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Psychoneuroimmunology

Permission graciously given by the author to reproduce this paper

Psychoneuroimmunology

by
Miguel R. Fernandez
Baywater, WA Australia

 Psychoneuroimmunology (PNI)

    This is a field that brings together knowledge from multiple fields of study in endocrinology, immunology, psychology, neurology and other fields (Carlson, 2001). It has the potential to integrate the systems of the body into a unified view of how the body works and interacts with itself and its environment. PNI is the study of how all these mechanisms and bodily functions interact to produce states of health and disease (Raptor, undated). Petellier (1999) has stated that there is  however, no formal consensus on the actual definition of what constitutes PNI or its research. However, Carlson (20010, has pointed out that the …study of the interaction between the immune system and behavior (mediated by the nervous system) is called psychoneuroimmunology (p. 576). 

    Until very recently the dominant paradigm in medicine has been the Cartesian, dualistic view of the body. Medicine operated, and still largely does operate, under the assumption that the mind and the body are separate from one another. This paradigm has influenced western medicine for centuries. However this model has some significant problems. Descartes postulated that the mind and body had no effect on one another and were therefore two discrete systems. Descartes tried to describe both systems in terms of one another. This category (and fundamental) error made by Descartes fails to take into consideration that there is a link between what we do as corporeal beings, and how that affects our bodily functions (Raptor, undated).

    The study of PNI brings together information from psychology, neurology, endocrinology and immunology, well as others. This makes to study of PNI increasingly difficult because to truly understand PNI one would need a mastery of all these subjects. However, to understand the processes involved and the consequences involved with PNI, a basic knowledge of these systems is all that is required. 

The systems of the body that relate to PNI

    The neural system is perhaps one of the most complex systems in the body. The job of the nervous system is to receive and relay information from the body to the brain and vice versa. The neurons in humans connect and penetrate every square inch (centimeter) of the body. Once the nerves in the central nervous system are laid down they do not divide and cannot be replaced. Nerves communicate and transfer information by using neurotransmitters. These specialized biochemicals allow certain neurons to fire in certain ways. A nerve receives a signal and propagates that signal to the next neuron by using these neurotransmitters at the synaptic gap between the nerves (Raptor, undated). 

    The existence of a communication system between the immune system and the nervous system has been suggested by the discovery of nerve endings in the thymus, spleen, and bone marrow. This is significant because much of the activity of the immune system starts in these areas. There is also a connection between the nervous system and the cells of the immune system. Particular immune cells called lymphocytes, have receptor sites for neurotransmitters and neuropeptides. Receptor sites are places on the surface of the cells that allow them to communicate with their environment. Immune cells not only have receptor sites for neurotransmitters but also produce and excrete them as well (Raptor, undated). This suggests a bidirectional system of communication between these two systems because they speak the same biochemical language.

Picture of immune cell and receptor site

    The immune system’s role is to identify foreign materials in the body and infectious agents and rid the body of these agents. The body is in constant contact with infectious agents that could compromise health, and so the immune system is constantly at work removing these infectious agents from the body (Carlson, 2001). Leukocytes or white blood cells are the most important and the most widely know aspect of the immune system. A subgroup of leukocytes important in the study of PNI are called lymphocytes. Raptor (undated) notes that these are highly specialized cells that attack specific cells that the body recognizes as nonself.

    Two main types of lymphocytes are T and B cells. B-cells are responsible for the release of antibodies that seek out infectious bodies, and bind to them so they can then be eliminated from the body. T cells, a major factor in the spread of HIV throughout the body, are also essential to the immune response. Three major classes of T-cells exist. First, helper T-cells, the specific target of HIV in the body, is responsible for enhancing the immune response while Suppressor T-cells are responsible for reducing the immune response (O’Leary, 1994). Finally, Killer T-cells are responsible for the elimination of infectious agents. It should also be noted that the immune system is not only responsible for the elimination of foreign agents in the body, but is also responsible for recognizing and eliminating cancerous and pre-cancerous cells from the body. How then does the body mediate the communication between the immune system, which by first glance would seem to be capable of doing its job without the help of psychological processes, and the actual mental and emotional processes that take place every day? Raptor (undated) has pointed out that stress and emotions have been known for some time to be associated with substantial physiological changes, including the sympathetic adrenal-medullary (SAM) system and the hypothylamic-pitutitary-adrenocortical (HPAC) system. 

    These two major stress systems affect numerous aspects of immunity. Activation of the adrenocortical system often accompanies chronic stress, as well as clinical depression. SAM activation is accompanied by the release of epinephrine, norepinephrine, and other catecholamines into the blood stream, whereas the activation of the HPAC system results in the release of adrenocorticotropic hormone (ACTH) and corticosteroids (O'Leary, 1994). A simple example of these systems at work is the CRF-ACTH-CORTISOL pathway. The sympathetic nervous system activates the flight or fight response. This system constitutes the set of chemical interactions that take place in times of stress. For example, in a time of stress, like escaping danger, the SAM system is activated and your body recognizes the stressful situation and the hypothalamus in your brain releases CRF. This hormone travels to the pituitary gland that releases ACTH, another hormone. ACTH moves down to the adrenal glands, telling them to release epinephrine and norepinephrine, glucocorticoids, and cortisol into the blood stream. 

