A Genetic Basis for Stress-Neuroendocrine-Immune Interactions

描述(申请人提供)：虽然免疫系统曾经被认为是自主运作的，但现在有令人信服的证据表明，心理压力诱导的神经内分泌衍生多肽和激素在调节免疫的许多方面发挥着关键作用。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的免疫功能效应的主要中介，部分受阿片受体的调节。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(OPRM1；A118G核苷酸交换；氨基酸残基40位天冬氨酸到天冬氨酸的变化)中发现了一种相对常见的单核苷酸功能多态性(SNP)。有趣的是，这种SNP的分布与特定的种族和民族密切相关 最近，它的存在与对疼痛的敏感性增加和对阿片类药物的止痛反应减弱有关。此外，至少有一个A118G等位基因拷贝的个体表现出皮质醇基础水平升高和对行为应激源的皮质醇反应降低。皮质醇水平的这些变化如何影响对感染病原体的免疫以及疫苗接种后保护性免疫的发展仍有待确定。这里描述的研究结合了一位具有应激相关神经免疫学研究根基的基础科学家和一位对遗传-应激相互作用感兴趣和专业的临床科学家的兴趣和专业知识，以测试A118G基因多态改变HPA轴对急性和慢性心理应激的反应，进而影响基于细胞毒性T淋巴细胞(CTL)的针对单纯疱疹病毒(HSV)感染的适应性免疫反应的幅度的假设。这些研究将利用小鼠应激模型和HSV特异性免疫测量，这些研究人员对此有相当丰富的经验。这些研究将为长期研究提供基础，以确定这种A118G SNP对人类神经内分泌应激反应、先天和获得性免疫、对感染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使用，以最大限度地减少携带至少一个A118G等位基因副本的个人的压力水平，这些人可能无法有效地用言语表达他们的心理和身体压力感觉以及他们对减压干预的需求。 公共卫生相关性：这些研究将开始确定基因组成的微小变化如何控制心理压力期间产生的荷尔蒙，以及这些荷尔蒙如何影响一个人对传染病的自然免疫力以及接种疫苗所提供的免疫力。这类研究最终可能导致旨在减少应激对免疫的影响和/或减轻应激本身的治疗方法，特别是在那些其基因组成导致有害免疫功能抑制的个人中。

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. PUBLIC HEALTH RELEVANCE: These studies will begin to determine how very small changes in gene composition control the hormones that are produced during psychological stress and how these hormones affect one's natural immunity to infectious diseases and the immunity that is afforded by vaccination. Such studies could ultimately result in treatments that are designed to reduce the impact of stress on immunity and/or reduce the stress itself, particularly in those individuals whose genetic composition results in a detrimental suppression immune function.