Stress and Immunology

Stress is a body’s emotional and physical strain caused by its response to pressure^2. Stress can stem from negative emotional, physical, and/or psychological experiences. Emotional reactions may include an inability to concentrate or irritability and tension, while physical symptoms may exhibit an increased heart rate or a stress induced headache³. Although, there may seem to be a lot of negative effects due to stress, not all types of stress are destructive. Furthermore, it is nearly impossible to live without any stress! Stress adds excitement to life; however, if its not properly managed, it can harm a person’s quality of life.

Stressors are conditions that a person views as potential threats to their general state of mind ^1(p25). Moreover, one feels that the challenge faced is greater than the perceived resources to overcome the challenge ^1(p25). Stressors vary in type and in length of time. They can be physical, cognitive, or both and can be categorized into acute (rapid-onset), sub chronic (1-month), or chronic (months-years) based on their prolonged effect on a person (Table1). The category of the stressor may elicit a diverse neuro-endocrine response and alter the immune system ^3(p1620). Changes in the immune system can contribute to a greater predisposition to contracting an infection.

Stress affects the immune system differently.  Natural immunity is not specific towards a pathogen such as the neutrophils and macrophages that attack different pathogens through inflammation ^3(p1690). The macrophages release molecules called cytokines, which cause fever and inflammation. Cytokines, however, utilize IL-1, IL-6 and TNFa to promote recovery from an infection. Natural immunology is also supported by mast cells, eosinophils and natural killer cells, which fight allergies, parasitic reactions, and foreign cells, respectively ^2(p603).

  

               ã 2001 Blackwell Science Ltd, Clinical and Experimental Allergy, 31, 25±31

 

Specific immunity is comprised of lymphocytes, which are antigen-specific cells that divide to create more cells with the same antigen. This response takes longer to become effective in the body. There are three types of lymphocytes: T-helpers cells 1 and 2, T-cytotoxic cells, and B-cells. The B-cells produce antibodies that can neutralize bacterial toxins by binding the free virus and then utilizing opsonization ^2(p603).

Stress produces a series of physiological and behavioral responses from the host that activates both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system (SNS). When the hypothalamus receives an excitatory stimulus, it secretes corticotropin-releasing hormone (CRH).  CRH travels to the anterior pituitary gland and stimulates corticotrophs to release adrenocorticotropic hormone (ACTH).  ACTH stimulates cortisol production through the adrenal cortex.  Activation of the SNS increases the secretion of epinephrine and norepinephrine in the nerve termini as well as in the adrenal medulla ^1(p25).

 Stress affects the immune response via sympathetic fibers traveling from the brain to the primary and secondary lymphoid tissue. The sympathetic fibers release substances that bind to receptors and influence responses on cells. In addition, the hypothalamic pituitary adrenal axis, the sympathetic adrenal medullary axis and the hypothalamic pituitary ovarian axis secrete adrenal and pituitary hormones as well as brain peptides (Figure 3) ^2(p604-605). Finally, the immune system is altered in its attempt to manage stress.

 

 

 

 

 

 Figure 1: http://www.vitalifenetworks.com/VL_Cortisol.php

 

Th1 cytokines activate cellular immunity, while the Th2 cytokines activate humoral immunity. Chronic stress causes a suppression of Th1 cytokines and activates the Th2 cytokines. While a diminished Th1 mediated response could increase infections, an enhanced Th2 reaction may increase allergies as well as asthma ^5(p207).

 

 

 

 

 

 

 

 

 

_{http://www.afsafund.org/research_1998.html: Copyright © 1998-2011}

Figure 4- shifting to Th2

 

 

 

 

 

 

Figure 2- ã2001 Blackwell Science Ltd, Clinical and Experimental Allergy, 31, 25±31

 

 

 

 

 

Figure 3:

Ronald Glaser and Janice K. Kiecolt-Glaser

Nature Reviews Immunology 5, 243-251 (March 2005)

 

 

Clinical applications

Stress and viral infections:

Some of the diseases proven to increase their recurrence as stress levels increases are: upper respiratory infections and the progression of Human Immunodeficiency Virus.

