Fourth Year Medicine (Honours)
University of Tasmania
Our medical studies encompass many areas of medical science, and immunology is an example of just one. Traditionally, we have been taught that our immune system exists to protect us from pathogens; however, in recent years, this romantic view of the immune system has been challenged and it is now well recognised that it is also involved in whole-body homeostasis and cross talks to other regulating systems of the body. This is the notion of psychoneuroimmunology (PNI). This text will briefly review the current understanding of PNI and how it features prominently in clinical practice as a part of the ‘whole person’ model of patient care and, especially, in terms of stress and depression. With this in mind, PNI is an emerging medical discipline that warrants integration and consideration in future medical care and practice.
At first glance, immunology may be viewed by some as an esoteric medical science that simply provides us with the molecular and cellular mechanisms of disease and immunity. It is a subject that all medical students have to face and no doubt can find quite challenging as well. Yet, in recent times, its role in helping us understand mental health and why individuals behave in certain ways has become increasingly appreciated. [1,2] The novel area of study that attempts to explain this intricate and convoluted relationship between the mind, behaviour, nervous system, endocrine system and finally the immune system is, quite appropriately, termed psychoneuroimmunology (PNI) or sometimes psychoendoneuroimmunology.  This was probably something that was never mentioned during our studies because it is quite radical and somewhat ambiguous. So what, then, is PNI all about and why is it important?
Many of us may have come across patients that epitomise the association between mental disturbances and physical manifestations of disease. Indeed, it is this biopsychosocial model that is well documented and instilled into the minds of medical students. [4-7] The mechanism behind this, although something best left to science, is nonetheless interesting to know and appreciate as medical students. This is PNI.
The basic science of psychoneuroimmunology
The notion that behaviour and the manifestation of disease were linked was probably first raised by Galen (129-199 AD) who noticed that melancholic women were more likely to develop breast cancer than sanguine women.  The modern push for PNI probably began in the 1920s to 1930s when Metal’nikof and colleagues conducted several preliminary experiments in various animals showing that the immune system can be classically conditioned.  New interest in this area was established by Solomon et al. who, in 1964, coined the term ‘psychoimmunology’ ; however, the concept of PNI was firmly established by the American behavioural scientist Dr Robert Ader in his revolutionary 1981 book, ‘Psychoneuroimmunology.’ This book described the dynamic molecular and clinical manifestations of PNI through various early experiments. [11,12] In one initial experiment, Ader and fellow researchers successfully demonstrated that the immune system can be conditioned, similarly to Metal’nikov. After pairing saccharin with the immunosuppressive agent, cyclophosphamide, and administering this to some rats, they found that saccharin administration alone, at a later date, was able to induce an immunosuppressive state marked by reduced titres of haemagglutinating antibodies to injected sheep erythrocytes. 
The authors postulated that non-specific stress associated with the conditioning process would have elicited such a result. By extension and based on earlier research,  the authors believed psychological, emotional or physical stress probably act through hypothalamic pathways to induce immunomodulation which manifests itself in various ways. 
Stress, depression and PNI
A prominent aspect of PNI focuses on the bi-directional relationship between the immune system and stress and depression, where one affects the other. [4,15] The precise mechanisms are complicated but are ultimately characterised by the stress-induced dysregulation, (either activation or depression), of the hypothalamic-pituitaryadrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes.  Because of the pleiotropic effects of these hormones, they can induce a dysfunctioning immune system partly through modulating the concentration of certain cytokines in the blood.  Endocrine and autonomic pathways upregulate pro-inflammatory cytokines (such as interleukin (IL)-1β, IL-6 and tumour necrosis factor-α (TNF-α)) that can exert their effects at the brain through direct (i.e., circumventricular organs) and indirect access ports (via aff erent nerve fi bres). [17,18] Such pro-inflammatory cytokines therefore stimulate the HPA axis and activate it leading to the rapid production of corticotropin-releasing hormone. [19-21] Eventually, cortisol is produced which, in turn, suppresses the pro-inflammatory cytokines. Interestingly, receptors for these cytokines have also been found on the pituitary and adrenal glands, thereby serving the ability to integrate neuroendocrine signals at all three levels of the HPA axis. [21,22] Cortisol also has significant eff ects on mood, behaviour and cognition. On a short-term basis, it may be beneficial; making an animal more alert and responsive. However, increased periods of elevation may give rise to impaired cognition, fatigue and apathy. 
