Suppression of antigen-specific Th2 cell-dependent IgM and IgG1 productionfollowing norepinephrine depletion in vivo

The mechanism by which the Th2 cell-dependent Ab response is modulated by t he sympathetic neurotransmitter norepinephrine (NE) was investigated. Our m odel system used the severe combined immunodeficient (scid) mouse that was depleted of NE with 6-hydroxydopamine before reconstitution with a clone of beta(2)-adrenergic receptor (beta 2AR)(neg) KLH-specific Th2 cells and res ting trinitrophenyl (TNP)-specific beta 2ARP(pos) B cells enriched from the spleens of unimmunized mice, Following challenge with TNP-keyhole limpet h emocyanin (KLH), Ab production in these mice was hapten-, carrier-, and all otype-specific as wed as MHC restricted. Depletion of NE resulted in a 50-7 5% suppression of the primary anti-TNP IgM response compared with that of N E-intact controls, while the secondary IgM response returned to control lev els. In contrast, both the primary and secondary anti-TNP IgG1 responses we re suppressed by 85 and 40%, respectively. Using NE-intact mice exposed to either a beta AR- or alpha AR-selective antagonist, the effect of NE on the Ab response was shown to be mediated by the PAR. In addition, administrati on of a beta 2AR-selective agonist to NE-depleted mice partially reversed t he suppressed Ab response that resulted from NE depletion. Expression of th e beta 2AR on TNP-specific B cells was confirmed by radioligand binding, im munofluorescence, and cAMP analysis. Also, while splenic histology was comp arable in NE-intact and NE-depleted mice before Ag exposure, follicle expan sion and germinal center formation were suppressed in NE-depleted mice afte r Ag exposure. Taken together, these results suggest that NE stimulation of the beta 2AR expressed on B cells is necessary for the maintenance of an o ptimal primary and secondary Th2 cell-dependent All response in vivo.