EVOLVING CONCEPTS ARTICLE
Stress is everywhere. In evolutionary terms, given the range of stressful environmental challenges faced, the human race could not have evolved without developing successful physiological strategies to cope with and overcome potentially life-threatening challenges on a daily basis.
The need for a robust response to an acute stress is well-established. Not only do we as individuals have to accommodate ourselves successfully to a dynamically changing environment, the course of history itself has been determined by those who have mounted the most successful responses to aggressive challenges on a grand scale.
Much of the scientific literature (and almost all of the popular press) has focused on the negative effects of stress on immune functions and the deleterious consequences on health. There is a considerable body of evidence in animals and humans which demonstrates that chronic stress exerts a negative influence on general health and specific disease processes. But what is often overlooked are the positive effects which acute stressors can exert on our immune system and consequently on our health. It would seem to be an evolutionary imperative, that positive responses to danger should influence long-term survival and that this implies development of a more robust species. It doesn’t make any evolutionary sense that all stress should be bad. If it were, protohuman life would have died out soon after it crawled out.
Positive effects of acute stress on immune responses were reported in early research into psychoneuroimmunological interactions (PNI) (Blecha et al., 1982) and the literature has been regularly reviewed (Dantzer and Kelley, 1989; Glaser and Kiecolt-Glaser, 2005; Dhabhar, 2009; Dhabhar, 2014) so why the need to touch on this now? Because insufficient research is being conducted into these links in humans. The basic neuroendocrinology of the major stress-mediating pathways is understood. The impact of the major stress hormones catecholamines and glucocorticoids on promoting survival of a healthy and robust human population is not. We need to learn much more about the positive effects of stress on health if we are to understand how we have survived and thrived.
There is a roadmap to follow which can guide research into the links between a stressor and a health/illness outcome with underlying neuroendocrine/immune mechanisms. It is worth quoting at length from the paper by George Solomon (1997):
‘There are far too few studies which directly correlate PNI changes with effects on the health of the individual. Hopefully this deficit will be remedied before long. There is, however, a long tradition of clinical research on the influence of psychosocial factors on health and the progress of disease. This may be described as A→C research with A being psychosocial factors, B immunological change and C disease outcome…..What is now needed is A→B→C research which demonstrates that psychosocial or experimental influences on immune function have consequences for health’.
Human studies which demonstrate a link between PNI and health/disease outcomes have almost exclusively been of the A→B or A→C type (Jaremka et. 2013; Walburn et al. 2009; Lien et al. 2007; Haavet et al., 2004; Cohen et al., 2002; Hamrick et al., 2002; Kiecolt-Glaser, 1999). The studies of Vedhara et al. (2001) on elderly carers of dementia patients and that of Fawzy et al. (1993) on cancer patients are rare examples of A→B→C studies.
All these studies without exception have shown deleterious effects of chronic stress on immune functions and/or health. A much smaller but equally important body of evidence has emerged showing immunostimulatory effects of acute stress in rodents (McEwen et al., 1997; Dhabhar and McEwen, 1997; Dhabhar, 2009). It has been proposed that the transient increases in cortisol in response to stress may be beneficial in combating disease (Dhabhar et al., 2010) and recovery from surgery (Rosenberger et al., 2009). There is also evidence for protective effects of stress on inflammation in rodent models which may provide insight into the ways in which stress can impact on autoimmune disease in humans (Jessop et al., 2004; Stefanski et al., 2013).