In the brain, an active role is played by the once-thought insignificant glial cells which participate at the so-called tripartite synapse (glial cell plus pre- and post-synaptic neurons).  It is this unit that is fundamental to much of the central nervous system activity of the PNI system. Pro-inflammatory cytokines like interferon (IFN)-α and IL-1β released from peripheral and central (microglia and astrocytes) sources can alter dopaminergic signals, basal ganglial circuitry, hippocampal functioning and so on. Consequently, this induces behavioural changes of anhedonia, memory impairment and other similar behaviours. [18,25] Since IFN-α receptors have been found on microglia in the brain,  IFN-α likely also causes further local inflammation and further disruption of dopaminergic signals. Excessively activated microglia by a range of inflammatory cytokines can therefore cause direct neurotoxicity and neuropathology.  Additionally, these cytokines can induce activity of the indoleamine 2,3-dioxygenase enzyme (found in astrocytes and microglia) which metabolise the precursor of serotonin, tryptophan. The result is a reduction of serotonin and the production of various products, including quinolinic acid, an NMDA (N-methyl-D-aspartate) receptor agonist which leads to excess glutamate and neurodegeneration. These mechanisms are postulated to contribute to the pathogenesis of depression; however, the precise mechanisms of which are yet to be fully elucidated. [28-30]
Recent research into behavioural epigenetics has also provided an additional interesting link whereby stressors to the psychosocial environment can modulate gene expression within the neuroimmune, physiological and behavioural internal environments. This may account for the long-term aforementioned changes in immune function. 
Depression has also been shown to activate the HPA and SAM axes as well through inflammatory processes, [28,32] which in turn exacerbates any pre-existing depressive behaviours.  This inflammatory theory of depression sheds light onto the complicated pathophysiology of depression, adding to the already well-characterised theory of serotonergic neurotransmission deficiency. [28,33] Interestingly, proinfl ammatory cytokines have been shown to modulate serotonergic activity in the brain as well, [34,35] which provides further insight into this complex disorder. There is question as to whether or not this may have its roots with evolution where the body diverts energy resources away from other areas to the immune system for the promotion of anti-pathogenic activity during stress and depression.  For instance, with threat of an injury or wound in an acute situation (the stressor), cortisol (a natural immunosuppressant) would be released via the HPA axis. This aids in energy conservation which in turn, and paradoxically, attempts to minimise the non-helpful effect of immunosuppression in times of infection risks.  Depressive behaviour such as lethargy has also been said to have stemmed from the need to conserve energy to promote fever and inflammation.  Ultimately, the evolutionary aspects of PNI are under current speculation and investigation to elicit the precise links and relationships. 
The alterations of the immune system in stress and depression have implications for other areas of medicine as well. Though conclusive clinical experiments are lacking, it has been strongly hypothesised that this imbalanced immune state can contribute to a plethora of medical ailments. Depression, characterised by a general pro-inflammatory state with oxidative and nitrosative stress, [33,37] can contribute to poor wound healing; and exacerbate chronic infections and pain. [38,39] Stress similarly entails a dysregulated immune system and may contribute to the aforementioned conditions plus cardiovascular disease and minor infectious diseases such as the common cold. [40- 44] The link with cancer is somewhat more controversial but both may, in some way, predispose to the development of it through numerous mechanisms such as reduced immune surveillance by immune cells (cytotoxic T cells and natural killer cells), general inflammation and genomic instability. [45,46]
Highlighting the bidirectionality of the PNI paradigm, secondary inflammation caused by a myriad of neurological diseases (e.g., Huntington’s disease, Alzheimer’s disease) and local and systemic disorders (e.g., systemic lupus erythematosus, stroke, cardiovascular disease and diabetes mellitus) may very well contribute to the pathogenesis of co-existing depression.  This may account for the close association of depression and such diseases. Underlying neurochemical changes have been observed in many of these diseases—especially the neurological disease examples—and it has been suggested that depression vulnerability is proportional to how well one can ‘adapt’ to said neurochemical imbalances. [48,49]
Through an immunophysiological point-of-view, these links certainly makes sense; but it is important to note that there could be other confounding factors, such as increased alcohol consumption and other associated behaviours that accompany stress and depression that can contribute to pathology.  The question therefore remains as to how much the mind plays in the pathogenesis of physical ailments. Figure 1 summarises the general PNI model as it relates to stress and depression.
Having explored the discipline of PNI, what is the importance of this for clinical practice? Because of the links between stress and depression; altered immunity; other ill-effects and behaviour, [3,12] it seems fitting that if we can address a patient’s underlying stress or depression, we may be able to improve the course of their illness or prevent, to a certain extent, the onset of certain diseases by correcting immune system dysregulation. 
