Suppression of antigen-specific Th2 cell-dependent IgM and IgG1 production following norepinephrine depletion in vivo.
Suppression of antigen-specific Th2 cell-dependent IgM and IgG1 production following norepinephrine depletion in vivo.
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DOI：
10.4049/jimmunol.162.9.5299
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发表时间：
1999-05
影响因子：
4.4
通讯作者：
A. Kohm;V. Sanders
中科院分区：
文献类型：
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作者：
A. Kohm;V. Sanders
研究了交感神经递质去甲肾上腺素 (NE) 调节 Th2 细胞依赖性抗体反应的机制。我们的模型系统使用严重联合免疫缺陷 (scid) 小鼠，该小鼠在用 β2 肾上腺素能受体 (beta2AR)neg KLH 特异性 Th2 细胞克隆和从未免疫小鼠脾脏中富集的静息三硝基苯基 (TNP) 特异性 β2ARpos B 细胞重建之前，用 6-羟基多巴胺耗尽了 NE。在用 TNP-匙孔血蓝蛋白 (KLH) 攻击后，这些小鼠中的抗体产生具有半抗原、载体和同种异型特异性以及 MHC 限制。与 NE 完整对照相比，NE 的消耗导致初级抗 TNP IgM 反应抑制 50-75%，而次级 IgM 反应则恢复到对照水平。相比之下，初级和次级抗 TNP IgG1 反应分别被抑制 85% 和 40%。使用暴露于βAR或αAR选择性拮抗剂的NE完整小鼠，NE对Ab反应的影响被证明是由βAR介导的。此外，对 NE 耗尽的小鼠施用 β2AR 选择性激动剂部分逆转了 NE 耗尽导致的 Ab 反应抑制。通过放射性配体结合、免疫荧光和 cAMP 分析证实了 TNP 特异性 B 细胞上 beta2AR 的表达。此外，虽然在 Ag 暴露前，NE 完整小鼠和 NE 耗尽小鼠的脾脏组织学相当，但 Ag 暴露后，NE 耗尽小鼠中的卵泡扩张和生发中心形成受到抑制。综上所述，这些结果表明，NE 刺激 B 细胞上表达的 beta2AR 对于维持体内最佳的初级和次级 Th2 细胞依赖性抗体反应是必要的。
The mechanism by which the Th2 cell-dependent Ab response is modulated by the sympathetic neurotransmitter norepinephrine (NE) was investigated. Our model system used the severe combined immunodeficient (scid) mouse that was depleted of NE with 6-hydroxydopamine before reconstitution with a clone of beta2-adrenergic receptor (beta2AR)neg KLH-specific Th2 cells and resting trinitrophenyl (TNP)-specific beta2ARpos B cells enriched from the spleens of unimmunized mice. Following challenge with TNP-keyhole limpet hemocyanin (KLH), Ab production in these mice was hapten-, carrier-, and allotype-specific as well as MHC restricted. Depletion of NE resulted in a 50-75% suppression of the primary anti-TNP IgM response compared with that of NE-intact controls, while the secondary IgM response returned to control levels. In contrast, both the primary and secondary anti-TNP IgG1 responses were suppressed by 85 and 40%, respectively. Using NE-intact mice exposed to either a betaAR- or alphaAR-selective antagonist, the effect of NE on the Ab response was shown to be mediated by the betaAR. In addition, administration of a beta2AR-selective agonist to NE-depleted mice partially reversed the suppressed Ab response that resulted from NE depletion. Expression of the beta2AR on TNP-specific B cells was confirmed by radioligand binding, immunofluorescence, and cAMP analysis. Also, while splenic histology was comparable in NE-intact and NE-depleted mice before Ag exposure, follicle expansion and germinal center formation were suppressed in NE-depleted mice after Ag exposure. Taken together, these results suggest that NE stimulation of the beta2AR expressed on B cells is necessary for the maintenance of an optimal primary and secondary Th2 cell-dependent Ab response in vivo.