Peripheral and central nervous system inflammation associated with military sexual trauma and PTSD

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Military sexual trauma (MST) is unfortunately common in Veterans, particularly in women, and has life- long consequences for physical and mental health. MST, which includes both sexual assault and harassment, is strongly associated with post-traumatic stress disorder (PTSD) and co-morbid conditions including, depression, anxiety, substance use, obesity and eating disorders, chronic pain, and autoimmunity. While other psychiatric conditions, including depression and anxiety, are associated with inflammation, PTSD is uniquely associated with a >50% increase in autoimmune disorder prevalence (e.g., rheumatoid arthritis, thyroiditis, and inflammatory bowel disease). Exposure to MST further increases the risk of developing an autoimmune disorder by over two-fold. Although increased peripheral inflammation is well characterized in PTSD, it is unclear if peripheral inflammation reflects a disruption in immune signaling in the central nervous system (CNS). Moreover, phenotyping the immune dysregulation that occurs with PTSD has almost exclusively occurred through cross-sectional data collection. However, without longitudinal studies that track immune biomarkers in conjunction with symptoms, it is unknown if immune biomarkers have clinical utility in guiding treatment. Furthermore, while epidemiological data support that trauma disorders, particularly MST, may have shared risk factors with autoimmune disorders, it is unknown if MST confers unique effects on immune signaling. Filling these gaps is critical to understanding if and how immune dysregulation contributes to symptom "state" in Veterans with MST to inform its viability as a potential mechanism for targeted treatment. This proposal will address these knowledge gaps by quantifying circulating inflammatory cytokines in Veterans with MST-related PTSD (+MST/+PTSD) and comparing cytokine levels to Veterans without PTSD or MST. In addition to examining circulating plasma cytokines, we will also measure cytokines and miRNA isolated from and astrocyte-derived exosomes (ADEs), which are extracellular vesicles that carry RNA and protein cargo to the blood from the CNS. Measuring biomarkers from exosome populations derived from CNS- tissue sources can non-invasively assess neuroinflammation and compare peripheral vs. central inflammation links to PTSD symptoms. We hypothesize that levels of baseline peripheral (plasma) and central (exosome) inflammatory markers will be altered in female Veterans with +MST/+PTSD compared to female Veterans without MST or PTSD. Based on the existing literature of psychoneuroimmunologic correlates of PTSD, we will quantify IL-1β, IL-2, IL-6, IFNγ, and TNFα cytokines from both plasma and exosome cargo using multiplex arrays. We will also quantify immune regulatory miRNA from exosome cargo. In the +MST/+PTSD group, we will also collect plasma samples at 3- and 6-month follow-up visits to determine if inflammatory biomarkers are associated with symptom trajectory across time. A highly stable marker that does not track with symptoms would suggest it is a marker of risk. In contrast, if a marker changes alongside symptom severity over time, it may be a marker of mechanisms driving symptom change. We hypothesize that immune marker profiles will correspond with symptom trajectory over time. The biological consequences of MST represent a significant health burden for Veterans, especially women with already higher MST and autoimmunity rates. Understanding the mechanistic link between MST and peripheral and central inflammation will inform our understanding of immune disruption as a biomarker for diagnosis, prognosis, and potential treatment targets. Building on the applicant's experience studying immune signaling and immune contributions to PTSD risk, the proposed training plan will provide the necessary skills to independently design and implement novel biomarker-guided approaches to improve patients' lives with neuropsychiatric illness. Completing the proposed research will further support the VA mission towards developing precision medicine tools for Veteran care in Women's and mental health.