Simply acknowledging the relationship between stress and their role in the pathogenesis, maintenance and susceptibility of diseases is certainly not enough, and healthcare professionals should consider the mental state of mind for every patient that presents before them. It is fortunate, then, that a myriad of simple stress-management strategies could be employed to improve their mental welfare, depending on their individual circumstances. Such strategies include various relaxation techniques, meditation, tai chi, hypnosis and mindfulness practice. These have, importantly, proven cost-eff ective and lead to self-care and self-efficacy. [51,52]
As an example, mindfulness has received considerable attention in its role of alleviating stress and depression.  Defined as the increased awareness and attention to present, moment-to-moment thoughts and experiences, mindfulness therapy has shown remarkable efficacy in the promotion of positive mental states and quality of life. [52-54] This is particularly important in this age of chronic diseases and their associated unwelcomed psychological consequences.  Furthermore, and in light of the discussion above on PNI, there is evidence that mindfulness practice induces physiological responses in brain and immune function. [55,56] This suggests that its benefits are mediated, at least in part, through such positive immunological alterations that modulate disease processes.
With the growing understanding of the cellular and molecular mechanisms behind stress, depression and other similar psychiatric disorders, a host of novel pharmacological interventions to target the previously discussed biological pathways are actively being researched. Most notably is the proposition of the role of anti-inflammatories in ameliorating such conditions where patients present in an increased inflammatory state. This is largely based on experimental work where antagonists to pro-inflammatory cytokines and/or their receptors improve sickness behaviours in animals.  As an example, the cholesterol-lowering statins have been found to have intrinsic anti- inflammatory and antioxidant properties. In a study of patients taking statins for cardiovascular disease, it was found that statins had a substantial protective effect on the risk of developing depression. This suggests that the drug acts, at least in part, to decrease systemic inflammatory and oxidative processes that characterise depression.  Other drugs being researched aim to tackle additional pathways such as those involving neurotransmitters and their receptors.
Of the neuroendocrine arm of PNI, current research is looking at ways to reverse HPA axis activation.  Some tested drugs that act on specific parts of the HPA axis seem to show promise; however, a major problem is tailoring the correct drug to the correct patient, for not all patients will present with the same neuroendocrine profile. [58,59] Neuroendocrine manipulation can also be used to treat or act as an adjunct to other non-HPA axis-mediated diseases. For example, administration of melatonin and IL-2 was able to increase the survival time in patients with certain solid tumours.  Needless to say, a great amount of research is further warranted to test and understand possible pharmaceutical agents.
Discussion and Conclusion
The exciting and revolutionary field of PNI has now provided us with the internal links of all the major regulating systems of the human body. The complex interactions that take place is, indeed, a tribute to the complexity of our design, and has provided a basis or mechanism of how our mind and behaviour can infl uence our physical health. As a result, serious stressors—be them emotional, mental or physical—can wreak havoc on our delicate internal environment and predispose to physical ailments, which can further exacerbate the inciting stressors and our mental state. For said psychological stress or depression, it seems appropriate that if healthcare professionals can ameliorate the severity of these, they may be able to further improve the physical health of an individual. How much so is a matter of debate and further investigation. Conversely, as demonstrated by the bi-directionality model of PNI, addressing or ‘fi xing’ the organic pathology may be conducive to the mental state of patients’ minds.
Whilst clinical approaches have been sharply juxtaposed to a very theoretical and scientific review of PNI, this has been deliberately done to hopefully demonstrate how mind-body therapies can exert their physical benefits. Accordingly, valued mind-body therapies deserve as much attention as the scientific study of molecular pharmacology. It is also important to note that even these two approaches (pharmacology and mind-body therapies) are almost certainly the tip of the iceberg; for there is certainly a vast amount more to be further explored in our therapeutic approach to medical conditions. For example, how does a practitioner-patient relationship fit into this grand scheme of things, and how much of a role does it play? No doubt a decent part for sure. Furthermore, whilst the PNI framework provides good foundations for which to explain, (at a basic level), the mechanisms behind the development of stress, depression and associated ailments, further insight is needed into the biological basis of these. For example, a symphony of intricate factors (such as the up-regulation of inflammation-induced enzymes, neurotransmitter changes, dysfunction of intracellular signalling, induced autoimmune activity, neurodegeneration and decreased serum levels of antioxidants and zinc) are at play for the signs and symptoms of depression. [61,62] Thus, the complex pathogenesis of psychological stress and depression begs for further clinical and scientific research into unravelling its mysteries. Nevertheless, with a sound basis behind mindfulness, other similar mind-body therapies and novel pharmacological approaches, it seems suitable for these to be further integrated into primary care  and other areas of medicine as an adjuvant to current treatments. If we can achieve this, then medicine undoubtedly has more potent tools in its armamentarium of strategies to address and alleviate the growing burden of chronic disease.
My thanks go to Dr E Warnecke and Prof S Pridmore for their support.
Conflicts of interest
A Lee: firstname.lastname@example.org