Stress and the Immune System: A Delicate Balance

by Whitney Crouch, RDN, CLT

What is stress?

An integrated definition of stress states that it is a constellation of events, starting with a stimulus (stressor) that precipitates a reaction in the brain (stress perception) and results in the activation of the physiological fight-or-flight systems in the body (stress response).¹

Stress is a fact of life. We all face stressors of some sort in our day-to-day lives; whether psychological, physiological, or physical. We have evolved with stress, and many of us have learned techniques to manage various stressors, so it makes sense to explore the biological ways in which stress impacts our health.

Research has shown that varying degrees and durations of stress affect each of us differently, and short-term stress (lasting from minutes to a few hours) may actually benefit our immune health; in contrast, weeks, months, or years of stress can be detrimental to our health.²

To help lay the groundwork for understanding immune responses, let’s review the basic framework of the human immune system.

The immune system is a complex network of messengers in a chain of command that includes multiple branches—much like the military. The innate immune system represents the dominant defense system against most organisms; it has a fast response to infection but has no immunological memory.³ The adaptive immune system has immunological memory that promotes quick elimination of pathogens when reinfection with the same pathogen occurs. It includes T and B lymphocytes and antibodies.⁴

Physiological stress

Many of us are familiar with the “fight-or-flight” response—you may envision an emergency situation like being chased by a lion or needing to react quickly to another dangerous situation. You may even feel your heart racing just thinking about such a scenario. This is the effect of the sympathetic nervous system: stimulus (lion) plus reaction in brain (stress perception), creating a fight-or-flight response in your body (stress response). This reaction is the result of norepinephrine (noradrenaline) and epinephrine (adrenaline), released by the sympathetic nervous system, along with corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), and cortisol, which arise following activation of the hypothalamic–pituitary–adrenal (HPA) axis.²

In a perceived threatening scenario, where the sympathetic nervous system response is stimulated, norepinephrine and epinephrine potentiate increased arousal, alertness, focus, and core temperature. At the same time, pain thresholds, cardiovascular output, respiratory rate, and blood flow to the brain and skeletal muscles also increase.⁵

Interestingly, a review of the science suggests that acute stress activates the immune system. Immune activation may be critical for responding to the immediate demands of a stressful situation, especially if the situation results in wounding or infection. Mechanisms of immuno-enhancement include changes in dendritic cells, neutrophils, macrophages, and lymphocyte trafficking, maturation, and function, as well as local and systemic production of cytokines.² All of these factors support the onset of the inflammatory process, which is necessary for normal wound healing.²

While short-term stress can be an immune stimulator, the same is not true of long-term physiological stress.¹ Long-term stress suppresses, or dysregulates, innate and adaptive immune responses. This is achieved by altering Type 1- Type 2 cytokine balance, inducing low-grade and chronic inflammation, and by suppressing the numbers, trafficking, and overall efficacy of immune protective cells.²

Psychological stress

Just as we all have differing genetic and biochemical composition, we also have varying responses to stressors. There are significant individual differences in stress perception, processing, appraisal, and coping.⁶ Sometimes there may be a crossover between the mind and body, as in the fight-or-flight response. The stimulus may be stressful mentally and require physical action.

But what about psychological stress that poses no pressing physical danger? Perhaps a stressful work project requiring a few long days and nights? Or the droning on of work, relationship, or other emotional woes? There are many lifestyle factors that may come into play when individuals experience long-standing mental stress. Financial and social support factors have been studied, as well as nutritional intake, sleep quality, and lifestyle decisions (exercise frequency, alcohol consumption, drug use, etc.).⁵ All of these factors play indirect roles in stress-related immunosuppression; however, many direct effects on immunity have also been demonstrated.^5-7

One study looked at 24 college students, 13 with a history of asthma and 11 without. Their blood draws for laboratory testing were completed midway through a semester (nontesting time, for baseline) and during a period of academic testing.⁷ Questionnaires were also filled out at these times that reviewed the subjects’ responses around depression, anxiety, stress, and test attitude/anxiety. Blood markers of inflammation called cytokines were studied in these subjects, looking at cytokines belonging to the Th1 and Th2 profiles. While these profiles, and likely a mixed profile, work together in the body to provide balanced immune responses, health conditions arise when there is an imbalance.⁷ For example, a predominant Th1-type cytokine pattern has been observed in the pathogenesis of autoimmune disorders, such as Hashimoto’s thyroiditis and rheumatoid arthritis.^8-9 A predominant pattern of Th2-type cytokine production is linked to the pathogenesis of allergic disease such as asthma.¹⁰

