Dysregulated Immune State in PTSD Contributes to Microglial Inflammation

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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.