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Allostatic Load and the Immune System: Social Support Goes a Long Way!

Course Authors

Bruce S. McEwen, Ph.D.

Dr. McEwen reports no commercial conflict of interest.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 
Learning Objectives

Upon completion of this Cyberounds®, you should be able to:

  • Describe how the concepts of allostasis and allostatic load apply to the immune system

  • Describe how social support and social conflict have opposite effects on the resistance to diseases like viral infections and cancer

  • Discuss how avoiding social isolation and venting emotions can have beneficial effects on resistance to disease.

 

We are only too aware of situations in which we continue to experience feelings of anxiety and distress at all hours when something is really bothering us. We also know of diseases like arthritis and psoriasis in which inflammatory and autoimmune processes persist and cause discomfort and damage.

As discussed in a previous conference, allostatic load is the concept that the body's own attempts to adapt to stress contribute to pathophysiological changes and lead to disease. It refers to the wear and tear on the body produced by repeated elevations of allostatic systems, especially when they are not needed. We define stress as daily hassles, conflicts and worries on the job and at home. This model, as introduced in our introductory Cyberounds® Psychiatry/Neuroscience, emphasizes that allostatic load is a very gradual process that can be counteracted by healthful behaviors, such as regular, moderate exercise, and exacerbated by unhealthy behaviors, such as eating a fat-rich diet or smoking, and by stressful experiences.

To help you devise ways to begin to help your patients apply this information to their own lives, my co-moderator, Dean Krahn, has embarked on a discussion of impulsivity and control of choices of behaviors that can be beneficial or harmful. We have discussed broadly the relationship between stress and its effects on disease processes and introduced the terms, allostasis and allostatic load. Allostasis refers to the body's mounting an active response, like increasing heart rate and blood pressure or putting out stress hormones, in order to re-establish homeostasis in the face of a challenge. The challenge can be as simple as standing up and walking to the refrigerator or as complex as resolving an argument with your spouse or coming to grips with work-related worries and anxieties.

Allostasis involves activation of ACTH and glucocorticoid secretion, as well as catecholamine release, and it also includes the general and specific responses of the immune system when these are called into action. When blood pressure, stress hormones and immune function are activated, they then need to be turned off when the challenge is over and, yet, this is not always the case. We also noted that allostatic load has long-term effects upon key systems of the body, such as the cardiovascular and metabolic systems, the brain and the immune system.

In that earlier conference, we also noted that social interactions can have an effect on allostatic load. Social interactions can be soothing and supportive, but they can also involve conflict and competition for status and influence, as well as the venting of emotions. They are among the most powerful controllers of allostasis and contributors to allostatic load. Elsewhere, we have discussed the cardiovascular and metabolic systems. This conference deals with the immune system. As we will discuss below, social support, for example, has subtle but powerful effects that protect against the common cold and increase the chances of survival from breast cancer.

Allostatic Load in the Immune System

The immune system provides a variety of defense mechanisms, ranging from innate to acquired cellular and humoral immunity. Innate immunity refers to a host of defense mechanisms that are mobilized rapidly to ward off pathogens - including endogenous antibiotic agents, natural killer cells, the mobilization and movement of immune cells to sites where a pathogen has entered the body, and the acute phase response that precedes acquistion of new long-term immunity. Acquired immunity refers to the production of antibodies and cellular immune responses and results in an immunological "memory" of a previous encounter with a particular pathogen and the resulting acquired immune response.

These mechanisms constitute various types of allostasis within the immune system itself that are turned on in order to counteract a challenge and re-establish homeostasis by eliminating infection. At the same time, other allostatic systems such as the stress hormone axis involving the secretion of ACTH and cortisol and the autononomic nervous system act to regulate the immune system by containing acute phase responses and dampening cellular immunity, while at the same time increasing humoral immunity.(19) It is important to emphasize that not all of the effects of stress hormones are suppressive towards immune function. An acute stress causes lymphocytes and macrophages to redistribute throughout the body and to "marginate" upon, i.e., bind to, blood vessel walls and within certain tissues such as the skin, lymph nodes and bone marrow. This "trafficking" of immune cells is mediated, in part, by adrenal steroids (8),(12),(17),(19),(22) and it occurs even if a specific immune challenge is not encountered. The lymphocytopenia resulting from stress or stress hormone elevation has been misinterpreted in the past as due to massive destruction of immune cells by stress hormones. This is definitely not true and stress-induced lymphocyte reductions from the blood stream are reversible in a number of hours.

