Invited reviewBiomarkers of PTSD: Neuropeptides and immune signaling
Highlights
► Review of evidence that cellular immunity is implicated in PTSD risk and resilience. ► Indications for specific neuroendocrine-immune abnormalities in PTSD are emerging. ► Strong evidence for systemic inflammation and harmful health consequences in PTSD. ► CNS inflammation is implicated in major depression and potentially also in PTSD. ► Need for research on immune system contribution to PTSD vulnerability / progression.
Introduction
In 1927, the Nobel Prize was granted to psychiatrist Julius Wagner-Jauregg for his success in altering the course of a mental illness by using an infectious agent to induce a fever, a treatment that illuminated the profound influence of the immune system on the brain (Howes et al., 2009, Raju, 1998). It took another half century for science to explain mechanisms underlying his success, but ultimately new methods, e.g. the ability to clone the genes encoding cytokines and their receptors, provided essential tools to identify immune system peptide mediators, the cytokines in the brain circuitry and to demonstrate their roles in the central nervous system (CNS) (Licinio and Wong, 2003). The prior discovery of CNS neurotransmitters, corticotrophin-releasing hormone (CRH) (Vale et al., 1983) and norepinephrine (NE) (Euler, 1946) and the fundamental role of these peptides and their effector systems, the hypothalamic pituitary adrenal (HPA) axis and sympathetic nervous system (SNS) in the stress response, permitted detection of the multiple bi-directional immune–neuroendocrine interactions at all levels of the organism; within the brain circuitry, in the periphery and at the blood–brain barrier interface (Chrousos, 2009, Elenkov et al., 2005, Sternberg, 2006, Thayer and Sternberg, 2010, Yirmiya and Goshen, 2010). More remarkably, in the past decade investigations have demonstrated immune roles in the CNS beyond neuroprotection and inflammation, presenting increasingly strong evidence for the participation of immune system mediators in core behavioral functions such as adult neurogenesis, as well as in processes that underlay synaptic plasticity, e.g. learning, memory (Khairova et al., 2009, McAfoose and Baune, 2009, Ransohoff, 2009, Yirmiya and Goshen, 2010).
Furthermore, the emerging awareness that immune system cells and molecules are physiological participants in the response to psychological stress, unassociated with infectious or physical injury, has led to a conceptual shift in understanding of the interrelations of immune system, brain and behavior (Besedovsky and Del Rey, 2010, Kioussis and Pachnis, 2009, McAfoose and Baune, 2009, Molina-Holgado and Molina-Holgado, 2010, Schwartz and Shechter, 2010). Key concepts in this emerging model are that the nervous and immune systems co-evolved and continue to share mechanisms of gene regulation, signaling, cell communication and supracellular organization; that cascades unleashed under normal physiological conditions and in response to psychological, physical, or infectious challenges are tightly controlled, specific to the challenge encountered, and serve to maintain adequate metabolic, adaptive-coping and defensive functions; and, that the immune system supports the brain, i.e. that adequate functioning of immune mechanisms are essential for learning and memory under basal conditions and to support an optimal coping response (Besedovsky and Del Rey, 2010, Kioussis and Pachnis, 2009, Meffert and Baltimore, 2005, Molina-Holgado and Molina-Holgado, 2010, Schwartz and Shechter, 2010, Su et al., 2010, Yirmiya and Goshen, 2010).
There is a rapidly expanding literature on stress, acute and chronic, and its contribution to innate immune system activation leading to peripheral inflammation, which is associated with early morbidity and mortality (Elenkov et al., 2005, Fransson et al., 2010, Gianaros and Manuck, 2010, Seeman et al., 2010, Wassel et al., 2010). This literature links excessive CNS stress responsivity via intermediate physiology, e.g. basal levels of autonomic cardiac control, stressor evoked hemodynamic reactivity, diurnal variation in cortisol output and an increase in pro-inflammatory biomarkers, to negative health outcomes (Gianaros et al., 2009, Gianaros and Sheu, 2009, McEwen and Gianaros, 2010b). PTSD is among the disorders that show evidence of enhanced CNS reactivity, increased inflammation and deleterious health consequences; evidence reviewed in 2003 will be expanded upon and discussed (Baker et al., 2003).
Likewise, in the past decade, an impressive body of research has accumulated on the role of the innate immune system and inflammation in the pathophysiology of major depressive disorder (MDD) (Hayley and Anisman, 2005, Loftis et al., 2010, Miller et al., 2009, Raison et al., 2006, Raison et al., 2010). Given the commonality of depressive symptoms in individuals with PTSD, many of the physiological mechanisms invoked in the MDD literature may be relevant to PTSD, especially for individuals with co-morbid PTSD/MDD. Interestingly there are data to suggest that the underlying genetics of inflammation and mental health outcomes may be partially shared. A twin study that sought to determine if inflammation and MDD share common genes found a significant genetic correlation between the inflammatory cytokine marker, interleukin-6 (IL-6) and depressive symptoms (ρG = 0.22, p = 0.046), indicating that a portion of the covariance between them could be explained by shared genetic influences (Su et al., 2009).
