by Anjali Chandra
We have all heard of the amazing fight-or flight response: the man lifting a 3,000 pound stock Camaro, the woman fending herself against a bear with just a backpack, and the man outrunning a flaming sphere. Adrenaline surging, our body prepares to defend itself against a perceived threat. Our brain engages our muscles, sensory modalities and chemical signaling pathways in such a way that we may perform feats beyond those of any imaginable human strength.
Stress can activate the sympathetic nervous system in an extraordinary manner. The synchrony of hormones, nerve cells, musculoskeletal tissues and cognitive processes associated with the sympathetic nervous system is awesome, and in many ways, beautiful.
However, repeated or continued exposure to stress can paralyze the body in this hyper-aroused state. Over time, this condition can have detrimental effects on one’s overall health, and immunity, thereby leaving the body susceptible to disease.1
CHRONIC STRESS AND IMMUNE RESPONSE
Stress is a non-homeostatic condition, something that pushes an organism out of its realm of comfort—physically, psychologically or both. According to the American Psychological association, psychological stress is an uncomfortable “emotional experience accompanied by predictable, biochemical, physiological and behavioral changes.”2
External stressors include abuse, or discrimination in the workplace. On the other hand, anxiety about a particular event comprises an internal stressor.
Stressors can also be classified according to the duration and onset of their effects.3 Acute time-limited stressors consist of things like seeing a threatening animal, hunger or public speaking. Stressful event sequences are prefaced by a catastrophic event and consist of smaller related challenges.
Chronic stress can be defined as a relatively stable pervasive force that leads an individual to transform his or her identity, and modify his or her social roles. One distinguishing feature of a chronic stressor is that the individual experiencing it does not know when or if it will terminate. Caring for a loved one with dementia, an abusive relationships, refugee status, and physical disability due to a traumatic injury are all examples of chronic stressors.
Before delving into how stress impacts the immune system, it is important to investigate the basic workings of the immune system. Immune response consists of two broad domains: natural immunity and specific immunity. Natural immunity is the body’s general defense against a variety of pathogens. This consists of neutrophils and macrophages involved in inflammatory response, and cytokines which facilitate communication and wound healing. Another important element of the natural immune mechanism is the killer cell. Killer cells lyse cells that lack the molecular marker designating other cells as native to an organism.4 Complement proteins are the final part of the natural defense team. Complement proteins are important in antibody mediated immunity.
On the other hand, specific immunity as the name implies is generally tailored to particular threats. Lymphocytes are antigen specific, meaning they respond to one particular invader. T-cytotoxic lymphocytes recognize and lyse antigen expressing cells. B cells generate antibodies which target the antigen and reinforce natural immunity, and T-helper cells generate cytokines to enhance the rest of the response mechanisms.
Immunity in Homo sapiens can be further divided into cellular and humoral response. Th1 helper lymphocytes, T-cytotoxic cells and natural killer cells regulate cellular immunity, a response to intracellular pathogens like viruses. On the other hand, humoral response, which is focused on extracellular invaders like bacteria and parasites, is coordinated by Th-2 helper cells, B cells and mast cells.4
PSYCHONEUROIMMUNOLOGY
Psychoneuroimmunology (PNI), also known as Psychoendoneuroimmunology (PENI) is an interdisciplinary field that seeks to unearth the relationship between the brain’s emotional and cognitive processes, and the body in both health and disease.5 PNI focuses on the interaction between the nervous system, endocrine function and immune response.6
University of Rochester Medical Center faculty member Dr. Robert Ader coined the phrase “psychoneuroimmunology” in the early 1970’s, in light of his research regarding immunosuppression in classical conditioning.5 Dr. Adler’s study revealed that saccharin and cyclophosphamide, a gastrointestinal irritant used to suppress immunity, conditioned not only taste-aversion but also immune-suppression in rats.6
Following Dr. Adler a husband-wife team of researchers at the Ohio State University College of Medicine extended the association between stress and weakened immunity to human subjects. They measured immunity in students over one decade of examination periods and found that year after year, during that three-day span, the students’ killer cell levels dropped; they nearly stopped synthesizing gamma interferon, an immune-protectant, and their T-cells were largely unresponsive. This was the first time that stress was directly correlated to compromised immunity for humans in the laboratory setting.
It is important to note however that they were only studying individuals for a three-day period. The first corroborated set of conclusions regarding the effect of chronic stress or compromised mental state on immunity came in Dr. Suzanne Segerstrom and Dr. Gregory Miller’s meta-analysis of some 300 papers connecting psychological stress to elements of immune response. Their investigation revealed that chronic stress negatively impacted both cellular and body-fluid mediated immunity.7
Segerstom and Miller report that early studies demonstrate a reduction in the activity of natural killer cells, stunted lymphocyte proliferation and blunted response to vaccine-based inoculations in chronically stressed individuals. Increased prevalence of infectious and neoplastic diseases among the chronically stressed demographic was attributed to this weakened immunity.
