The long-term objective of our research is to achieve a better understanding of the mechanism by which the sympathetic neurotransmitter norepinephrine (NE) regulates immune system function. In our laboratory, two key discoveries have been made recently in vitro and need to be pursued aggressively in vivo. First, beta-2-adrenergic receptor (beta-2 AR) stimulation on a B cell by NE or a selective agonist in vitro induces an increase in the amount of Th2/IL-4-dependent IgG1, but not Thl/IFN-gamma-dependent IgG2a, via a mechanism that involves an increase in B cell responsiveness to IL-4, as well as an increase in the level of B cell-associated CD86 (B7-2) expression and signaling. Second, IgG2a production in vitro increases when the beta-2 AR on a TH1 cell is stimulated to increase the level of production of the IgG2a-promoting cytokine IFN-gamma. Also, depletion of NE in either a Th1/B cell of Th2/B cell model system in vivo inhibits the level of both serum IgG2a and IgG1, but splenic follicular expansion and germinal center formation are affected in the Th2/B cell model system only. We propose to focus the present study on resolving whether or not the initial key discoveries made in vitro can be validated in vivo, as well as to determine if CD86 signaling in a B cell affects the responsiveness of a B cell to IF-4, but not to IFN-gamma. We propose to test a two part hypothesis. First, NE increases the level of IgG1 in vivo by binding to the beta-2 AR on a B cell to increase the level of CD86 expression on, and signaling in, a B cell. And second, NE increases the level of IgG2a in vivo by binding to the beta-2 AR on a Thl cell to increase the level of IFN-gamma produced, without affecting the level of B cell responsiveness to IFN-gamma. To determine if beta-2 AR and CD86 stimulation render the B cell responsive to Th2-mediated signals, but not to Th-1 mediated signals, an in vivo model system will be used in which a scid mouse is kept NE-intact or is NE-depleted before being reconstituted with either beta-2 AR(neg)-Th2 cells or beta-2 AR(pos or neg)-Thl cells and beta-2 AR(pos or neg)-B cells. After reconstitution, these mice will be administered various immunologic stimuli and pharmacologic agonists and antagonists. The significance of the proposed research is that it will help us to understand an endogenous homeostatic mechanism that may regulate the level of IgG1 and IgG2a immunity that is necessary for either the neutralization or lysis of infectious organisms, respectively, as well as how dysregulation of this homeostatic mechanism may contribute to the development and progression of IgG1-vs. IgG2a-mediated diseases of the immune and nervous system.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-2 (01))
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Esch, Thomas R
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Ohio State University
Schools of Medicine
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Sanders, Virginia M (2012) The beta2-adrenergic receptor on T and B lymphocytes: do we understand it yet? Brain Behav Immun 26:195-200
Kin, Nicholas W; Sanders, Virginia M (2006) CD86 stimulation on a B cell activates the phosphatidylinositol 3-kinase/Akt and phospholipase C gamma 2/protein kinase C alpha beta signaling pathways. J Immunol 176:6727-35
Podojil, Joseph R; Sanders, Virginia M (2005) CD86 and beta2-adrenergic receptor stimulation regulate B-cell activity cooperatively. Trends Immunol 26:180-5
Podojil, Joseph R; Kin, Nicholas W; Sanders, Virginia M (2004) CD86 and beta2-adrenergic receptor signaling pathways, respectively, increase Oct-2 and OCA-B Expression and binding to the 3'-IgH enhancer in B cells. J Biol Chem 279:23394-404
Sanders, Virginia M; Kasprowicz, Deborah J; Swanson-Mungerson, Michelle A et al. (2003) Adaptive immunity in mice lacking the beta(2)-adrenergic receptor. Brain Behav Immun 17:55-67
Podojil, Joseph R; Sanders, Virginia M (2003) Selective regulation of mature IgG1 transcription by CD86 and beta 2-adrenergic receptor stimulation. J Immunol 170:5143-51
Sanders, Virginia M; Straub, Rainer H (2002) Norepinephrine, the beta-adrenergic receptor, and immunity. Brain Behav Immun 16:290-332
Kohm, Adam P; Mozaffarian, Afsaneh; Sanders, Virginia M (2002) B cell receptor- and beta 2-adrenergic receptor-induced regulation of B7-2 (CD86) expression in B cells. J Immunol 168:6314-22
Kohm, A P; Sanders, V M (2001) Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol Rev 53:487-525
Kohm, A P; Sanders, V M (2000) Norepinephrine: a messenger from the brain to the immune system. Immunol Today 21:539-42