A person with high stress levels may cause an increase in the production of

interleukin 6 (IL-6), which is an inflammatory cytokine. The release of IL-6 can be related to secretion of glucocorticoids (stress hormone) by the adrenal gland.⁶

Although the secretion of glucocorticoids play a crucial role in reducing stress levels, and contributes to feeling energetic and more alert, too much of it will generate undesirable consequences to the immune system. Gluco-corticoids, specifically cortisol, inhibit the production of interleukin 2 (IL-2), which normally stimulate the production of CD4 cells to help fight an infection. Cortisol also inhibits T cell proliferation^7. Therefore, this mechanism increases the probability of an infection by disabling the normal reaction of the immune system to counteract and combat the infection.

 

Upper Respiratory Infections:

• rhinitis (inflammation of the nasal mucosa)
• sinusitis
• common cold (nasopharyngitis)
• laryngitis

HIV: increased stress may cause the disease’s progression to increase due to lower number of CD-4 cells in the patient¹.

 

Connecting Asthma with Stress

There is a relationship shown between emotion, stress and asthma. Dr. Pramod Kelkar from the American Academy of Asthma Allergy and Immunology stated⁸, “Asthma is triggered by many things, and one of them is stress”. One study^1(p27) showed when comparing asthmatics to health controls that the patients with asthma had higher levels of life stress and negative emotions, such as panic. Another study^1(p27) found that extreme emotional manifestations can exacerbate asthma symptoms. Recently^1(p27), an intervention study concluded that psychological stress plays an important role in asthma based on the results that asthmatics who wrote about past stressful experiences had an improvement in the predicted FEV1(Forced Expiratory Volume in 1 second) compared to those who did not, as well as decreases in self-reported distress levels.

Dr. Pramod Kelkar also noted ^8(p1) that asthma is not a psychosomatic disease and that it only triggers symptoms if you already have the disease, but does not lead you to developing asthma. Stress-mediated exacerbations of asthma can occur through various mechanisms^8(p1): Vagal mediated airway hyper-responsiveness or cytokine disregulation.

• Vagal mediated airway hyper-responsiveness:

Dr. Pramod Kelkar^8(p1) explained that uncontrolled emotions can stimulate sympathetic nerves and cause constriction of the smooth muscles of the airways in the lungs, which can worsen wheezing, coughing, and chest tightness in people with asthma.

• Cytokine Disregulation: Lymphocytes and monocytes have many stress hormone receptors⁹ (CRH, ACTH, cortisol, norepinephrine, and epinephrine) and in order to reach cells of immune system they directly innervate lymphoid organs. So, when neuroendocrine hormones are released ^9(p241) during a stressful event, they can potentially alter the course of asthma. Moreover, chronic stress induces a shift in the type-1/type-2 cytokine balance toward a predominant type-2 cytokine response ^9(p241), which favor the inflammatory characteristics of asthma and allergic diseases. 

Interestingly, incidence and prevalence of asthma is increasing and is higher in urban areas versus rural areas^9(p241), which can be contributed to the higher chronic stress levels of those living in urban areas, and may be contributed to the well-appreciated higher chronic stress levels associated with urban living.

Ulcerative Colitis and Stress

Ulcerative colitis is an inflammatory bowel disease affecting the large intestine and rectum. It is characterized by inflammation and ulcers/sores affecting this generalized area with a more probable concentration in the sigmoid colon ¹⁴.

 

Additional symptoms of ulcerative colitis include abdominal pain, cramps, rectal hemorrhage, blood in the stool, diarrhea, irregular bowel movements, fever and loss of appetite ¹⁴. If left untreated, ulcerative colitis may eventually lead to scarring of the bile duct, liver damage, and an increased risk for colon cancer ¹⁴.

 

A definitive cause for ulcerative colitis has yet to be identified, although studies have suggested that it may be related to an autoimmune response, which exaggerates the functions of the normal intestinal flora ¹⁴ via to an overproduction of cytokines and TNF alpha. Individuals with ulcerative colitis thus present with elevated levels of interleukin-6 and 13 as well as high levels of TNF alpha 10.

 

Chronic psychological stress has been shown to exacerbate the effects of ulcerative colitis, often including flare-ups of those in remission and worsening the severity and/or occurrence of associated symptoms ^{14, 10}. Individuals with ulcerative colitis are more prone to stress than the general population due to the added anxiety of everyday life accommodations related to the disease ^10,13. These may include the incidence of “bowel accidents”, digestive problems, and the need for frequent bathroom visits.