In this study, the production of interferon gamma (IFN-g) and IL-2 (Th1-type cytokines) was reduced significantly during the final examination period, whereas IL-6 (Th2-type cytokine) production was increased significantly during the same period.⁷ The pattern of change in IL-2 and IL-6 production was consistent for samples prepared by two different methods—mononuclear cell (MNC) cultures and whole-blood cultures.⁷

Another significant finding from these studies, demonstrating the effects of stress, were reports of delayed wound healing.¹¹ In a small study of 11 dental students, punch biopsies were administered to the hard palate at two different times—during summer vacation and three days before a major examination period for a term. Students took an average of three days longer to completely heal the 3.5-mm wound during examinations, i.e., 40% longer to heal a small, standardized wound during the higher stress period.¹¹ This was attributed to the decreased serum levels of IL-1β, a key interleukin involved in normal wound healing.¹¹

Multiple studies have also evaluated the immune response to long-term emotional stress such as that related to the role of caregiver to an ill or elderly relative, the emotional stress following a difficult divorce, and even the stress related to loneliness.^13-16 Common to these studies was the increased risk for viral illness, reemergence of latent viruses (Epstein-Barr, herpes simplex, and cytomegalovirus), and onset of autoimmune disease.^5,12-16

• One study looked at self-reported data and blood samples obtained from 38 married women and 38 separated/divorced women. Among married subjects, poorer marital quality was associated with greater depression and a poorer response on three qualitative measures of immune function. Women who had been separated one year or less had significantly poorer qualitative and quantitative immune function than their sociodemographically matched married counterparts.¹³
• Another study looked at self-reported data and blood samples obtained from 32 separated or divorced men and 32 sociodemographically matched married men. Separated/divorced men were more distressed and lonelier and reported significantly more recent illness than did married men; the former also had significantly poorer values on two functional indices of immunity (antibody titers to two herpes viruses), while not differing significantly on quantitative indices (percentages of helper and suppressor cells and their ratio). Among married men, poorer marital quality was associated with greater distress and a poorer response on one functional immunological measure, antibody to Epstein-Barr virus (EBV), as well as lower helper/suppressor ratios. Among separated/divorced subjects, those who had separated within the past year and who had initiated the separation were less distressed, reported better health, and had a better performance on one functional immunological assay (EBV antibody titers) than did noninitiators.¹⁴
• In a short-term study of 31 older couples (average age: 67 years) who had been married an average of 42 years, 5 blood samples were drawn during a 30-minute conflict discussion and a 15-minute recovery session. Both men and women who showed relatively poorer immunological responses across three functional displayed more negative behavior during conflict. Assays tested included the blastogenic response to two T-cell mitogens and antibody titers to latent Epstein-Barr virus. The researchers concluded that abrasive marital interactions may have physiological consequences even among older adults in long-term marriages.¹⁵
• Another study looked at 18 age- and sex- matched mothers of handicapped children ages 5-26 years. Multiple questionnaires were administered to assess the study subject’s stress level and mental health. Study subjects and age/sex-matched subjects underwent blood testing for the immune assay at the same time and day. The assays revealed that the caregivers had a lower percent of T cells, higher percent of T suppressor/cytotoxic cells, and a lower T helper:suppressor ratio compared to controls. There was also a trend toward lower T helper cells in caregivers.¹⁶

These studies provide useful insights into the biological impact of diverse, real-life stressors on the body’s immune system. Larger and longer-term studies are warranted to further elucidate the effects of altered T helper and suppressor cells on the body.

Data has also shown long-term, or repeated, psychological stress to be  strongly associated with detrimental effects on the cardiovascular system.^17-19  In 2004, results from a large meta-analysis of almost 300 independent studies over 30 years indicated that psychological stress was associated with suppression of the immune system  with a number of immunological diseases such as inflammatory bowel disease, allergic disease, atopic dermatitis, and celiac disease.^20-24 In studying psychological stress’s effects on the immune system, these studies included assays looking at all blood cells, immunoglobulins, cytokines, functional assays, and cell proliferation under various conditions.²⁰

Lastly, in children with a history of recurrent colds and flu and who demonstrated higher levels of psychological stress, research has shown salivary IgA/albumin ratio to be lower, indicating a potential link between stress and colds and flu.²⁵

Lifestyle approaches for stress management

While the side effects of stress are far-reaching, there are some lifestyle-related activities that can help quell the effects of life’s worries. One method, supported by considerable evidence, is the practice of mindfulness and meditation. Meditation represents a mental training framework for cultivating the state of mindful awareness in daily life. A 2016 meta-analysis looked at five outcomes of mindfulness meditation, including circulating and stimulated inflammatory proteins, cellular transcription factors and gene expression, immune cell count, immune cell aging, and antibody response – revealing potentially positive effects on these specific markers of inflammation, cell-mediated immunity, and biological aging.²⁶

Regular aerobic exercise, acupuncture, breathing exercises, and progressive muscular relaxation also help individuals to manage stress.²⁷

More studies are needed to explore the physiological benefits of mindfulness and other stress-management techniques, but there is hope for finding a preferred tactic to support all personality types and stressors.