However, the core symptoms of PTSD that persist after emotionally traumatic events, such as intrusive and disruptive recurrence of distressing emotion-laden memories, avoidance of those memories, and continued CNS arousal and excess reactivity are distinctly different from core symptoms of MDD, thus are unlikely to be fully explained by physiological mechanisms uncovered for MDD (Miller et al., 2009, Raison et al., 2010, Shelton and Miller, 2010). But, given recent advances in pre-clinical research showing the role of immune cells, e.g. microglia and astrocytes, and pro-inflammatory CNS cytokines, such as IL-6, interleukin 1 (IL-1), and tumor necrosis factor alpha (TNF-α) in crucial brain functions such as learning and memory, where they interact with neuronal glutamate and γ-aminobutyric acid (GABA) signaling to modulate long term potentiation (LTP) as well as to support neurogenesis, the infrastructure is in place for an immune system role in the resolution or exacerbation of fear-based memories following a traumatic event (for reviews see Tambuyzer et al., 2009, Verkhratsky, 2010, Yirmiya and Goshen, 2010). Likewise, another recently published line of pre-clinical evidence suggests that during stress, components of the acquired immune system, protective T cells, can traffic to the cerebrospinal fluid (CSF) blood brain barrier (BBB) interface, directed there by molecules such as chemokines and glucocorticoids (Lewitus et al., 2008, Ransohoff, 2009). These cells have been hypothesized to play a neuroprotective role in the context of emotional stress, injury and infection (for reviews see Miller, 2009, Schwartz and Shechter, 2010).
The clinical literature on immune mediators in PTSD is in its infancy, consisting mostly of data on peripheral immune markers, with the exception of a single CSF study of cytokines in PTSD (for reviews see Baker et al., 2001, Baker et al., 2003, Gill et al., 2009). The current research will be discussed in light of the expanding literature on inflammation as well as the emerging understanding of the relationship between inflammation, depressive symptoms and adult neurogenesis. Additionally, aspects of the pre-clinical literature supporting the role of the immune system in brain plasticity will be reviewed in regards to how these studies may apply to PTSD vulnerability, as will be the literature hypothesizing a protective role for central trafficking T cells in PTSD and depression.
Section snippets
The stress response, neural-immune communication and epigenetics
In humans, the neuroendocrine stress response systems of fight or flight, the HPA axis and SNS, are activated by psychological stress; the catecholamine effectors, NE and epinephrine (E) being released within seconds of the stress, and the end effector of the HPA axis, cortisol following by a lag of approximately 10 min (Sapolsky et al., 2000). Cortisol and the catecholamines exert effects on the immune system via signal transduction pathways activated by glucocorticoid (GR) and adrenal (ADR)
PTSD and peripheral inflammation
Inflammatory biomarkers, in particular circulating levels of pro-inflammatory cytokines, e.g. IL-1β IL-6, TNF-α and acute phase reactants, e.g. the pentraxin C-reactive protein (CRP) have proven to be effective predictors of future morbidity and mortality (Hansel et al., 2010, Wassel et al., 2010). Inflammation is not only associated with, but also may participate in the pathogenesis of multiple features of the cardiometabolic syndrome (Esposito and Giugliano, 2004); thus CRP serves as both a
PTSD, inflammation and depressive symptoms
Depressive symptoms are common in individuals with PTSD and rates of diagnosed PTSD/MDD co-morbidity are high, but the nature of this overlap is poorly understood (Ginzburg et al., 2010). Some attributes, e.g. neuroendocrinology, fear inhibition, laterality, differ between PTSD and MDD as well as in PTSD with and without depressive symptoms (Baker et al., 2003) for review; (Jovanovic et al., 2010, Kemp et al., 2010). Other attributes, such as immune system abnormalities and diminished
Does the immune system play a role in risk and resilience?
So far, largely unexplored, is the question of whether the immune system interacts with the neuroendocrine stress system in the post-trauma time period, either as a predictor of risk, a contributor to PTSD development, or promoter of resilience. So far, most studies on the immune system and PTSD have been conducted in a cross-sectional manner long after diagnosis has been established. Thus the neuroendocrine–immune physiology so far described for PTSD is that of a chronic illness. However,
Summary
In summary, the evidence for systemic inflammation and deleterious health consequences in PTSD is strong. Given this evidence treatment strategies to reduce inflammation that target biobehavioral factors may prove to be of some benefit (O'Connor and Irwin, 2010). There is emerging evidence for specific neuroendocrine-immune abnormalities in PTSD, with possible differences between PTSD/MDD− and PTSD/MDD+. As yet, there is insufficient information to provide answers about the immune system
Acknowledgments
Drs. Baker and Nievergelt are supported in part by VA (HSR&D), DOD (BUMED, CDMRP) Research, and by the VA Center of Excellence for Stress and Mental Health. Dr. Nievergelt is also supported by grants from NIMH (1 U01 MH092758-01) and NIA (1 R01 AG030474-01A2) and Dr. O’Connor is supported by HL58120 MD000220 (EXPORT/CRCHD) andRR031980 (CTSA).
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2022, PsychoneuroendocrinologyCitation Excerpt :There is evidence that systemic inflammation and significant health consequences are particularly important in PTSD patients. Furthermore, an association between cellular immunity, PTSD risk, and resilience has been demonstrated (Baker et al., 2012). It is understood that the inflammatory processes in patients with MDD and a comorbid disease together with neuroendocrine effects and behavioral factors linked to depression are all linked through a feedback loop (Fig. 2).
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