On the other hand, acute stress has been shown to enhance immune response by triggering a redistribution of immune cells to maximize efficiency. This model has been modified to suggest that instead of spending energy in reorganizing efforts the immune system will shift from specific processes to natural immunity which “are better suited to managing the potential complications of life-threatening situations” since they are rapid response mechanisms.
However, to determine how chronic stress may be increasing disease prevalence, if at all, researchers needed to determine how chronic stressors shifted the balance of immune response. An early proposal was that chronic stress has a paradoxical effect, simultaneously enhancing and suppressing immune response through cytokine mediation, specifically the suppression of Th1 neoplastic disease fighting cytokines, while enhancing the production of Th2 cytokines which increase allergy and autoimmune disease risk. Thus, far this model appears to be consistent with the increased infection and neoplastic disease susceptibility and heightened allergic and autoimmune disordered physiology seen in chronically stressed individuals.8
PATHOLOGY OF STRESS
Dr. Firdaus Dhabhar’s article in the Journal of Neuroimmunology published in 2009 confirms the deleterious effect of chronic stress on Th1 function. Dhabhar’s investigation found that in addition to promoting pro-inflammatory pathways and specifically Th2 cytokine activity, it also increased the body’s natural immunosuppressive mechanisms or regulatory T cells.
Cortisol may be a key player in this Th1 to Th2 shift. Dhabhar reports that glucocorticoids, or stress-related hormones, when administered at a pharmacological level suppress immune response whereas their effect is mixed at a physiological level. More generally speaking, cortisol is an indicator of immune system functioning. Within a certain range, the lower the level of baseline cortisol, the healthier the immune response mechanisms.9
In acute stress mechanisms, low-doses of adrenal stress hormones enhance skin cell-mediated immunity(CMI). On the other hand, chronic corticosterone significantly suppressed CMI. These conclusions were supported by another study which demonstrated that low levels of corticosterone may enhances anti-T cell receptor-induced lymphocyte production during early stages of T-cell activation, in addition to T-cell responses to IL2, both of which indicate immunity enhancement.
However, a bevy of articles and academic mediums report that glucocorticoids can also be immunosuppressive.10 More support for the immunosuppressive effects of chronic stress comes from a recent study by Jianfeng Jin and colleagues who found that chronic stress induces the accumulation of myeloid-derived suppressor cells in the bone marrow of mice. These cells “inhibited the cytokine release of macrophages as well as T cell responsiveness.”11
Thus, whether it be by way of glucocorticoids, or myeloid-derived suppressor cells, chronic stress has a strong association with immunosuppression.
MANIFESTATIONS OF IMMUNOSUPPRESSION
One manifestation of immunosuppression is decreased vaccine activity. One investigation reported that when the influenza vaccine was given to cohort of older adults, including a group caring for spouses with dementia. The efficacy period of the vaccine for the caregivers was only 6 months were as the non-caregiver’s influenza antibody levels remained stable.
A study published in the New England Journal of Medicine reports that chronically high levels of stress, accounting for other variables such as seasons, substance youth, sleep, exercise and baseline antibody levels, increased susceptibility to acute rhinitis. This links chronic stressed induced immunosuppression with increase susceptibility to infection.
The relationship between stress and cancer has been an area of much interest, and investigation. Dr. David Speigel, a researcher and psychiatrist at Stanford University reports that natural killer cells is markedly low amongst chronically stressed individuals.
Furthermore, Dhabhar illustrates that chronic stress may reinforce pro-inflammatory pathways.12 Chronically elevated cortisol levels desensitize cellular receptors for cortisol and other stress hormones that normally regulate inflammatory response. This Glucocorticoid resistance increases Interleukin-1 activity and Tumor-necrosis factor to promote chronic inflammation.13
IMPLICATIONS
Broadly speaking, these investigations suggest that chronic stress has a two-fold effect. (1) being increased Th2 activity associated with inflammation and increased risk for allergic and autoimmune response, and (2) a reduction in Th1 and leukocyte activity along with enhanced immunosuppressive mechanisms which promotes cancer and infection risk while also decreasing the efficacy of vaccines and wound healing. However, the enhanced immunosuppression may decrease risk for autoimmune disease to some degree.
