Psychoneuroimmunology: Bi-directional Interactions Between the Brain and the Nervous System
Melissa WachtermanYou do not need to have an MD or a Ph.D. in human physiology to make some general observations about the connection between the mind and body when it comes to getting sick. Think back on the times within the past 3 years when you came down with an illness of one sort or another. If you are like most people, you were probably more likely to become ill during or just after a stressful period of time (e.g. exams, big job presentation, when your in-laws visited) than during times of low-stress (e.g. vacation, kids go to camp for the week, spouse takes over the cooking and cleaning). The fact that phrases like "youÕre worrying yourself sick" exist suggests that we experientially and/or intuitively know that there is some link by which our thoughts, feelings, and behaviors can have an effect on our susceptibility to becoming sick. Such a causational connection would require that the nervous system and the immune system be linked in some way so as to allow for communication between the two systems. This paper aims to draw upon theories and experimental findings within the field of psychoneuroimmunology (PNI) in order to assess the support for mechanisms by which our nervous systems and immune systems interact.
"Psychoneuroimmunology", is defined by Ronald Glaser, one of the premier researchers in the field, as a "field that studies the interactions between the central nervous system, the endocrine system and the immune system; the impact of behavior/stress on these interactions; and the implications for health of these interactions" (1) . The term was first used in 1974 by Robert Ader who was the first person to perform experiments that demonstrated that the brain could influence the immune system (2) .. In his classical conditioning experiment, Ader paired a conditioned stimulus (saccharin solution) with an unconditioned stimulus, a drug called Cytotaxan, which is known to decrease the number of T-lymphocytes in rats. When the immune system is compromised by a decline in the T-lymphocyte count, it is referred to as immunosuppression; therefore, Cytotaxan can be classified as an unconditioned stimulus for immunosuppression. After several pairings, the rats were presented with the saccharin solution (CS) in the absence of Cytotaxan (US), and a blood sample was taken so the ratsÕ T-lymphocytes could be counted. The result was a decline in the T-lymphocyte count, indicating that conditioned immunosuppression had occurred(3) . Further research revealed that even just the perception of a stressor was enough to cause changes in the immune system. Given that this research was done on rats, applications of the findings to human subjects must be broached with caution. Human studies have suggested that stressors such as the decreased amounts of sleep, tension, and varied eating patterns that occur during final exams can put stress on the immune system and result in more students becoming ill during exam period. Furthermore, applying AderÕs findings about conditioned stimuli in rats, it is possible that the immune system may respond in a similar way during exams the next year, even in the absence of physical stressors, indicating that the perception of stress has become a conditioned stimulus for immunosuppression (3) .
While the realm of classical conditioning research just discussed presents evidence for conditioned immunosuppression, it does not offer much insight into the mechanism by which the brain and the immune system interact. As we will see, there is a great deal of experimental evidence supporting the existence of bi-directional pathways connecting the brain and the immune system. There are two main pathways that connect the brain and the immune system, namely the autonomic nervous system (made up of the sympathetic and parasympathetic components) and the hypothalamic-pituitary-adrenal axis (HPA) (4) . In order for the two systems to influence one another, they must have a mechanism by which to communicate. The main type of communication is mediated by chemical messengers, which are released by nerve cells, endocrine organs, and immune cells. We will look in more detail at the mechanisms behind these forms of chemical transmission, but, generally speaking, the nervous system affects immune system activity in two different ways, directly and indirectly. The direct effect is via the synapsing of neurons with white blood cells in lymphoid tissues, while the indirect effect is through blood-borne neurotransmitters and hormones, which activate receptors on white blood cell surfaces(5) . In addition, it has been established that the immune system acts upon the nervous system through cytokines released by immune cells (1) .
The immune system is composed of lymphoid tissues, and the fact that these tissues are innervated with sympathetic nerve fibers adds support to the theory that the central nervous system can directly influences the immune system. Not only do nerve fibers form neuroeffector junctions with lymphocytes and macrophages (crucial components of the immune system, i.e. white blood cells), but certain neurotransmitters secreted from these nerves are able to have effects on far off lymphocytes and macrophages, which have receptors for the neurotransmitters. An example of one such neurotransmitter is noradrenaline, which binds to beta adrenergic receptors on lymphocytes (4) .
While there is no doubt that direct neuronal communication occurs between sympathetic nerves and cells of the immune system, this is by no means the whole story. As stated earlier, the hypothalamic-pituitary-adrenal axis (HPA) is a central link between the central nervous system and the immune system. An increased expression of corticotropin-releasing hormone (CRH) through the hypothalamus results in the formation of adrenocorticotropin hormone (ACTH), which subsequently signals the adrenal cortex to increase levels of glucocorticoid hormones, which act to downregulate parts of the immune response(6) .
So at this point, hopefully, you are at least somewhat convinced that there are pathways that link the brain and the immune system. Yet, you may still be left wondering, "So what? How is all of this connected with the observation that the times that I get sick almost always coincide with periods of time when I am really stressed out?" Ding ding ding Ð the crucial buzz word in this discussion Ð "stress". At the outset I must warn you that you may be a little bit let down by the status of what has, to date, been proven experimentally, on the matter. As I will demonstrate, there is a lot of evidence for stress-related immune impairment in humans, yet what remains uncertain is the clinical significance of the altered immunity that accompanies psychological stress (7) . In other words, a wealth of data exists to support the claim that aspects of your immune system are compromised by stress, yet more work needs to be done to prove that the effects are strong enough and prolonged enough to render you more vulnerable to infection and illness.