Citations

1. Dhabhar FS et al. Acute stress enhances while chronic stress suppresses immune function in vivo: a potential role for leukocyte trafficking. Brain Behav Immun. 1997;11:286–306.
2. Dhabhar FS. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res. 2014;58(2-3):193-210.
3. Ken I et al. Nosocomial infections. Contin Educ Anaesth Crit Care Pain. 2005;5:14–17.
4. Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease: Principles of Innate and Adaptive Immunity. 5th ed, New York: Garland Science; 2001.
5. Vitlic A et al. Stress, ageing and their influence on functional, cellular and molecular aspects of the immune system. Age (Dordr). 2014;36(3):9631.
6. Gunnar M et al. The neurobiology of stress and development. Annu Rev Psychol. 2007;58:145–173.
7. Kang DH et al. Th1 and Th2 cytokine responses to academic stress. Res Nurs Health. 2001;24(4):245–257.
8. Del Prete GF et al. High potential to tumor necrosis factor alpha (TNF-alpha) production of thyroid infiltrating T lymphocytes in Hashimoto’s thyroiditis: a peculiar feature of destructive thyroid autoimmunity. Autoimmunity. 1989;4:267-276.
9. Dolhain RJ et al. Shift toward T lymphocytes with a T helper 1 cytokine secretion profile in the joints of patients with rheumatoid arthritis. Arthritis & Rheumatism. 1996;39:1961-1969.
10. Ackerman V et al. Detection of cytokines and their cell sources in bronchial biopsy specimens from asthmatic patients. Relationship to atopic status, symptoms, and level of airway hyperresponsiveness. Chest. 1994;105:687-696.
11. Marucha PT et al. Mucosal wound healing is impaired by examination stress. Psychosom Med. 1998;60(3):362–365.
12. Nowak M. The evolution of viruses—competition between horizontal and vertical transmission of mobile genes. J Theor Biol. 1991;150(3):339–347.
13. Kiecolt-Glaser JK et al. Marital quality, marital disruption, and immune function. Psychosom Med. 1987;49(1):13–34.
14. Kiecolt-Glaser JK et al. Marital discord and immunity in males. Psychosom Med. 1988;50(3):213–229.
15. Kiecolt-Glaser JK et al. Marital conflict in older adults: endocrinological and immunological correlates. Psychosom Med. 1997;59(4):339–349.
16. Pariante CM et al. Chronic caregiving stress alters peripheral blood immune parameters: the role of age and severity of stress. Psychother Psychosom. 1997;66(4):199–207.
17. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338(3):171–179.
18. Phillips AC et al. Cardiovascular and cortisol reactions to acute psychological stress and adiposity: cross-sectional and prospective associations in the Dutch famine birth cohort study. Psychosom Med. 2012;74(7):699–710.
19. Sedova L et al. Diet-induced obesity delays cardiovascular recovery from stress in spontaneously hypertensive rats. Obes Res. 2004;12(12):1951–1958.
20. Segerstrom SC et al. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull. 2004;130:601–630.
21. Mawdsley JE et al. Psychological stress in IBD: new insights into pathogenic and therapeutic implications. Gut. 2005;54:1481–1491.
22. Montoro J et al. Stress and allergy. J Investig Allergol Clin Immunol. 2009;19(Suppl.1):40–47.
23. Arndt J et al. Stress and atopic dermatitis. Curr Allergy Asthma Rep. 2008;8:312–317.
24. Mårild K et al. Psychological stress and coeliac disease in childhood: a cohort study. BMC Gastroenterol. 2010;10:106.
25. Drummond PD et al. Increased psychosocial stress and decreased mucosal immunity in children with recurrent upper respiratory tract infections. J Psychosom Res. 1997;43(3):271–278.
26. Black DS et al. Mindfulness meditation and the immune system: a systematic review of randomized controlled trials. Ann N Y Acad Sci. 2016;1373(1):13-24.
27. Harvard Health Publishing. Exercising to relax. https://www.health.harvard.edu/staying-healthy/exercising-to-relax. Published July 13, 2018. Accessed November 23, 2018.

Whitney Crouch, RDN, CLT

Whitney Crouch is a Registered Dietitian who received her undergraduate degree in Clinical Nutrition from the University of California, Davis. She has over 10 years of experience across multiple areas of dietetics, specializing in integrative and functional nutrition and food sensitivities. When she’s not writing about nutrition or educating others, she’s spending time with her husband and young son. She’s often found running around the bay near her home with the family’s dog or in the kitchen cooking up new ideas to help her picky eater expand his palate.