Role of Neuroendocrine Stress Response in Inflammatory and Behavioral Illness.

项目I：汗斑生物标记物：临床研究。我们以前发现，神经和免疫生物标记物可以在汗液中检测到，并与临床缓解期的一组患有严重抑郁障碍(MDD)的女性的血浆水平密切相关(Marque-Deak，2006，J免疫学方法；Cizza 2008，生物精神病学)。尤其是促炎细胞因子升高，交感神经肽Y(NPY)和感觉/疼痛相关神经肽P物质(SP)和降钙素基因相关肽(CGRP)升高，而副交感神经肽血管活性肠肽(VIP)显著降低。这一模式与MDD从副交感音调向交感音调的转变以及潜在的促炎状态一致，这可能是MDD对已知与MDD共同表达的疾病的易感性增加的原因，包括心血管疾病、骨质疏松症和糖尿病。此外，生物标记物水平与抑郁和焦虑症状密切相关，表明这些生物标记物的功能意义。为了确定特定生物标记物特征反映特定疾病或健康状况的程度，在2010财年，我们与其他NIH研究所和校外机构合作，在五个正在进行的IRB批准的临床方案中应用汗片生物标记物，包括：(I)埃默里大学TRD-Infliximab研究。(Ii)巴西--强迫症研究(NIH IRB 3737号议定书)；(3)Emory/CDC CFS研究(Emory University IRB 000551-2005年，NIMH OHSR豁免#4026)；(Iv)NCCAM--太极/癌症幸存者研究(NCI#06-AT-0016)；(V)GSA--工作环境研究(NIA IRB 2003-142)。研究(V)的结果(GSA工作场所研究)表明，工作场所环境的物理特征与生理应激反应的测量变化有关，这表明，与新办公室相比，占据旧办公室空间的受试者在醒来时唾液皮质醇的上升更大，心率变异性的昼夜变化更平缓(塞耶等人)。2010欧元J心脏康复)。 项目II综述：糖皮质激素抵抗、炎症和行为的动物模型：在我们评估孕酮对免疫细胞(DC)功能和成熟的影响以及女性性激素在宿主防御中的作用的研究中，我们发现，在非妊娠相关浓度下，通过孕酮受体(PR)介导的机制，孕酮抑制成熟DC促炎细胞因子的产生、细胞表面标志物的表达(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抗原的摄取几乎没有影响(Butts等人)。2009方法：Mol Biol；Butts et al.2010粘膜免疫)。这些效应可与糖皮质激素对DC功能的影响相媲美，表明孕酮在调节女性的先天免疫和获得性免疫中起重要作用。我们还发现，孕酮对DC功能的影响在啮齿动物的动情周期中是不同的，并且依赖于PR的表达，在体外和体内的整个周期中，PR的表达是不同的，并且对不同组织的DC也有不同的影响。这表明，在整个发情周期中，雌性动物的免疫反应在生理上是不同的，这对在发情周期和妊娠期间对感染和炎症的临床易感性具有重要的意义。荷尔蒙状态的这种生理波动也可能影响对情绪起作用的细胞反应。由于已知细胞因子可以影响情绪，并可能在某些形式的抑郁症以及疾病行为中的情绪变化中发挥作用，孕酮等因素可以改变细胞产生的细胞因子，从而导致女性在整个生命周期中对情绪障碍的不同易感性。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有关(Butts等人。2010年出版《Brain Beh Immun》。)提示GR的表达可能在局部炎症的严重程度及其病理后遗症中起一定作用。

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.