When the stress ends and stress hormone secretion is turned off, immune cells demarginate and return to the bloodstream. However, when a specific immune challenge occurs in a tissue like the skin, as is the case in delayed-type hypersensitivity, acute stress enhances the redistribution of lymphocytes and macrophages to the site at which a pathogen or other antigen is present. (9),(10) Delayed-type hypersensitivity involves the activation of an immunological "memory" and the immune-enhancing effects of even a single acute stress depends on adrenal secretion and lasts for a number of days.

Thus, acute stress has the effect of mobilizing immune cells and calling them to their battle stations where they can directly confront the adversary. This is a form of allostasis and it enhances responses for which there is an established immunologic "memory."(9),(10)(13) If the immunologic memory is for a pathogen or a tumor cell, the result of stress is presumably beneficial. On the contrary, if the immunologic memory leads to an autoimmune response or allergic response, then stress is likely to exacerbate a pathological state.

What happens, however, when allostatic load is produced by repeated stress? Here the evidence obtained thus far indicates that the outcome is completely different because the delayed type hypersensitivity response is substantially inhibited rather than being enhanced.(11) Certain aspects of immunity are also impaired by chronic stress, including the proliferation of lymphocytes and the production of cytokines.(19) The consequences of suppressed cellular immunity resulting from chronic stress include increased severity of the common cold, accompanied by increased cold virus antibody titers.(6) In experimental animals, repeated stress also leads to recurrent endotoxemia, which decreases HPA axis reactivity to a variety of stimuli as well as decreasing production of the cytokine tumor necrosis factor alpha.(15)

The Perils and Benefits of Low Stress Hormone Production

There is a type of allostatic load that is actually caused by inadequate allostatic responses of the stress hormone axis and results in compensatory increases by other allostatic systems, such as the inflammatory cytokines. When one system does not respond adequately to a stressful stimulus, the activity and allostatic responses of other systems increase because the underactive system is not providing the usual counter-regulation. For example, if adrenal steroid secretion does not increase in response to stress, there is elevated production of inflammatory cytokines which are normally opposed, or counter-regulated, by adrenal steroids.(23)

The negative effects of this enhanced inflammatory response are illustrated by Lewis rats, because this strain of rats is very susceptible to autoimmune and inflammatory disturbances. They have an intrinsic, genetically-based insufficiency of their hypothalamic corticotropin releasing factor (CRF) system that leads to hyporesponsiveness of stress hormone production. Not all instances of low stress hormone activity are genetically-based and, in some cases, they can be induced by experiences. In a strain of aggressive laboratory rats, living together in a "visible burrow system" in which their behavior can be recorded by hidden cameras, rats that become subordinate have a stress-induced state of stress hyporesponsiveness.(2),(20) In these rats, the stress hormone response to experimenter-applied stressors is very limited and hypothalamic corticotropin releasing factor messenger RNA levels are abnormally low.(1)

Lowering Stress Hormone Activity Through Social Support

There are human counterparts with low stress hormone activity, such as adults with fibromyalgia(7),(16) and chronic fatigue syndrome ,(28) and children with atopic dermatitis.(3) It is likely that some of the pathology of fibromyalgia and chronic fatigue syndrome may be related to the inadequate allostatic response of the stress hormone axis. What this means is that inadequate levels of cortisol will allow inflammatory process and other mechanisms that lead to pain to operate at a higher-than-normal level.

There are other, more natural and beneficial ways in which the stress hormone axis can be made to operate at a lower level--lower allostasis leads to lower allostatic load. Social support, such as close relations with family and friends, among animals and humans has been shown, in many instances, to reduce allostasis of the stress axis and results in lower stress hormone levels.(26) Transcendental meditation has been shown to have similar benefits.(18) Avoiding isolation and having friends and being outgoing and social has a beneficial effect on susceptibility to the common cold, in spite of the obvious fact that increased social interactions increase the likelihood of being exposed to infections.(4) In contrast, social conflict and tension can suppress beneficial aspects of immunity,(5) with daily hassles and worries leading to more infections such as the common cold.(4),(6)

What Can Be Done?

