Clinical and laboratory studies show that a bidirectional relationship exists between the nervous and immune systems. An understanding of how this relationship influences neuroimmune function will encourage the development of novel therapies for treating disorders associated with each system individually, such as depression or autoimmunity. The purpose of this proposal is to study the role of norepinephrine (NE) in the T cell- dependent antibody response. Findings show that lymphoid organs are innervated by NE-containing fibers and that both B cells and CD4+ T-helper (Th) cells express beta2-adrenoceptors (beta2ARs) that bind NE. However, studies have produced conflicting and controversial results about the role of NE and activation of the beta2AR in a T cell-dependent antibody response. To address this dilemma, we propose that NE differentially affects antibody production by differentially affecting the Th cell subsets providing help to B cells. Two findings suggest that Th cell subsets may respond differently to activation of the beta2AR. First, our preliminary findings show that Th1 cells, but not Th2 cells, express betaARs that transduce signals to increase intracellular cAMP concentration. Second, an elevation in intracellular cAMP inhibits cytokine secretion by Th1 cells, but not by Th2 cells. Thus, although both Th cell subsets are capable of providing help to B cells, the cytokine support provided by Th1 cells may be inhibited by NE binding to the beta2AR. Therefore, the predominance of one Th cell subset over the other may profoundly affect how NE will modulate the antibody response. To address this possibility, we propose the hypothesis that norepinephrine binding to the beta2AR increases the frequency of B cells capable of differentiating into antibody-secreting cells, but differentially affects the amount of antibody produced by these B cells by inhibiting the help provided by one Th cell subset without affecting the help provided by the other. To evaluate this hypothesis, murine antigen-specific Th1 and Th2 clones and enriched populations of resting antigen-specific virgin B cells will be used in vitro to address the following specific aims: 1) To determine if activation of the beta2AR differentially modulates antibody production in a Th1- and Th-2 dependent response; 2) To determine the level of beta2AR expression on resting cells and to determine if cell activation by means of T cell-B interaction alters expression; 3) To determine the Th cell mechanism responsible for mediating the differential antibody response; and 4) To determine the mechanism responsible for mediating the beta2AR-induced increase in the frequency of B cells capable of differentiating into antibody-secreting cells. Completion of the experiments proposed will contribute to a better understanding of the apparently conflicting role of the sympathetic nervous system in modulation of the Th cell-dependent antibody response.
| Sanders, Virginia M (2012) The beta2-adrenergic receptor on T and B lymphocytes: do we understand it yet? Brain Behav Immun 26:195-200 |
| McAlees, Jaclyn W; Smith, Laura T; Erbe, Robert S et al. (2011) Epigenetic regulation of beta2-adrenergic receptor expression in T(H)1 and T(H)2 cells. Brain Behav Immun 25:408-15 |
| Lucin, Kurt M; Sanders, Virginia M; Popovich, Phillip G (2009) Stress hormones collaborate to induce lymphocyte apoptosis after high level spinal cord injury. J Neurochem 110:1409-21 |
| McAlees, Jaclyn W; Sanders, Virginia M (2009) Hematopoietic protein tyrosine phosphatase mediates beta2-adrenergic receptor-induced regulation of p38 mitogen-activated protein kinase in B lymphocytes. Mol Cell Biol 29:675-86 |