In spite of this compelling evidence in experimental animals, there has been a surprising reticence to take these observations forward to test the positive effects of stress in the human population. Few human studies have been performed and certainly none which satisfy the A→B→C roadmap. One paper reported that higher cortisol on school entry is associated with lower incidence of upper respiratory tract infections (URI) and hypothesized that increased cortisol in response to the naturalistic stress of school transition may prime the immune system to develop resistance to URI in early childhood (Turner-Cobb et al., 2011). The nature of such putative priming may, based on animal studies, be leukocyte migration to bronchial tissues, proliferation of T and B cells, and activation of the anti-viral NK defense cells. This is certainly a hypothesis which can be tested by the Solomon criteria in an expanded longitudinal study. The parameter A is the cortisol response to the initial exposure to the novel environment of school, C is the health outcome in terms of URI and B could be measurement of salivary IgA. Frequent measurement of cortisol over a period of weeks may permit distinction between a subgroup of children who mount a transient cortisol response (acute stress) and those who don’t (chronic stress), perhaps with quite different URI outcomes.
Interestingly, reports that exam stress in students are associated with higher incidence of URI compared to the lower incidence of URI in the school entry study may serve as evidence that different types of acute stressors may have quite opposite effects on health. Perhaps the effect depends to what degree the subject associates the stress with apprehension (‘get me out of here’) or excitement (‘bring it on’). Personal perception of stress as either a negative or a positive influence may be self-fulfilling on health outcomes (Keller et al., 2012). Subliminal perception of parental stress in early childhood may also adversely affect later health in ways not yet understood (Nygren et al. 2015).
There are many studies which could be performed to shed further light on this crucial area. The stress paradigm of school entry is by no means unusual. The world is full of naturalistic stressors which stimulate catecholamines and glucocorticoids and could be incorporated into a study design. Health outcome can be measured. Stress hormones and immune responses can be quantified (and not just catecholamines and glucocorticoids, other stress-responsive pathways may be important such as neuropeptides in immune tissues, cytokines in the brain). Techniques to measure stress hormones and immune factors relatively non-invasively in humans are becoming more widely available (Riis et al., 2015).
In conclusion, it is difficult to think of an area as important as the positive influence of stress on health for which there is so much evidence in rodents and yet has received so little attention in humans. We need to be saying more than ‘stress has implications for our health’. We need to know whether these implications are positive or negative in the ways that they impact on health and what underlying physiological mechanisms are involved. Most of all, we need to be clear about what we mean by stress and to distinguish between different kinds of stress: acute or chronic, negative or positive, immunoinhibitory or stimulatory, and we should utilise the A→B→C overarching approach to experimental design. If some kinds of stress really have the potential to make us stronger, healthier and more capable of engaging with our environment, not just with immediate challenges but in terms of longevity and life quality, we need to harness the lessons of stress, not to always treat it as a problem.
David S. Jessop – Faculty of Medicine and Dentistry, University of Bristol, UK;
Blecha, F., Barry, R.A., Kelley, K.W., 1982. Stress induced alterations in delayed type hypersensitivity to SRBC and contact sensitivity to DNFB in mice. Proc. Soc. Exp.Biol.Med.169,239-246.
Cohen, S., Hamrick, N., Rodriguez, M.S., Feldman, P.J., Rabin, B.S., Manuck, S.B., 2002. Reactivity and vulnerability to stress-associated risk for upper respiratory illness. Psychosom. Med. 64, 302-310.
Dhabhar, F.S., Saul, A.N., Daugherty, C., Holmes, T.H., Bouley, D.M., Oberyszyn, T.M., 2010. Short-term stress enhances cellular immunity and increases early resistance to squamous cell carcinoma. Brain Behav. Immun. 24,127-137.
Dantzer, R., Kelley, K.W., 1989. Stress and immunity: An integrated view of relationships between the brain and the immune system. Life Sciences 44, 1995-2008.
Dhabhar, F.S., 2009. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation 16, 300-317.
Dhabhar, F.S., McEwen, B.S., 1997. Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking. Brain Behav. Immun. 11, 286-306.
Fawzy, F.I., Fawzy, N.W., Hyun, C.S., Elashoff, R., Guthrie, D., Fahey, J.L., Morton, D.L., 1993. Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later. Arch. Gen. Psychiatry 50, 681-899.