 

Stress itself induces the secretion of adrenaline as well as cytokines as part of the fight-or-flight response ¹⁰. These cytokines ultimately stimulate the immune system, thereby producing an inflammatory response ¹⁰. The most relevant cytokine involved in this mechanism is interleukin-6 (IL-6), a pro-inflammatory cytokine. Individuals experiencing chronic stress have a reduced capacity for the productions of gluco-corticoid hormones that suppress the synthesis of IL-6 ¹¹, thereby presenting elevated IL-6 which further increase/spike during times of stress ¹³.

 

The second theory illustrating the relationship between stress and inflammatory diseases, including ulcerative colitis, relates colonic mucin with stress and CD4 lymphocytes ¹². Stress has been shown to reduce colonic mucin and increase colon permeability ¹². Stress can induce colitis flares by allowing luminal contents to easily penetrate, reactivating sensitized CD4 cells in the colon ¹². The stimulated reactivation of remised inflammation consequently requires the action of CD4 lymphocytes for stress induction ¹².

 

Thus, chronic stress has been shown to impair the immune system’s ability to respond to hormonal signals that would otherwise induce an inflammatory response ¹¹. This provides an immunological association between stress and its exacerbating inflammatory effects on ulcerative colitis ¹¹. This knowledge is of benefit for the treatment of ulcerative colitis in medical practice. Reduced stress in these patients increases their prognosis by diminishing the probability of flare-ups and enhancing the effectiveness of their treatment regimens. 

 

 

 

 

 

 

 

Image credit: © Andrea Bricco/Brand X/Corbis

 

 

 Questions:

 

Lymphocytes in our body are capable of eliciting different reactions in response to stress. Which lymphocyte sub-class is associated with an inflammatory reaction causing allergic symptoms?

A. Natural Killers

B. Cytotoxic lymphocytes

C. Th1

D. Th2

E. B cells

 

Asthmatic patients live in a constant inflammatory state of their lungs. Several factors can cause exacerbation of their symptoms. Which of the following can be a trigger of an asthmatic attack

A. Clean environment

B. Smoke free house

C. Allergy control

D. Drink plenty of water

E. Losing your job

 

Which of the following is an example of a reactivation of infection trigger by stress?

A. Herpes

B. Measles

C. Polio

D. H1N1 influenza

E. Hepatitis A

 

How does stress influence the immune function?

Stress produces changes in the body through its effects on the anterior-pituitary adrenal-cortex system and the sympathetic nervous system. T cell and B cells are important components of the immune system because they have receptors for glucocorticoids, epinephrine, norepineprhine, which are hormones that are released during stress period. Stimulation of the receptors of the immune system cells activate the production of cytokines that can elicit the suppression or activation of specific immune function. Stress may produce a shifting from anti-inflammatory cytokines Th1 to pro inflammatory cytokines Th2 increasing the possibilities of causing allergies, asthma, infections and autoimmune diseases.

 

How does stress affect susceptibility to infectious disease?

It has been difficult to show unequivocally that stress causes increase susceptibility to infectious diseases in humans. Studies have demonstrated that certain diseases like herpes and respiratory infections are frequent in people with chronic stress.

If we have a shift from Th1 to Th2 cytokines release, there would be suppression of cell mediated immunity with suppression of CD4 +, decrease in NK cell and cytotoxic lymphocytes cells making the host susceptible to infections. Although it is important to know that decline in some aspects of immune function may induce compensatory increases in others.

 

What are the types of stressors? Is there a specific time frame for stress duration?

Stressors may be classified by the factor that elicit it or by the time evolution. Factors that may elicit stress include cognitive, physical, and chemical. Another classification of stress can be made by the duration either being acute (minutes to hours), sub chronic (less than a month) or chronic (months to years).

Different types of stress as well as duration of stress may produce different neuro-endocrine responses and immune alterations.

 

 

References

 

1- Agarwall SK, Marshall GD. Stress effects on immunity and its application to clinical Immunology. Clinical and Experimental Allergy. 2001; 31:25-31.