    These chemicals seem to be the most significant chemicals in the mediation of stress. Cortisol and the glucocorticoids have a significant immunosuppressive effect. Epinephrine and norepinephrine are responsible for the butterfly in you stomach effect, as well as much more, and act similarly to adrenalin. The cortisol and glucocorticoid chemicals redistribute the immune cells and in some cases can kill immune cells (Sapolsky, 1994). This a very simple summary of a very complex system, and there are many other chemicals involved in stress mediated immunosuppression, however the extent to which they act and the exact mechanisms by which they act are unclear. The chemicals above are perhaps the most understood at this time. However, it should be noted that the SAM system is most stimulated during times of long term or chronic stress, whereas the sympathetic nervous system is activated in times of more immediate response to stress in the short term (Raptor, undated).

The stress pathway

    According to Sapolsky (1994), the glucocorticoids are an interesting set of chemicals. Released in times of stress, they act throughout the body and seem to be directly related to the control of immune function. They have a direct effect on the number and efficacy of lymphocytes throughout the body. Their job is primarily immunosuppressive. They halt the formation of new T-cells and can even cause the T-cells they come in contact with to destroy themselves. 

    In addition to these, other major classes of PNI-significant chemicals have been uncovered. The endogenous opioids and neuropeptides have significant effect on the body’s communication between the brain and immune system. These chemicals are also released into the blood stream in response to stress (Raptor, undated). Perhaps, the most widely talked about class of neuropeptides have been endorphins. These chemicals effect pain, and have been shown to be present in the blood without bodily pain or physical stress.

    Neuropeptides, as their name implies, are chemicals that affect the nervous system as well as the immune system. Evidence suggests that they play the key role in the communication between the nervous system and the immune system as well as the actual mediation of brain states, and their effects on immune function.

    Neuropeptides are also known as opioid peptides. The chemical structure and effect that they have on the body are similar to what chemicals like opium and morphine do in the body. Pert (1985) notes that it seems interesting that the chemicals that are thought to mediate emotional states are natural analogs to psychoactive drugs. We know that psychoactive drugs can alter brain states, and it makes sense that if there were going to be chemicals that mediated brain states, they would be psychoactive as well. It is also interesting that one of the places in the brain that is most innervated with receptors for these chemicals is the limbic system, one of the key areas in the brain associated with emotion (Pert 1985). The link becomes clearer together with the fact that there are receptors on lymphocytes for all the neurotransmitters currently known. This suggests a clear connection between mind and body, and a common chemical language by which they communicate (O'Leary 1994). 

    The literature is unclear at this point about what role these chemicals actually play in immune mediation. It is clear that neuropeptides have an effect on the immune system however it is unclear whether it is an enhancing or a suppressing effect (Raptor, undated). This is because several experiments have shown that results vary with the amount of neuropeptides used in experiments (Sapolsky, 1994). This is one question that needs to be answered. O’Leary (1994) adds that information on these chemicals keeps coming in, and some of the latest research shows that activation of the sympathetic nervous system releases norepinephrine, which in combination with the neuropeptides, has a immune enhancing effect.

    Therefore, the communication system between the neural system and the immune system can be accounted for, so where does the psychological aspect of PNI come into play? In theory, science should be able to show that states of mind, (i.e., subjective experience) can and does influence immune function, as well as immune function effecting mental states because of the bi-direction system of communication that exists between theses two systems. The mind, however, can be a tricky thing to measure and to quantify. O Leary (1994), best stated the conundrum as hopeful that a comprehensive view of psychoneuroimmunological phenomena will eventually include specification of the association between specific subjective states, neuroendocrine processes, and immune function.

    Perhaps one of the best way to go about quantifying specific brain states and the resulting physiological changes, comes from animal models. Two experiments, using mice as biological models, stand out in research into PNI. The first experiment involved mice and the thirst response. The major chemical in the brain that mediates thirst is angiotensin, which is a neuropeptide. When angiotensin is artificially introduced into the area of the brains of mice that have a lot of receptors for angiotensin, the mice will begin to drink water within 10 seconds (Pert 1985). This means that the chemical altered the brain state of the animal into thinking it was thirsty. A chemical, a neuropeptide, mediated a brain state.

    This is a very simple model that may not apply to more complex states of emotion like anger or fear, but it does show clearly that neuropeptides have a direct effect on brain states

    The second significant experiment conducted by Soloman (1985), took mice and subjected them to two types of electrical shock treatment. One group of mice received random and uncontrollable shock, and the second group of mice received shock that they could stop or control. The group of mice that received the uncontrolled shock had marked decrease in lymphocyte proliferation over the group that received the controllable shock. In addition, the group of mice that received the controllable shock did not seem to have any difference in immune function or lymphocyte proliferation over controls. This would suggest that subjective brain states like hopelessness , the ability to adapt and comfort are significant to the study of PNI.