Stress, which has been loosely defined as "a state of threatened homeostasis" (8) ., has repeatedly been shown to result in changes in the immune systemÕs ability to mount a response to an immune challenge. It has been shown that the impact on the immune response varies depending on if the stress is short-term or long-term. Temporary stress, present for a couple of minutes, seems to stimulate immunity, while persistent stress has been shown to depress immunity (2)(9) . NK cells are believed to be a central component of the immune systemÕs surveillance mechanism, as they destroy malignant cells. Since past research has demonstrated that stress destroys NK cells, stress can compromise the immune systemÕs ability to identify invader cells, and thus may well lead to illness and disease(10). Stress is also associated with considerable desensitization of beta adrenergic receptors of peripheral lymphocytes. It is thought that this is caused by hormonal factors such as epinephrine and norepinephrine, which are released in abundant quantities during a stress response and are known to have an impact on these receptors (2) . In terms of the HPAÕs role, numerous studies have shown that stress can upregulate the expression of corticotropin-releasing hormone (CRH), which has a cascade effect that results in increased levels of glucocorticoid hormones, which downregulate multiple aspects of the immune response (6) .
This is not the whole story though. One of the first statements made in this paper about the link between the brain and the immune system asserted that it is bi-directional. Yet, so far the discussion has been unidirectional, focusing only on how the immune system is affected by the sympathetic nervous system and the HPA. Of course, we know from behavioral observations that the reverse seems to be true as well. Perhaps at some point in your life when you were sick, someone told you that "its all in your head". As we will see, such an observation is partially correct. While the infection, be it bacterial or viral, most probably occurred at one of more places in your body, there is increasing evidence that suggests that "sickness behavior" such as fever, increased sleep, loss of appetite, and fatigue is the result of the immune system impacting the nervous system (11) . The physiological and psychological effects of immune activation (together called "sickness behavior") are mediated by molecules called cytokines, which are released from activated immune cells and carried through the HPA that connects the immune system and the brain. Just about all known cytokines or their receptors have been discovered to exist in cells of the central nervous system, including neurons. Therefore, cytokines, which used to be considered unique to the immune system, are now recognized as a "common chemical language for communication within and between the [nervous system and the immune system]" (12) . Nonetheless, the roles of cytokines expressed in the brain and of cytokines in the immune system are quite dissimilar. Neuronal cytokines are central to the death and survival of neurons. Peripheral cytokines act like hormones. When they are mobilized in response to antigens or inflammatory stimuli in the periphery, they can, among other actions, stimulate neuronal pathways and, thereby, activate "sickness behaviors" that occurs with illness (13) . More specifically, within the brain, immune-related information stimulates several brain areas, and causes glia cells and neurons to secrete cytokines such as interleukin (IL)-1, IL-2, and IL-6, interferon gamma, and tumor necrosis factor (14) . These cytokines are regulated by the presence of glucocorticoids (15) . Recent research has revealed that glucocorticoids help inhibit the production of cytokines, and thus minimize the behavioral effects of cytokines (i.e. sickness behavior). For example, in one experiment, a bacterial infection that activated the HPA axis resulted in elevated secretion of glucocorticoids (produced by the adrenal glands), and no sickness behaviors in intact rats. However, when the identical dose of bacteria was introduced into rats whose adrenal glands had been removed, sickness behaviors were observed. If glucocorticoid pellets were introduced as a substitute for the adrenal glands, sickness behaviors were again avoided (15) .
So where does all this leave us? How will the ever-increasing research about the bi-directional connection between the nervous system and immune system influence medical practice in the future? It is conceivable that in the future it will be possible to intervene in the chemical pathways that link the brain and the immune system. For example, there is a lot of interest in using corticotropin-releasing hormone (CRH) antagonists in order to disrupt the hormonal pathway that translates stress from the brain to the immune system (1) . Along the same lines, there are implications for managing sickness behaviors either by giving specific antagonists to cytokines  or by giving agonists for corticosteroids such as glucocorticoids, which inhibit the production of cytokines (15) . Medical science is not there yet, but research into the safety and efficacy of such treatments is under way (1) .
WWW Sources1) Implications of Stress 
3) Immunosuppression and Theory 
4) Psychoneuroimmunology 
9) Health Psychology 
12) Cytokines as Bridges 
14) Illness, Cytokines, and Depression 
Comments made prior to 2007
anyone there know about mind to immune cell communication? I keep
reading scientific papers about the molecules the two systems use for
communicating in vitro studies,but not how the mind could influence a
particular neuron to produce a particular molecule to transmit a
message to a immune cell.
Like a neuron talking to an immune cell that attacks a cancer cell,or a pathogen of some type.
My understanding of neuroscience says it is so. The brain controls and moniters all atoms in the body constantly. Every atom we breathe,eat,or drink.The brain moves these atoms or molecules around to suit the bodies need,especially the brains need for its own metabolism. So why does this communication between mind and body fail sometimes? I don`t understand how it could fail? Please any comments or research you know about what I`m talking about. Thank you ... David Hagert, 21 November 2005