2-Segerstrom SC, Miller EG. Psychological stress and the human Immune System: A meta-

analytic study of 30 years of inquiry. Psychol Bull. 2004; 130(4): 601–630.

3-Barger ST, Marsland AL, Bachen EA, Manuck SB. Repressive coping and blood measures of disease risk: Lipids and endocrine and immunological responses to a laboratory stressor. Journal of Applied Social Psychology. 2000; 30:1619–1638.

4-Marsland AL, Cohen S, Rabin BS, Manuck SB. Associations between stress, trait negative affect, acute immune reactivity, and antibody response to hepatitis B injection in healthy young adults. Health Psychology. [DOI: 10.1037//0278-6133.20.1.4].2001; 20:4–11. Available at: http://www.psy.cmu.edu/~scohen/marscohrabin01.pdf. Accessed January 5, 2011.

5-Chiappelli F, Manfrini E, Franceschi C, Cossarizza A, Black KL, de Kloet ER, Azmitia EC, Landfield PW. Steroid regulation of cytokines: Relevance for Th1 to Th2 shift? Brain corticosteroid receptors: Studies on the mechanism, function, and neurotoxicity of corticosteroid action. Annals of the New York Academy of Sciences.1994; 746: 204–215.

6-Cohen, S., Doyle, W. & Skoner, D. Psychological Stress, cytokine production, and severity of upper respiratory illness. Psychosomatic Medicine. 199;61:175–180

http://www.psychosomaticmedicine.org/content/61/2/175.full.pdf+html

7-Constanzo, Linda. Physiolog. 4th Ed.2010. Saunders/Elsevier ;493

8-Hatfield H. When stress levels go up, asthma symptoms can go into overdrive. What’s the link, and how can asthma and anxiety be managed? Web MD. 2007. Available at www.webmd.com/asthma/features/asthma-and-anxiety. Accessed March 22, 2011.

9-Marshall GD. Jr, Agarwal SK. Stress, immune regulation, and immunity: applications for asthma. Allergy Asthma Proc. 2000; 21(4): 241-6.

10- Libov, C. The link between stress and ulcerative colitis: research shows this GI ailment feeds on your tension. WebMD the Magazine, Retrieved from http://www.webmd.com/ibd-crohns-disease/ulcerative-colitis/features/link-between-stress-ulcerative-colitis. Accessed March 28, 2011.

11- Miller, GE, Cohen, S, & Ritchey, AK. Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychology. 2002;m21:6:531-41. Retrieved from http://www.psy.cmu.edu/~scohen/healthpsych%202002.pdf. Accessed March 28, 2011. Document ID: 10.1037//0278-6133.21.6.531

12- Qiu, BS, Vallance, BA, Blennerhassett, PA, & Collins, SM. The role of cd4+ lymphocytes in the susceptibility of mice to stress-induced reactivation of experimental colitis. Nature America. 1999;5:10. Retrieved from: http://farncombe.mcmaster.ca/documents/Qiuetal.NatureMedicine19995101178-1182.pdf. Accessed March 28, 2011

13- Tsukasa Kuroki, Akihide Ohta, Yosuke Aoki, Seiji Kawasaki, Nozomi Sugimoto, Hibiki Ootani, Seiji Tsunada, Ryuichi Iwakiri, Kazuma Fujimoto. Stress maladjustment in the pathoetiology of ulcerative colitis. Journal of Gastroenterology  [serial online]. 2007;42:522-7.  Available from: ProQuest Health and Medical Complete. Accessed March 28, 2011, Document ID: 1311123381. 

14- Ulcerative colitis - topic overview. (n.d.) Retrieved from http://www.webmd.com/ibd-crohns-disease/ulcerative-colitis/ulcerative-colitis-topic-overview. Accessed March 28, 2011.

15- Scott E. Stress and health stress: How it affects your body, and how you can stay healthier. About.com. 2009. Available at: http://stress.about.com/od/stresshealth/a/stresshealth.htm. Accessed March 2, 2011.

16- Glaser R, Kiecolt-Glaser JK. Figure 3: Stress-associated modulation of the hormone response by the central nervous system. Nature Reviews Immunology. 2005; 5: 243-251. Available at: http://www.nature.com/nri/journal/v5/n3/fig_tab/nri1571_F1.html. Accessed January 25, 2011.

 

 

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