Glaser, R., Kiecolt-Glaser, J.K., 2005. Stress-induced immune dysfunction: implications for health. Nat. Rev. Immunol. 5, 243-251.
Haavet, O.R., Straand, J., Saugstad, O.D., Grünfeld, B., 2004. Illness and exposure to negative life experiences in adolescence: two sides of the same coin? A study of 15-year-olds in Oslo, Norway. Acta Paediatr. 93, 405-411.
Hamrick, N., Cohen, S., Rodriguez, M.S., 2002. Being popular can be healthy or unhealthy: stress, social network diversity, and incidence of upper respiratory infection. Health Psychol. 21, 294-298.
Jaremka, L.M., Glaser, R., Malarkey, W.B., Kiecolt-Glaser, J.K., 2013. Marital distress prospectively predicts poorer cellular immune function. Psychoneuroendocrinology 38, 2713-2719.
Keller, A., Litzelman, K., Wisk, L.E., Maddox, T., Cheng, E.R., Creswell, P.D., Witt, W.P., 2012. Does the Perception that Stress Affects Health Matter? The Association with Health and Mortality. Health Psychol. 31, 677–684.
Kiecolt-Glaser, J.K., 1999. Stress, personal relationships, and immune function: health implications. Brain Behav. Immun. 13, 61-72.
Lien, L., Haavet, O.R., Thoresen, M., Heyerdahl, S., Bjertness, E., 2007. Mental health problems, negative life events, perceived pressure and the frequency of acute infections among adolescents. Results from a cross-sectional, multicultural, population-based study. Acta Paediatr. 96, 301-306.
McEwen, B.S., Biron, C.A., Brunson, K.W., Bulloch, K., Chambers, W.H., Dhabhar, F.S., Goldfarb, R.H., Kitson, R.P., Miller, A.H., Spencer, R.L., Weiss, J.M., 1997. The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res. Brain Res. Rev. 23, 79-133.
Nygren, M., Carstensen, J., Koch, F., Ludvigsson, J., Frostell, A., 2015. Experience of a serious life event increases the risk for childhood type 1 diabetes: the ABIS population-based prospective cohort study. Diabetologia [Epub ahead of print]
Riis, J.L., Granger, D.A., DiPietro, J.A., Bandeen-Roche, K., Johnson, S.B., 2015. Salivary cytokines as a minimally-invasive measure of immune functioning in young children: Correlates of individual differences and sensitivity to laboratory stress. Dev. Psychobiol. 57,153-167.
Rosenberger, P.H., Ickovics, J.R., Epel, E., Nadler, E., Jokl, P., Fulkerson, J.P., Tillie, J.M., Dhabhar, F.S., 2009. Surgical stress-induced immune cell redistribution profiles predict short-term and long-term postsurgical recovery. A prospective study. J. Bone Joint Surg. Am. 91, 2783-2794.
Solomon, G.F., 1997. Clinical and social Implications of stress-induced neuroendocrine-immune interactions, in: Buckingham, J.C., Gillies, G.E., Cowell, A-M. (Eds). Stress, Stress Hormones and the Immune System. John Wiley and Sons, London, pp. 385-401.
Stefanski, V., Hemschemeier, S.K., Schunke, K., Hahnel, A., Wolff, C., Straub, R.H., 2013. Differential effect of severe and moderate social stress on blood immune and endocrine measures and susceptibility to collagen type II arthritis in male rats. Brain Behav. Immun. 29, 156-165.
Turner-Cobb, J.M., Rixon, L., Jessop, D.S., 2011. Hypothalamic-pituitary-adrenal axis activity and upper respiratory tract infection in young children transitioning to primary school. Psychopharmacology (Berl). 214, 309-317.
Vedhara, K., Cox, N.K., Wilcock, G.K., Perks, P., Hunt, M., Anderson, S., Lightman, S.L., Shanks, N.M., 2001. Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination. Lancet 353, 627-631.