PTSD is Associated With an Excess of Inflammatory Immune Activities

Perspectives in Psychiatric Care, Oct 2009 by Gill, Jessica M, Saligan, Leo, Woods, Stephanie, Page, Gayle

PURPOSE. Post-traumatic stress disorder (PTSD) is associated with inflammatory-related medical conditions. This review examines studies of immune function in individuals with PTSD to determine if excessive inflammation is associated with PTSD.

CONCLUSIONS. Current studies suggest an excess of inflammatory actions of the immune system in individuals with chronic PTSD. High levels of inflammatory cytokines have also been linked to PTSD vulnerability in traumatized individuals. There is also evidence that excessive inflammation is in part due to insufficient regulation by cortisol.

PRACTICE IMPLICATIONS. An excess of inflammatory immune activity may contribute to health declines in individuals with PTSD, and treating PTSD symptoms may reduce these risks.

Search terms: Cortisol, immune, inflammatory, PTSD, trauma

Post-traumatic stress disorder (PTSD) may develop following exposure to a traumatic event and is associated with debilitating physical and psychological health declines (Boscarino, 2006; Keane, Marshall, & Taft, 2006; Kimerling, 2004). In the United States, lifetime prevalence rates of PTSD have been estimated to be 5% for men and 10% for women (Breslau, 2002; Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995; Schnurr, Friedman, & Bernardy, 2002). Symptoms of PTSD include re-experiencing the traumatic event through intrusive dreams or thoughts; physiologic arousal to stimuli that represent the trauma; numbing of feelings and avoidance of thoughts, feelings, people, and activities that symbolize the trauma.

The immune system is well regulated; however, psychological stress can exert an excessive demand on regulatory functions, particularly if the stressor is excessive or prolonged, resulting in risk for excessive inflammation (Fries, Hesse, Hellhammer, & Hellhammer, 2005). Current studies have reported immune function alterations in individuals with PTSD, yet the data are inconclusive, leading to an insufficient understanding of the nature of immune function alterations in PTSD. Chronic PTSD has been associated with excessive inflammation, yet this finding is not universal. The purpose of this critical review is to determine the nature of immune function in individuals with PTSD. (For assistance with the terms used in this article, please see the Appendix.)

Background

The Stress Response

When an individual encounters a stressor such as a traumatic event, the hypothalamic-pituitary-adrenal (HPA) axis becomes activated, resulting in higher levels of Cortisol, nor-epinephrine, and epinephrine to help the individual respond to the stressor in an acute manner (i.e., the fight or flight response). Cortisol's role is to augment energy resources by reducing the activity of bodily systems, including the immune system, as well as elevating blood glucose levels. Cortisol also extinguishes the acute stress response by activating the negative feedback system on the HPA axis and the hippocampus through glucocorticoid receptors (GCR) (Fries et al., 2005; Weiss, 2007). These mechanisms are protective if the stressor is acute; however, if the stressor is excessive or prolonged, adaptations can increase the risk for excessive inflammation (Pervanidou et al., 2007; Sternberg, 2006).

Balance of Immune Function

The immune system is affected in PTSD, resulting in excess inflammation and health risks (see Figure 1). Following a trauma, the HPA axis is activated. In PTSD, the HPA axis is often dysregulated, resulting in altered Cortisol activity and levels. A dysregulated HPA axis may result in excessive inflammation through insufficient regulation of immune function. Naïve CD4 cells usually differentiate to produce primarily either cellmediated (ThI) cytokines (interleukin [IL] IL-2, IL-8, IL-12, interferon [IFN]) or humoral (Th2) cytokines (IL-4, IL-10, IL-13), depending on the cytokine milieu, levels and activity of Cortisol, and other substances (Padgett & Glaser, 2003). Epigenetic factors also drive T-cell differentiation into specific subsets by inducing chromatin remodeling and altering transcriptional accessibility of key cytokine genes, and these changes are carried over throughout cell division to ensure selective survival of either ThI or Th2 dominant cytokine producing T-cells (Sawalha, 2008). An imbalance of immune activities can occur if naïve CD4 cells produce differential amounts of cell-mediated or humoral cytokines, and this imbalance can be difficult to correct (Kiecolt-Glaser et al., 2003; Raison & Miller, 2003). However, cytokines also work synergistically. Pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α], IL-1β, and IL-6) initiate a spectrum of biological activities that coordinate the body's response to antigens. Therefore, an appropriate balance of ThI, Th2, and acute-phase-reaction cytokines are needed to provide optimal host protection by the immune system.

Bidirectional Communication between the HPA Axis and the Immune System

Immune responses are regulated by the HPA axis in an effort to protect the individual from excessive inflammation. The HPA axis releases Cortisol and dehydroepiandrosterone (DHEA), and their balance modulates the immune response. During stress, cortisol levels are elevated, causing a reduction in ThI immune responses. Cortisol alters this balance by binding with GCR in lymphocytes that inhibit nuclear factor kappa B and other intracellular proinflammatory signaling pathways. This results in a shift to a predominance of humoral (Th2) immune activities (Raison & Miller, 2003).