Most of us aspire to a worry-free life style full of beneficial, supportive social interactions with a healthy diet and plenty of sleep and exercise, but few of us feel we achieve this ideal, except perhaps for short periods of our lives. Nevertheless, it is a worthy goal and one for which there is increasing evidence that these factors contribute to reducing allostatic load and improving health. And it almost goes without saying that physicians can provide helpful counsel and encouragement to their patients on these matters.

In another conference, we discussed the health-damaging effects of work-related stress, emphasizing consequences of anger, hostility and lack of control upon the cardiovascular system and we noted that there have been a few successful interventions designed to reorganize forms of work to reduce time pressures and tedium and give employees greater sense of control. Although there have not been specific studies to date regarding work stress and infectious illnesses like the common cold, the improvements seen in health and attitude towards work after reorganization of the Volvo production line(21) are very encouraging in that regard.

While conditions in the workplace are something over which patients and physicians have little control (and this lack of a sense of control is one of the factors exacerbating workplace stress), in this conference we have noted the pervasive influence of positive and negative social interactions on allostatic load, something over which individuals can exert a good bit more control.

One aspect that deserves special attention is social isolation.(26) People who isolate themselves from others or simply hide their emotions and feelings have a poorer prognosis for survival from various forms of cancer. This is something fairly readily determined during the course of a medical examination. Interventions that increase social support, encourage individuals to express their emotions and enhance coping with their disease have been shown to prolong the lifespan of patients with breast cancer,(27) lymphomas (25) and malignant melanoma.(14) This is an area that deserves special recognition and attention in the counselling that physicians can provide their patients and will be the subject of an upcoming conference.

In our next Cyberounds® we will discuss allostatic load as it impacts on the brain, which is, after all, the master controller of our thoughts and emotions and the control center for our abiliity to feel stressed and to cope. Unfortunately, we will see that the brain is vulnerable, too, to the effects of stress.


