A Genetic Basis for Stress-Neuroendocrine-Immune Interactions

描述（由申请人提供）：尽管免疫系统曾被认为是自主发挥功能的，但现在有令人信服的证据表明，心理应激诱导的神经内分泌衍生肽和激素在调节免疫的许多方面发挥关键作用。下丘脑-垂体-肾上腺（HPA）轴的激活和皮质酮/皮质醇的产生是应激诱导免疫功能效应的主要介质，部分受阿片受体调节。然而，调节HPA轴活性的遗传因素尚未阐明。 最近在人类阿片受体基因中发现了一种相对常见的单核苷酸功能多态性（SNP）（OPRM 1; A118 G核苷酸交换;氨基酸残基40处的天冬酰胺至天冬氨酸变化）。有趣的是，这种SNP的分布与特定种族和人种的分布沿着 并且它的存在最近与对疼痛的敏感性增加和对阿片样物质的镇痛反应降低有关。此外，具有该A118 G等位基因的至少一个拷贝的个体表现出皮质醇的基础水平增加和对行为应激的皮质醇反应降低。皮质醇水平的这些变化如何影响对传染性病原体的免疫力以及对疫苗接种的保护性免疫力的发展仍有待确定。本文所述的研究联合收割机结合了基础科学家的兴趣和专业知识，其研究根源是应激相关的神经免疫学，以及临床医生-科学家对遗传-应激相互作用的兴趣和专业知识，以测试A118 G多态性改变HPA轴对急性和慢性心理应激的反应的假设，这反过来，影响对单纯疱疹病毒（HSV）感染的基于细胞毒性T淋巴细胞（CTL）的适应性免疫应答的程度。这些研究将利用小鼠应激模型和HSV特异性免疫的测量，这些研究者具有相当丰富的经验。这些研究将为长期研究提供基础，以确定这种A118 G SNP对人类神经内分泌应激反应、先天性和适应性免疫、对感染性病原体的抵抗力以及对疫苗接种的反应能力的影响。这些研究的结果反过来可能会促进干预策略的利用，以最大限度地减少那些携带至少一个A118 G等位基因拷贝的个体的压力水平，这些个体可能无法有效地表达他们的心理和身体压力感受以及他们对减压干预的需求。

DESCRIPTION (provided by applicant): Although the immune system was once thought to function autonomously, there is now compelling evidence that psychological stress-induced, neuroendocrine-derived peptides and hormones play a key role in regulating numerous aspects of immunity. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and the production of corticosterone/cortisol is a major mediator of stress-induced effects on immune function and is modulated, in part, by the ¿ opioid receptor. However, the genetic factors which regulate HPA axis activity have not yet been elucidated. A relatively common single nucleotide functional polymorphism (SNP) has recently been identified in the human ¿ opioid receptor gene (OPRM1; A118G nucleotide exchange; asparagine-to-aspartic acid change at amino acid residue 40). Interestingly, the distribution of this SNP is closely aligned along specific races and ethnicities and its presence has recently been associated with increased sensitivity to pain and a reduced analgesic response to opioids. In addition, individuals having at least one copy of this A118G allele exhibit increased basal levels of cortisol and a decreased cortisol response to a behavioral stressor. How these alterations in the levels of cortisol affect immunity to infectious pathogens and the development of protective immunity in response to vaccinations remains to be determined. The studies described herein combine the interests and expertise of a basic scientist with research roots in stress-associated neuroimmunology and a clinician-scientist with interest and expertise in genetic-stress interactions, to test the hypothesis that the A118G polymorphism alters the HPA axis response to acute and chronic psychological stress which, in turn, affects the magnitude of the cytotoxic T lymphocyte (CTL)-based adaptive immune response to herpes simplex virus (HSV) infection. These studies will utilize a murine model of stress and measurements of HSV-specific immunity with which these investigators have considerable experience. Such studies will provide a foundation for longer-term studies to determine the impact of this A118G SNP on the human neuroendocrine response to stress, innate and adaptive immunity, resistance to infectious pathogens, and the ability to respond to vaccinations. The results from these studies may, in turn, promote the utilization of interventional strategies to minimize the levels of stress in individuals who harbor at least one copy of the A118G allele and who may not be able to effectively verbalize their feelings of psychological and physical stress and their need for stress-reduction intervention.