Neuromodulation of the Antibody Response

描述（由申请方提供）：过敏反应的症状与IgE水平相关。然而，IgE在过敏反应中的确切作用尚未明确。因此，了解IgE反应是如何调节的将加速治疗干预措施的发展，以保持过敏反应的可控性。虽然调节通过类别转换重组产生IgE的B细胞的数量的免疫因子被充分表征，但是关于在成熟IgE转录水平上调节由B细胞产生的IgE的量的内在和外在因子知之甚少。这个研究项目的目标是双重的。首先，我们建议确定的机制，通过刺激B细胞上的AR的神经递质去甲肾上腺素（NE）参与IgE反应。第二，我们建议使用AR刺激对B细胞诱导的调节作用来帮助识别新的，并澄清公认的，IgE反应在AR刺激缺乏的情况下内在调节的机制。我们的实验室表明，22 AR刺激B细胞参与体内正常的IgE反应，并且加入NE或A β受体，AR激动剂对活化的B细胞培养物的作用增加了产生的IgE水平，而不影响类别转换重组（CSR），通过一种似乎抑制造血蛋白酪氨酸磷酸酶（HePTP）的机制，并增强p38 MAPK磷酸化以介导ADAM 10的增加，ADAM 10将膜CD 23切割成可溶形式。到目前为止，尚未在B细胞中研究AR介导的HePTP调节以控制p38 MAPK磷酸化，并且似乎是IgE调节所特有的。此外，连接p38 MAPK活化与ADAM 10表达和调节其sCD 23裂解（介导IgE调节）的基本免疫学机制仍不清楚。我们建议检验这样的假设，即对活化的B细胞的AR刺激调节蛋白酪氨酸磷酸酶，以增加活化诱导的信号传导途径的水平，从而促进成熟IgE转录速率的增加。检验我们假设的相关性在于，这些发现将定义IgE产生所特有的新型信号传导中间体，然后可以通过治疗来靶向IgE介导的过敏反应，并可能解释为什么长期常规AR激动剂治疗和/或应激会加剧过敏发作。公共卫生相关性：IgE与过敏反应有关。众所周知，压力会增加过敏反应的严重程度。我们建议研究神经系统在压力下释放的神经递质如何影响IgE的产生，这样我们就可以开发药物来帮助那些有不良反应的人。

DESCRIPTION (provided by applicant): The symptoms of an allergic response are associated with the level of IgE. However, the exact role of IgE in an allergic response is not well defined. Therefore, understanding how the IgE response is regulated will hasten the development of therapeutic interventions to keep an allergic response manageable. While immune factors that regulate the number of B cells that produce IgE through class switch recombination are well-characterized, little is known about the intrinsic and extrinsic factors that regulate the amount of IgE produced by a B cell at the level of mature IgE transcription. The goal of this research project is two-fold. First, we propose to identify the mechanism by which stimulation of the ¿AR on a B cell by the neurotransmitter norepinephrine (NE) participates in an IgE response. And second, we propose to use the modulatory effect induced by ¿AR stimulation on a B cell to help identify new, and clarify accepted, mechanisms by which the IgE response is regulated intrinsically in the absence of ¿AR stimulation. Our laboratory showed that 22AR stimulation on a B cell participates in a normal IgE response in vivo, and that the addition of NE or a ¿AR agonist to a culture of activated B cells increases the level of IgE produced, without affecting class switch recombination (CSR), through a mechanism that appears to inactivate Hematopoetic protein tyrosine phosphatase (HePTP) and enhance p38 MAPK phosphorylation to mediate an increase in ADAM10, which cleaves membrane CD23 to a soluble form. Thus far, ¿AR mediated regulation of HePTP to control p38 MAPK phosphorylation has not been studied in a B cell and appears to be unique to IgE regulation. Also, the basic immunological mechanism that links p38 MAPK activation to ADAM10 expression and regulation of its cleavage of sCD23, which mediates regulation of IgE, remains unknown. We propose to test the hypothesis that ¿AR stimulation on an activated B cell regulates a protein tyrosine phosphatase to augment the level of activation- induced signaling pathways to promote an increase in the rate of mature IgE transcription. The relevance of testing our hypothesis is that the findings will define novel signaling intermediates unique to IgE production, which may then be targeted by therapeutics to diminish an IgE-mediated allergic response, and may possibly explain why long-term conventional ¿AR agonist therapy and/or stress exacerbate an allergic episode. PUBLIC HEALTH RELEVANCE: IgE is associated with an allergic response. Stress is known to increase the severity of an allergic response. We propose to study how a neurotransmitter released by the nervous system during stress affects the production of IgE, so that we can develop drugs to help individuals that respond adversely.