Footnotes

1Albeck, D.S., McKittrick, C.R., Blanchard, D.C., Blanchard, R.J., Nikulina, J., McEwen, B.S. and Sakai, R.R. Chronic social stress alters expression of corticotrophin releasing factor and argninine vasopressin mRNA expression in rat brain. J. Neurosci. (1996).
2Blanchard, D.C., Sakai, R.R., McEwen, B.S., Weiss, S.M. and Blanchard,R.J. Subordination stress: behavioral, brain and neuroendocrine correlates,Behav.Brain Res. 58 (1993) 113-121.
3Buske-Kirschbaum, A., Jobst, S., Wustmans, A., Kirschbaum, C., Rauth, W. and Hellhammer, D.H. Attenuated free cortisol response to psychosocial stress in children with atopic dermatitis. Psychosom. Med. in press (1997).
4Cohen, S., Doyle, W.J., Skoner, D.P., Rabin, B.S. and Gwaltney, J.M.J. Social ties and susceptibility to the common cold, JAMA, 277 (1997) 1940-1944.
5Cohen, S., Kaplan, J.R., Cunnick, J.E., Manuck, S.B. and Rabin, B.S. Chronic social stress, affiliation and cellular immune response in nonhuman primates, Psychological Science, 3 (1992) 301-304.
6Cohen, S., Tyrrell, D.A.J. and Smith, A.P. Psychological stress and susceptibility to the common cold, The New England Journal of Medicine, 325 (1991) 606-612.
7Crofford, L.J., Pillemer, S.R., Kalogeras, K., Cash, J.M., Michelson, D., Kling, M.A., Sternberg, E.M., Gold, P.W., Chrousos, G.P. and Wilder, R.L. Hypothalamic-Pituitary-Adrenal Axis Perturbations in Patients with Fibromyalgia, Arthritis & Rheumatism, 37 (1994) 1583-1592.
8Dhabhar, F., Miller, A.H., Stein, M., McEwen, B.S. and Spencer, R. Diurnal and acute stress-induced changes in distribution of peripheral blood leukocyte subpopulations. Brain Behav.Immun. 8 (1994) 66-79.
9Dhabhar, F.S. Stress-induced enhancement of antigen-specific cell-mediated immunity: the role of hormones and leukocyte trafficking. Rockefeller University, New York, 1996, pp. Microfilm Index #-9708514.
10Dhabhar, F.S. and McEwen, B.S. Stress-induced enhancement of antigen-specific cell-mediated immunity, J. Immunology, 156 (1996) 2608-2615
11Dhabhar, F.S. and McEwen, B.S. Moderate stress enhances, and chronic stress suppresses, cell-mediated immunity in vivo. Abstracts, Soc. Neurosci. 22 (1996) #536.3-p 1350.(Abstract).
12Dhabhar, F.S., Miller, A.H., McEwen, B.S. and Spencer, R.L. Effects of stress on immune cell distribution: dynamics and hormonal mechanisms. The Journal of Immunology, 154 (1995) 5511-5527.
13Dhabhar, F.S., Miller, A.H., McEwen, B.S. and Spencer, R.L. Stress-Induced Changes in Blood Leukocyte Distribution: Role of Adrenal Steroid Hormones, The Journal of Immunology, 157 (1996) 1638-1644.
14Fawzy, F.I., Fawzy, N.W., Hyun, C.S., Guthrie, D., Fahey, J.L. and Morton, D. Malignant melanoma: effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival six years later. Arch. Gen. Psychiat. 50 (1993) 681-689.
15Hadid, R., Spinedi, E., Giovambattista, A., Chautard, T. and Gaillard, R.C. Decreased hypothalamo-pituitary-adrenal axis response to neuroendocrine challenge under repeated endotoxemia, Neuroimmunomodulation, 3 (1996) 62-68.
16Heim, C., Ehlert, U., Hanker, J. and Hellhammer, D.H. Abuse-related post-traumatic stress disorder and alterations of the hypothalamo-pituitary adrenal axis in women with chronic pelvic pain. Psychosom. Med. (1997).
17Herbert, T.B. and Cohen, S. Stress and immunity in humans: a meta-analytic review. Psychosomatic Med. 55 (1993) 364-379.
18MacLean, C.R.K., Walton, K.G., Wenneberg, S.R., Levitsky, D.K., Mandarino, J.P., Waziri, R., Hillis, S.L. and Schneider, R.H. Effects of the transcendental meditation program on adaptive mechanisms: changes in hormone levels and responses to stress after 4 months of practice, Psychoneuroendocrinology, 22 (1997) 277-295.
19McEwen, 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. and Weiss, J.M. Neural-Endocrine-Immune Interactions: The Role of Adrenocorticoids as Modulators of Immune Function in Health and Disease, Brain Res. Rev. 23 (1997) 79-133.
20McKittrick, C.R., Blanchard, D.C., Blanchard, R.J., McEwen, B.S. and Sakai, R.R. Serotonin receptor binding in a colony model of chronic social stress, Biological Psychiatry, 37 (1995) 383-393.
21Melin, B., Lundberg, U., Soderlund, J. and Granqvist, M. Psychological and physiological stress reactions of male and female assembly workers: a comparison between two different forms of work organization, Journal of Organizational Psychology, In Press (1997).
22Miller, A.H., Spencer, R.L., Hasset, J., Km, C., Rhee, R., Cira, D., Dhabhar, F.S., McEwen, B.S. and Stein, M. Effects of selective Type I and Type II adrenal steroid receptor agonists on immune cell distribution. Endocrinology, 135 (1994) 1934-1944.
23Munck, A., Guyre, P.M. and Holbrook, N.J. Physiological Functions of Glucocorticoids in Stress and Their Relation to Pharmacological Actions, Endocrine Review, 5 (1984) 25-43.
25Richardson, J.L., Shelton, D.R., Krailo, M. and Levine, A.M. The effect of compliance with treatment on survival among patients with hematologic malignancies. J. Clin. Oncol. 8 (1990) 356-364.
26Seeman, T.E. and McEwen, B.S. The impact of social environment characteristics on neuroendocrine regulation. Psychosomatic Medicine, 58 (1996) 459-471.
27Spiegel, D., Bloom, J.R., Kraemer, H.C. and Gottheil, E. Effect of psychosocial treatment on survival of patients with metastatic breast cancer, The Lancet, ii (1989) 888-891.
28Ur, E., White, P.D. and Grossman, A. Hypothesis: Cytokines May be Activated to Cause Depressive Illness and Chronic Fatigue Syndrome, Eur Arch Psychiatry Clin Neurosci, 241 (1992) 317-322.