A STUDY OF THE MECHANISM BY WHICH BETA2-ADRENERGIC RECEPTOR STIMULATION ON A B CELL REGULATES IgE PRODUCTION
| Main Author: | |
|---|---|
| Language: | English |
| Published: |
The Ohio State University / OhioLINK
2009
|
| Subjects: | |
| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=osu1243988870 |
| id |
ndltd-OhioLink-oai-etd.ohiolink.edu-osu1243988870 |
|---|---|
| record_format |
oai_dc |
| spelling |
ndltd-OhioLink-oai-etd.ohiolink.edu-osu12439888702021-08-03T05:56:21Z A STUDY OF THE MECHANISM BY WHICH BETA2-ADRENERGIC RECEPTOR STIMULATION ON A B CELL REGULATES IgE PRODUCTION McAlees, Jaclyn Walisa Immunology B cell IgE allergic asthma beta2-adrenergic receptor HePTP The goal of this dissertation was to determine if the β2AR on the B cell is a direct target for norepinephrine (NE) in vivo and to determine the mechanism by which β2AR stimulation regulates the level of IgE. Our laboratory and others reported previously that NE release in vivo and β2AR stimulation in vitro increase the amount of IgE produced by a B cell. Also, our laboratory reported that β2AR stimulation increases the amount of either IgG1 or IgE produced per B cell, without affecting class switch recombination (CSR). The mechanism responsible for the increase in IgG1 involves a β2AR-dependent activation of the cAMP/PKA/CREB pathway that increases activity of the 3’-IgH enhancer to increase the rate of IgG1 production. The use of B cells isolated from CREB-dominant negative mice revealed that CREB was necessary for the β2AR-induced increase in IgG1 but not the increase in IgE. These data were the first to suggest that the β2AR may activate different signaling pathways to regulate the levels of IgG1 or IgE produced. Thus, the hypothesis tested in this dissertation is that NE stimulates the β2AR on a B cell to activate a unique signaling pathway that increases the level of IgE, independently of the pathway activated to increase the level of IgG1. The present data using an animal model of allergic asthma are the first to show that NE stimulates the β2AR on the B cell directly. Using gene-deficient mice, pharmacological agents, and shRNA, we showed that the increase in the level of IgE involves a β2AR-dependent activation of the cAMP/PKA pathway that leads to phosphorylation and inactivation of HePTP, which is bound to inactive p38 MAPK. Phosphorylation of HePTP releases p38 MAPK into the cytoplasm of the cell where it is phosphorylated by upstream MAPK kinase molecules that were activated by CD40 receptor stimulation. The increase in phosphorylated p38 MAPK augments the production of soluble CD23, which mediates an increase the level of IgE, possibly via stimulation of the CD21/CD19 complex. Nuclear run-on analysis determined that the change in the level of IgE was due to an increase in the rate of transcription. Thus, our findings suggest that β2AR stimulation on a B cell modulates the level of IgE in vivo and in vitro, independently of CSR and the level of IgG1. The overall significance of this dissertation is that it is the first study to identify the β2AR on the B cell as a target for NE-induced modulation of an immune response in vivo and the first to identify the mechanism by which β2AR stimulation increases the level of IgE. The knowledge gained from this work contributes to the understanding of how the level of IgE is regulated in vivo, as well as how current allergic asthma therapies may affect the production of IgE, which might contribute the severity of disease. In addition, these findings identify novel molecular targets for therapeutic interventions to selectively regulate the β2AR-induced effects on IgE. 2009-09-08 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1243988870 http://rave.ohiolink.edu/etdc/view?acc_num=osu1243988870 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Immunology B cell IgE allergic asthma beta2-adrenergic receptor HePTP |
| spellingShingle |
Immunology B cell IgE allergic asthma beta2-adrenergic receptor HePTP McAlees, Jaclyn Walisa A STUDY OF THE MECHANISM BY WHICH BETA2-ADRENERGIC RECEPTOR STIMULATION ON A B CELL REGULATES IgE PRODUCTION |
| author |
McAlees, Jaclyn Walisa |
| author_facet |
McAlees, Jaclyn Walisa |
| author_sort |
McAlees, Jaclyn Walisa |
| title |
A STUDY OF THE MECHANISM BY WHICH BETA2-ADRENERGIC RECEPTOR STIMULATION ON A B CELL REGULATES IgE PRODUCTION |
| title_short |
A STUDY OF THE MECHANISM BY WHICH BETA2-ADRENERGIC RECEPTOR STIMULATION ON A B CELL REGULATES IgE PRODUCTION |
| title_full |
A STUDY OF THE MECHANISM BY WHICH BETA2-ADRENERGIC RECEPTOR STIMULATION ON A B CELL REGULATES IgE PRODUCTION |
| title_fullStr |
A STUDY OF THE MECHANISM BY WHICH BETA2-ADRENERGIC RECEPTOR STIMULATION ON A B CELL REGULATES IgE PRODUCTION |
| title_full_unstemmed |
A STUDY OF THE MECHANISM BY WHICH BETA2-ADRENERGIC RECEPTOR STIMULATION ON A B CELL REGULATES IgE PRODUCTION |
| title_sort |
study of the mechanism by which beta2-adrenergic receptor stimulation on a b cell regulates ige production |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2009 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1243988870 |
| work_keys_str_mv |
AT mcaleesjaclynwalisa astudyofthemechanismbywhichbeta2adrenergicreceptorstimulationonabcellregulatesigeproduction AT mcaleesjaclynwalisa studyofthemechanismbywhichbeta2adrenergicreceptorstimulationonabcellregulatesigeproduction |
| _version_ |
1719428110152105984 |