NEUROMODULATION IN THE ANTIBODY RESPONSE

临床和实验室研究表明，一种双向关系 存在于神经系统和免疫系统之间。了解如何 这种影响神经免疫功能的关系将鼓励 发展新的治疗方法来治疗与此相关的疾病 系统个体，如抑郁症或自身免疫性疾病。目的 本研究旨在研究去甲肾上腺素(NE)在T细胞中的作用。 依赖抗体反应。研究结果表明，淋巴器官 去甲肾上腺素纤维支配B细胞和CD_4~+T辅助细胞 (Th)细胞表达与去甲肾上腺素结合的β2肾上腺素受体。然而， 关于这一角色的研究产生了相互矛盾和有争议的结果 T细胞依赖抗体中去甲肾上腺素和β2受体的激活 回应。为了解决这一两难问题，我们提出了NE差异化 通过不同程度地影响Th细胞来影响抗体的产生 为B细胞提供帮助的亚群。两项发现表明Th细胞 子集可能对Beta2AR的激活做出不同的反应。首先，我们的 初步研究表明，Th1细胞表达，而Th2细胞不表达 转导信号以增加细胞内cAMP的β受体 集中精神。其次，细胞内cAMP的升高抑制了 Th1细胞分泌细胞因子，而Th2细胞不分泌细胞因子。因此，虽然 这两个Th细胞亚群都能够为B细胞提供帮助， NE结合Th1细胞可抑制Th1细胞提供的细胞因子支持 Beta2AR。因此，一个Th细胞亚群的优势优于 其他因素可能会深刻影响去甲肾上腺素如何调节抗体反应。 为了解决这种可能性，我们提出了去甲肾上腺素的假设 与Beta2AR结合可增加B细胞的频率 分化为抗体分泌细胞，但影响不同 这些B细胞通过抑制HELP产生的抗体量 由一个Th细胞子集提供，而不影响 其他的。为了评估这一假设，小鼠抗原特异性Th1和Th2 静息抗原特异性处女B细胞的克隆和富集群 将在体外用于解决以下具体目标：1) 确定Beta2AR的激活是否对抗体进行差异化调节 Th1和Th-2依赖反应的产生；2)确定 静息细胞上β2AR的表达水平及确定细胞是否 通过T细胞-B相互作用的激活改变表达；3) 确定负责调节差异的Th细胞机制 抗体反应；以及4)确定致病机制 介导β_2AR诱导的B细胞功能频率的增加 分化为抗体分泌细胞。已完成的 提出的实验将有助于更好地理解 交感神经系统在中枢神经系统中的作用 调节Th细胞依赖的抗体反应。

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.