoconstriction. However, our laboratory and others reported previously that ß2AR stimulation in vivo or in vitro by norepinephrine or an agonist drug increase the amount of IgE produced by a B cell on a per cell basis, without affecting class switch recombination, potentially worsening allergic asthma symptoms due to IgE in the long term. The proximal mechanism responsible for the increase in IgE involves a ß2AR-dependent activation of the cAMP/PKA/HePTP/p38 MAPK signaling pathways. The distal mechanism involves an increase in the generation of soluble CD23 (sCD23), a positive mediator of IgE production, which results from the cleavage of membrane-bound CD23 by A Disintegrin And Metalloprotease 10 (ADAM10). What remained unknown was the mechanism responsible for the ß2AR-mediated increase in sCD23, and if sCD23 was the ultimate mediator of the ß2AR-mediated increase in IgE. Recently, CD23 and ADAM10 were described on B cell-derived vesicles known as exosomes, suggesting a novel pathway by which ß2AR stimulation could regulate CD23 cleavage. Thus, the hypothesis tested in this dissertation is that ß2AR stimulation on a B cell enhances IgE production by increasing CD23 and ADAM10 expression on B cell-derived exosomes that play a role in mediating the ß2AR-associated increase in IgE production. The present data using an in vitro cell culture system are the first to show that ß2AR stimulation on a CD40L/IL-4-primed B cell enhanced the expression of CD23 and ADAM10 in the B cell in a PKA- and p38 MAPK-dependent manner. Using ß2AR-deficient mice and pharmacological agents, we showed that the ß2AR-dependent enhancement of CD23 and ADAM10 expression was detectable on exosomes, rather than on the cell surface. Exosomes from ß2AR agonist-exposed primed B cells were able to transfer the ß2AR-enhancing IgE effect to primed-only B cells, resulting in an increased amount of IgE produced on a per cell basis, rather than an increase in the number of cells that switch to IgE. Thus, our findings suggest that ß2AR stimulation on a B cell modulates the level of IgE production by increasing CD23 and ADAM10 expression on exosomes, which are ultimately responsible for mediating the effect. This is the first study to identify the distal mechanism by which ß2AR stimulation on a primed B cell increases the level of IgE. The knowledge gained from this work contributes to an understanding of the physiologically relevant mechanism by which the level of IgE is regulated both homeostatically by norepinephrine and during agonist therapy with a ß2AR agonist. The latter effect will help to predict the impact that current allergic asthma therapies may have on the level of IgE. In addition, these findings identify novel molecular targets for therapeutic interventions that can be used to selectively regulate the ß2AR-induced effects on IgE, while maintaining ß2AR-induced bronchoconstriction.
Virginia M Sanders, Ph.D. (Advisor)
Ian Davis, DVM Ph.D. (Committee Member)
Susheela Tridandapani, Ph.D. (Committee Member)
Joanne Turner, Ph.D. (Committee Member)
152 p.
Biology; Immunology; Neurobiology; Pharmacology
B cells; B lymphocytes; Immunoglobulin; IgE; exosomes; allergy; asthma; p38 MAPK; PKA; CD23; ADAM10; B2AR; adrenergic

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Citations

  • Padro, C. J. (2013). A Study of the Distal Molecular Mechanism by which Beta-2 Adrenergic Receptor Stimulation on a B Cell Regulates IgE Production [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1384763500

    APA Style (7th edition)

  • Padro, Caroline. A Study of the Distal Molecular Mechanism by which Beta-2 Adrenergic Receptor Stimulation on a B Cell Regulates IgE Production. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1384763500.

    MLA Style (8th edition)

  • Padro, Caroline. "A Study of the Distal Molecular Mechanism by which Beta-2 Adrenergic Receptor Stimulation on a B Cell Regulates IgE Production." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1384763500

    Chicago Manual of Style (17th edition)

osu1384763500
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© 2013, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.
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