Dysregulated Immune State in PTSD Contributes to Microglial Inflammation

自2002年以来，已有250多万美国军人被部署到阿富汗或伊拉克战区， 根据退伍军人事务部的报告，每六个人中就有一个从"持久自由行动"/"伊拉克自由行动"竞技场返回 创伤后应激障碍由于只有一半的创伤后应激障碍退伍军人对治疗有反应，替代治疗方法 需要探索。创伤后应激障碍不仅包括临床症状的集群，还包括免疫失衡 向炎症的方向发展对人类和动物模型的研究表明， 炎症可以刺激神经炎症，进而改变行为。更多的研究表明 创伤后免疫对创伤后应激障碍的贡献。然而，对PTSD受试者的免疫分析已经被证明是正确的。 偶然的，研究没有考虑恢复外周免疫平衡的可能性， 神经炎症作为PTSD的一种新的免疫治疗方法。 本研究的假设是，PTSD患者的免疫失调状态与疾病状态平行， 并且可以促进炎性脑细胞反应。还假设来自受试者的白细胞 创伤后应激障碍可以从高度炎症状态转向平衡调节状态， 刺激脑细胞炎症活动的能力。 基本原理：虽然目前的研究并没有提出炎症是PTSD的主要原因， 支持创伤暴露后炎症和PTSD之间的因果联系。几项研究 显示刺激外周炎症导致脑小胶质细胞的激活， 警惕性过高易怒和焦虑如果创伤后应激障碍患者的炎症倾向性白细胞仍然保留 可塑性，然后有机会免疫重定向到一个功能平衡的状态， 不促进脑细胞炎症活动。以下具体目标将检验本研究的假设： 目的#1：定义PTSD中的免疫失衡，并证明PTSD患者的免疫失调状态 PTSD受试者与疾病状态平行。 目的#2：确定PTSD受试者白细胞的增强的小胶质细胞活化能力。 目标#3：将PTSD受试者的炎症偏斜血液白细胞重定向至平衡状态。 目的#4：确定是否将PTSD受试者的炎症偏斜血液白细胞重定向到 平衡的状态会阻止他们激活小胶质细胞的能力。 为了限制变量的影响，本研究将涉及严格控制和相对均匀的 在OEF/OIF竞技场中，所有退伍军人都有类似的战斗暴露水平，但有些人患有创伤后应激障碍 其他人的创伤后应激障碍检测呈阴性预计拟议的研究将显示免疫失衡 PTSD患者的炎症表型，这种不平衡状态刺激小胶质细胞， 炎症活动。对于开发PTSD免疫治疗方法的目标来说， 评估免疫可塑性，以确定PTSD受试者的白细胞是否可以从免疫系统中重定向。 炎性转化为平衡调节状态，小胶质细胞活化能力降低。 对退伍军人健康的重要性：尽管有心理和药物治疗， 对于创伤后应激障碍，大约一半的退伍军人仍然对这些治疗没有反应。由于外围 炎症可以影响大脑的炎症和行为，我们的研究定义了外周免疫的影响， 对脑小胶质细胞炎症反应性的影响，以及探讨免疫重定向的可行性。 失衡将为PTSD的新免疫方法铺平道路。与VHA一致 卓越蓝图"改善退伍军人的健康和福祉，并开发新的健康治疗 退伍军人特有的问题”，这项研究的目标是扩大急需的治疗武器 创伤后应激障碍退伍军人的治疗方法

Over 2.5 million U.S. service members have been deployed to Afghanistan or Iraq war zones since 2002 and, according to reports from the Department of Veterans Affairs, one in every six returns from this OEF/OIF arena with PTSD. Since only half of the Veterans with PTSD response to treatment, alternate treatment approaches need to be explored. PTSD consists not only clusters of clinical symptoms, but also immune imbalances toward an inflammatory state. Studies of humans and with animal models have shown that peripheral inflammation can stimulate neuroinflammation and, in turn, alter behavior. Added studies have suggested immune contributions to PTSD following trauma. However, immune analyses with PTSD subjects have been haphazard and studies have not considered the possibility of restoring peripheral immune balance to lessen neuroinflammation as a novel immunotherapeutic approach for PTSD. The hypothesis of the present study is that the dysregulated immune state in PTSD parallels disease status, and can contribute to inflammatory brain cell reactivity. Also hypothesized is that leukocytes from subjects with PTSD can be redirected from a hyper-inflammatory state toward a balanced regulated state, thus quenching their ability to stimulate brain cell inflammatory activity. Rationale: While the present study does not propose inflammation to be the primary cause of PTSD, there is support for a causative linkage between inflammation and PTSD following trauma exposure. Several studies with human subjects showed that stimulation of peripheral inflammation results in activation of brain microglia, hypervigilence, irritability and anxiety. If inflammation-skewed leukocytes of PTSD subjects still retain plasticity, then then there is the opportunity for immune redirection to a functionally balanced state that does not facilitate brain cell inflammatory activity. The following specific aims will test the hypothesis of this study: Aim #1: Define the immune imbalances in PTSD and demonstrate that the dysregulated immune state of PTSD subjects parallels disease status. Aim #2: Identify the heightened microglial-activating capacity of leukocytes of PTSD subjects. Aim #3: Redirect inflammation-skewed blood leukocytes from subjects with PTSD to a balanced state. Aim #4: Determine if redirecting the inflammation-skewed blood leukocytes of subjects with PTSD to a balanced state blocks their microglial-activating ability. To limit the influence of variables, this study will involve a tightly-controlled and relatively homogeneous population of Veterans, all with similar levels of combat exposure in the OEF/OIF arena, but some with PTSD and others testing negative for PTSD. The proposed studies are expected to show immunological imbalance toward an inflammatory phenotype in PTSD patients and that this imbalanced status stimulates microglial inflammatory activity. Important for the goal of developing immunotherapeutic approaches for PTSD is assessment of immune plasticity to determine if leukocytes of PTSD subjects can be redirected from an inflammatory to a balanced regulated state with diminished microglial-activating capacity. Significance to Veterans’ health: Despite the availability of psychological and pharmacological treatments for PTSD, about half of combat Veterans remain unresponsive to these treatments. Since peripheral inflammation can impact on brain inflammation and behavior, our study to define the peripheral immune impact on brain microglial inflammatory reactivity, as well as to explore the feasibility of redirecting the immune imbalances will pave the way for a novel immunotherapeutic approaches for PTSD. Consistent with the VHA Blueprint for Excellence for “improving Veteran health and well-being, and developing novel treatment of health issues that are unique to Veterans”, this study’s goal is to expand a much-needed armament of treatment approaches for Veterans with PTSD.