CONTEXT
When explaining the Bidirectional effect of stress hormones on immune-response, Dhabar suggests that their effect is context based. Critical factors which influence whether the hormone enhances or suppresses immunity include: (1) Duration of stress: Acute or short-term stress experienced at the time of immune activation can enhance innate and adaptive immune responses. Chronic or longterm stress can suppress immunity by decreasing immune cell numbers and function and/or increasing active immunosuppressive mechanisms (e.g. regulatory T cells). Chronic stress can also dysregulate immune function by promoting proinflammatory and type-2 cytokine-driven responses. (2) Effects of stress on leukocyte distribution: Compartments that are enriched with immune cells during acute stress show immune enhancement, while those that are depleted of leukocytes, show immunosuppression. (3) The differential effects of physiologic versus pharmacologic concentrations of glucocorticoids, and the differential effects of endogenous versus synthetic glucocorticoids: Endogenous hormones in physiological concentrations can have immunoenhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immunosuppressive. (4) The timing of stressor or stress hormone exposure relative to the time of activation and time course of the immune response: Immunoenhancement is observed when acute stress is experienced at early stages of immune activation, while immunosuppression may be observed at late stages of the immune response.14
Dhabar’s contingencies reflect a larger trend in the field of psychoneuroimmunology. The effect that hormone levels, or for that matter stress, is very dependent on the duration of that stressor, as well as each individual’s biological defense mechanism. Apart from factors that researchers can control or mediate, much of relationship between chronic stress and the immune system depends on external variables like diet, sleep, exercise, substance use and other lifestyle factors.
The most valuable lesson that we can take from this is to design studies that account for, as much as possible, these individual variabilities, as was done in the study published in the New England Journal of Medicine on the relationship between chronic stress and acute rhinitis. It is these sorts of studies that can bring us as close as humanly possible to untangling the relationship between mind, and brain, between brain and body.
MOVING FORWARD
Repeated studies over the past 20 years have confirmed the correlation between chronic stress and suppressed immune response. But the next logical question is why? What advantage does immunosuppression have in the fight for survival?
The body may be conserving resources to direct to combat that perceived threat to which salience has been attributed. In order to provide a targeted approach, it shuts down other competing mechanisms which may require and therefore divert energy from what the brain has designated the most important goal or stimulus.
Dr. Speigel, the lead researcher in the study which demonstrated a marked decrease in natural killer cell activity amongst chronically-stressed populations also illustrates that group counseling or stress-management therapy for those already diagnosed with cancer may help to boost immune response. Cancer-patients who had an especially strong support network had low levels of cortisol than those who did not have the same support system.15
Yes, chronic stress has been associated with increased susceptibility to disease, but contrary to the perception of the anxious mind, much is still within one’s own loci of control. This control chiefly manifests itself in two ways. One, immunosuppression may depend on how we ourselves ascribe salience, and two, we can make lifestyle changes to reverse or prevent the immune-related effects of stress.
Without realizing it, the college student stressing about the midterm the next day may be consolidating maldaptive patterns which give rise to chronic stress. Whether it be immune-suppression, or the increased risk for cancer, the consequences of constant hyper-arousal are grave. On the other hand, reforming false attributions of salience, and seeking a supportive social network may thwart the consolidation of acute stressors.
So, take a deep breath. Calm down. Is it really worth the immuno-compromise?
Anjali Chandra ‘19 is a freshman in Canaday Hall.
Works Cited
- American Psychological Association. http://www.apa.org/research/action/immune.aspx (accessed Oct. 4, 2015), “Stress Weakens the Immune System”
- American Psychological Association. http://www.apa.org/helpcenter/understanding-chronic-stress.aspx (accessed Oct. 4, 2015)
- Stress. University of Maryland Medical Center. http://umm.edu/health/medical/reports/articles/stress (accessed Oct. 4, 2015).
- Segerstrom, S.C.; Miller, G.E. Psychol Bull. 2004, 130(4), 601-630.
- Ray, O. Ann N Y Acad Sci. 2004, 1032, 35-51.
- Ader, R, ILAR J, 1998, 39(1), 27-29.
- Robert Alder dies. University of Rochester Medical Center, https://www.urmc.rochester.edu/news/story/3370/robert-ader-founder-of-psychoneuroimmunology-dies.aspx (accessed Oct. 4, 2015).
- Ader, R; Cohen, N. Psychosom Med. 1975, 37(4), 333-340.
- Dhabar, F.S. Neuroimmunomodulation. 2009, 16, 300-301.
- Jin, J. Plos ONE [Online] 2013, 8(9), http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074497 (accessed Oct. 4, 2015).
- Jin, J. Plos ONE [Online] 2013, 8(9), http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074497 (accessed Oct. 4, 2015).
- Jockers, D. Natural News. http://www.naturalnews.com/041556_chronic_stress_immune_system_inflammation.html (accessed Oct. 4, 2015).
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