Role of Neuroendocrine Stress Response in Inflammatory and Behavioral Illness.

项目I.汗斑生物标志物：临床研究。我们先前表明，神经和免疫生物标志物在汗液中是可检测的，并且与临床缓解期的一组患有重性抑郁症（MDD）的女性的血浆水平强烈相关（Marques-Deak，2006，J Immunol Methods; Cizza 2008，Biol Psych）。具体而言，促炎细胞因子升高，交感神经肽神经肽Y（NPY）和感觉/疼痛相关神经肽，P物质（SP）和CGRP（降钙素基因相关肽），而副交感神经肽血管活性肠肽（VIP）显着降低。这种模式与MDD从副交感神经紧张到交感神经紧张的转变以及潜在的促炎状态一致，这可能导致对已知与MDD共病表达的疾病（包括心血管疾病、骨质疏松症和糖尿病）的易感性增强。此外，生物标志物水平与抑郁和焦虑症状密切相关，表明这些生物标志物谱的功能意义。为了确定特定生物标志物谱反映特定疾病或健康状况的程度，在2010财年，我们与其他NIH研究所和校外研究所合作，在五项正在进行的IRB批准的临床方案中应用了汗斑生物标志物，包括：（i）埃默里大学TRD-英夫利昔单抗研究。（Emory University IRB 00011734，NIMH OHSR豁免#4025）;（ii）巴西- OCD研究（NIH方案IRB 3737）;（iii）Emory/CDC CFS研究（Emory University IRB 000551-2005，NIMH OHSR豁免#4026）;（iv）NCCAM -太极/癌症幸存者研究（NCI方案#06-AT-0016）; GSA -工作环境研究（NIA IRB 2003-142）。研究（v）（GSA工作场所研究）的结果表明，工作场所环境的物理特征与生理应激反应的改变相关，如与新办公室空间中的受试者相比，在旧办公室空间中的受试者中唤醒时唾液皮质醇的更大上升和心率变异性的更平坦的昼夜节律变化所示（Thayer等人，2010 Eur J Prev Rehabil）。 项目II摘要：糖皮质激素抵抗、炎症和行为的动物模型：在我们的研究中，评估了孕酮对免疫细胞的影响，（树突状细胞，DC）的功能和成熟以及雌性性激素在宿主防御中的作用，我们发现孕酮在非妊娠相关浓度下并通过孕酮受体（PR）介导的机制抑制成熟DC产生促炎细胞因子，细胞表面标志物表达（共刺激分子和趋化因子受体）和刺激T细胞增殖，但对未成熟DC抗原摄取几乎没有影响（Butts et al.2009 Methods Mol Biol; Butts et al.2010 Mucobacterium Immunol）。这些效果，这是可比的糖皮质激素对DC功能，表明孕酮在调节女性的先天性和适应性免疫中起着重要的作用。我们还发现孕酮对DC功能的影响在整个啮齿动物发情周期中变化，并且依赖于PR表达，PR表达在体外和体内的整个周期中变化，并且还差异地影响来自不同组织的DC。这表明，女性的免疫反应在整个发情周期的生理变化，并在周期和怀孕期间对感染和炎症的临床易感性具有重要意义。激素状态的这种生理波动也可能影响在情绪中发挥作用的细胞反应。由于已知细胞因子会影响情绪，并且可能在某些形式的抑郁症以及疾病行为的情绪改变中发挥作用，因此改变细胞产生细胞因子的因素如孕酮可能有助于女性在整个生命周期中的不同情绪障碍易感性。在2010财年，我们还显示了免疫细胞中糖皮质激素受体（GR）表达的组织特异性差异，这与病毒感染小鼠模型中组织损伤的存在相关（Butts et al. in press 2010 Brain Beh Immun.）这表明GR表达可能在局部炎症的严重程度及其病理后遗症中起作用。

PROJECT I. Sweat Patch Biomarkers: Clinical Studies. We previously showed that neural and immune biomarkers are detectable in sweat and strongly correlate with plasma levels in a group of women with major depressive disorder (MDD) in clinical remission (Marques-Deak, 2006, J Immunol Methods; Cizza 2008, Biol Psych). Specifically, pro-inflammatory cytokines were elevated, as was the sympathetic neuropeptide neuropeptide Y (NPY) and the sensory/pain-related neuropeptides, substance P (SP) and CGRP (calcitonin gene-related peptide), while the parasympathetic neuropeptide vasoactive intestinal polypeptide (VIP) was significantly decreased. This pattern is consistent with a shift in MDD from parasympathetic to sympathetic tone, and an underlying pro-inflammatory state that could account for enhanced susceptibility to conditions known to be co-morbidly expressed with MDD, including cardiovascular disease, osteoporosis and diabetes. Moreover, biomarker levels strongly correlated with symptoms of depression and anxiety, indicating functional significance of these biomarker profiles. In order to determine the extent to which particular biomarker profiles reflect specific diseases or a state of health, in FY10 we are applying sweat patch biomarkers in five ongoing IRB approved clinical protocols in collaboration with other NIH institutes and extramural insitutions, including: (i) Emory University TRD-Infliximab Study. (Emory University IRB 00011734, NIMH OHSR Exemption #4025); (ii) Brazil - OCD Study (NIH protocol IRB 3737); (iii) Emory/CDC CFS Study (Emory University IRB 000551-2005, NIMH OHSR Exemption #4026); (iv) NCCAM - Tai Chi/Cancer Survivor Study (NCI protocol #06-AT-0016); (v) GSA - Work Environment Study (NIA IRB 2003-142). Results of study (v), (GSA Workplace Study) indicate that physical features of the workplace environment are associated with altered measures of the physiological stress response, as indicated by a greater rise in salivary cortisol upon awakening and flatter circadian variation of heart rate variability in subjects occupying old office space compared to those in new office space (Thayer et al. 2010 Eur J Cardiovasc Prev Rehabil). Project II Summary: Animal Models of Glucocorticoid Resistance, Inflammation and Behavior: In our studies evaluating the effects of progesterone on immune cell (dendritic cell, DC) function and maturation and the role of female sex hormones in host defense, we found that progesterone in non-pregnancy-associated concentrations and through a progesterone receptor (PR)-mediated mechanism suppresses mature DC production of pro-inflammatory cytokines, cell surface marker expression (co-stimulatory molecules and chemokine receptors) and stimulation of T cell proliferation, but has little effect on immature DC antigen uptake (Butts et al. 2009 Methods Mol Biol; Butts et al. 2010 Mucosal Immunol). These effects, which are comparable to those of glucocorticoids on DC function, indicate that progesterone plays an important role in regulation of innate and adaptive immunity in females. We also found that progesterone effects on DC function vary throughout the rodent estrus cycle and are dependent on PR expression, which varies throughout the cycle in vitro and in vivo, and also differentially affects DCs from different tissues. This indicates that females' immune responses vary physiologically throughout the estrus cycle, and has important implications for clinical susceptibility to infection and inflammation during the cycle and during pregnancy. Such physiological fluctuations in hormone status could also impact cellular responses that play a role in mood. Since cytokines are known to affect mood, and may play a role in some forms of depression as well as in mood alterations in sickness behavior, factors such as progesterone, which alter cytokine production by cells could contribute to differential mood disorder susceptibilities in females throughout the life cycle. In FY2010 we also showed tissue specific differences in glucocorticoid receptor (GR) expression in immune cells, which correlated with presence of tissue damage in a mouse model of viral infection (Butts et al. in press 2010 Brain Beh Immun.) This suggests that GR expression may play a role in severity of local inflammation and its pathological sequelae.