    There are problems with this experiment as well. Certain psychologists argue that emotions in humans are much more whole-brained activities, not localized to specific areas, than they are in animals. To the extent that this is true, animal models may be imperfect, but they do provide effective starting points for the exploration of the complex psychological aspects of PNI.

    A number of interesting experiments have been conducted into the psychological aspects of PNI. Soloman’s (1985) insight into the coping mechanisms of people in disease states is an interesting insight. His assumption was that trait characteristics should influence the susceptibility of an individual's immune system to alteration by exogenous events, including reactions to events. He found that women with an autoimmune disease (e.g., rheumatoid arthritis) showed higher instances of masochism, self-sacrifice, denial of hospitality, compliance-subservience, depression, and sensitivity to anger than did their healthy sisters. Similar to Geschwind and Behan (1984), Soloman (1985) also suggests that CNS involvement is further suggested by the finding that left-handedness, determined by the brain, is associated with increased risk of an autoimmune disease. Also, he found that individuals state of emotions influenced the course of an autoimmune disease. As a medical doctor, patients with weakened psychological defenses and consequent dysphoria were more likely to have rapidly progressing disease, to be more incapacitated, and respond less well to medical treatment.

    Some helpful research has been done with medical students as well. Students who reported high levels of distress over exams were examined. The finding, though largely inconclusive, showed that there was a marked decrease in immune response. (O 'Leary, 1994) A control group of medical students not under exam stress was compared to medical students under exam stress. The result was similar, but slightly more conclusive. Two weeks before exam time, students showed increased immune responsiveness as compared with baseline. At exam time the student showed marked decrease in immune function.

    Psychological exploration will become increasingly important in PNI research as more information comes in. The idea that subjective brain states effect immune function has profound implication for medicine and health psychology. If it can be definitively proven that brain states effect immune function, it would drastically change the approach to healing (Raptor, undated).

Stress

    Stress is an excellent model from which to judge the effects of the psychological experiences and the nervous system on the immune system. Stress research overlaps into the field of PNI because stress is the environmental condition under which homeostasis is interrupted (Raptor, undated). The pathways discussed earlier are activated by the body's response to stress.

    There is a direct positive correlation between increase in stress and decrease in lymphocyte proliferation (Pelletier, 1999). There also seems to be a correlation between the type and duration of stress and immune function. Under short-term stress, like the medical students under exam pressure, lymphocyte proliferation is seen to decrease (Pelletier, 1999). However, chronic stress, or stress over long periods of time, seem to have a much different effect on immune function. Chronic stress seems to be followed by chronic immune suppression. Of three studies of chronic stress reviewed by O'Leary (1994), all of them showed some kind of immune incompetence in the long term. Long-term immune impairment has serious health consequences. It can render the individual less capable of fighting off disease and it can cause the immune system to become less efficient at recognizing potentially cancerous cells as they arise in the body. However there are no current studies that can correlate this statement (Raptor, undated). This is a potential area of further research that needs to be examined closely to provide a more complete picture of immune function in relation to stress. We have all heard that saying "Don't work too hard or you'll get sick!. Data exists to support this. Increased stress does cause immunosuppression, however, there is still much to be done in the way of research.

    As the information from PNI research increasingly becomes part of the accepted wisdom, we may see a drastic shift in the way western medicine is practiced. As noted earlier, until recently the mind and body were considered separate. Sapolsky (1994) has pointed out the body was the thing that digested the food, and made you run and your brain was the thing that wrote poetry and processed signals. The two systems were autonomous. However clearly this is not the case. If it can be definitively proven that brain states can effect how our body deals with daily functions, we should see changes in the approach people have to their lives and day-to-day affairs, not to mention how they deal with stressful situations. There would also be a drastic change to the practice of clinical medicine.

    Research in PNI is telling us that we must be increasingly accountable for our own health. Our brain states affect our bodies’ ability to fight disease (Carlson, 2001). If this to be true then the states of mind with which we go into potentially stressful situations have a direct effect on how our bodies response to stress. If a business person who has been working 100 hour weeks comes down with the influenza, a doctor can now say that the over working has made him/her more susceptible to disease. It is also interesting that a similar person who is working 100 hour weeks in the same environment may never get sick at all because he/she has a different approach to the work on a psychological level; perhaps he/she liked the work more, perhaps it is easier work for that person, etc. However, this is not universally true. There are things like environment and genetics that play a large role in immune function. Therefore, one could not make the blanket statement that Well, he got sick because he was really stressed" or "she just needs to look at the situation differently and then she wouldn't get the flu. Sickness and disease states are multifactoral. PNI is simply one aspect of disease that must be considered (Raptor, undated).

    While generally incomplete, this emerging model of mind and body has significant implications for the practice of medicine in the western world. Currently the dominant paradigm does not put heavy weight on factors like environment and social interaction on health. With the emerging data that suggests a direct causative effect of the environmental factors like mood, emotions, and mental health on the physical wellbeing of the person. A model of medicine that includes these factors would vastly change the practice of medicine. Our intuitive knowledge of the connection between mental states of being and physical wellbeing could finally be substantiated in a scientific and broadly accepted manner.

References

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