Stress and the Immune System

Stress and the Immune System

Stress is defined as a specific response by the body to a stimulus that disturbs or interferes with the normal physiological equilibrium of an organism.¹ Stress is shown to alter the effect of the immune system by inhibiting its actions, resulting in a number of potential physiological and psychological setbacks, which include obesity, cardiovascular and gastrointestinal disease among others. Additionally, there is a strong relationship between the central nervous system and immune system. Homeostasis and hormonal regulation by CNS and specifically neuroendocrine responses to stress, which are mediated by hypothalamic CRF, could result in “increased levels of corticosteroids, catecholamines, and certain opiates, substances which are generally immunosuppressive.²”

1: Effects of Stress

Studies on obesity have found evidence that Leptin is produced and regulated by neurons. Leptin is an appetite and body weight regulator, which also regulates Th1. The neural influence affects the immune system through leptin. There are Leptin receptors on CD4+ T cells (Th-1 immunity) and their lack of leptin gene showed a high thymocyte apoptosis. During starvation, or low leptin period, the immune system will be suppressed. Thus, for microbial infections, limiting stress and adequate nutrition is absolutely necessary for the healing process; however, for autoimmune diseases, stress and starvation can be beneficial.³

Studies on mice have shown that the stress response has a negative effect on the gastrointestinal system. The enteric nervous system (gastrointestinal system) is closely related to the brain by the parasympathetic and sympathetic pathways. This is known as the “brain-gut” axis.⁴ Corticotropin Releasing Hormone (CRH) is released in response to stress.⁵ CRH is responsible for increasing colonic activity, as well as decreasing gastric emptying time, gastric acid secretion and small bowel transit time.⁵ Studies have also shown that the stress response increases the permeability of the intestine to large antigenic molecules, which leads to mast cell activation, degranulation and colonic mucin depletion.⁵ The colon develops an increased susceptibility to colonic inflammation. The stress response has also been related to various gastrointestinal diseases, including functional bowel disorders, inflammatory bowel disease, peptic ulcer disease and gastroesophageal reflux disease. Furthermore, CRH causes the release of ACTH from the pituitary which results in the increase of cortisol in the bloodstream. Cortisol acts as an immunosuppressant by inhibiting the T-cell growth factor production.

Figure 2: Stress

The effects of stress on heart function and development of coronary artery disease (CAD) have also been shown. Stress can lead to inflammation from T lymphocytes, monocytes, macrophages and inflammatory cytokines (IL-1 and IL-6), as well as increased fibrinogen proteins for thrombus development.⁶ These factors can cause vascular inflammation, leading to atherosclerosis, which is the leading cause of CAD. IL-1 and IL-6 levels can be used clinically to test for depressed or anxious patients who might need early prevention of cardiovascular disease.⁶

Psychological stress has been recognized as a contributor to immune deficient responses. Studies have shown that chronic psychological stress leads to a less effective immune response to hormonal fluctuations that occur with infection.⁷ This means that a person under severe emotional stress would not be able to mount a sufficient immune response as compared to an individual with a normal state or at least free of such a stress factor.

Finally, overall happiness or sadness have been studied as contributing variables in the ability of an individual to fight off the common cold.⁸ An overall positive attitude or mental state is directly associated with a shorter period of recovery, whereas a negative state would present with a longer illness time.

Discussion Questions:

1. What is stress?

2. What is the role of T lymphocytes, monocytes, macrophages and inflammatory cytokines in Coronary Artery Disease?

3. What is the role of Leptin and stress in the immune system?

Multiple Choice Questions:

1. Which hormone is released during the stress response?

a. CRH

b. ADH

c. ACTH

d. Leptin

e. All of the above

2. In which of the following disease(s) would stress be beneficial in the treatment of the patient?

a. Obesity due to increased Leptin

b. Autoimmune disease

c. Hypogonadotropism

d. Atherosclerosis

3.The release of what can lead to vascular inflammation

a. IL-1 and IL-6

b. Estrogen

c. Thyroid Hormone

d. ATP

References

1. Stress: Available at: http://dictionary.reference.com/browse/stress. Accessed April 11, 2010.

2. Black PH. Central Nervous System-Immune System Interactions: Psychoneuroendocrinology of Stress and Its Immune Consequences. American Society of Microbiologist. 1994. Vol 38, Pg.1-6. Available at: http://aac.asm.org/cgi/reprint/38/1/1.pdf. Accessed: April 29, 2010.

3. Steinman, L., et al. The intricate interplay among body weight, stress, and the immune response to friend or 1 foe. Journal of Clinical Investigation. 111(2):183-185, January 2003. Available at:http://www.jci.org/articles/view/17622/files/pdf Accessed: April 11, 2010.

4. Hedrich HJ, Bullock GR. The laboratory mouse. London: Academic Press; 2004

5. Bhativa V, Tandon RK. Stress and the Gastrointestinal tract. J Gastroenterol Hepatol. 2005 Mar;20(3):332-9.

6.Roger CM Ho et al. Research on Psychoneuroimmunology: Does stress influence Immunity and Cause Coronary Aftery Disease? Annals Academy of Medicine. 2010 Mar;39(3).

7. Miller, Cohen, & Ritchey, 2002. Beaton, David. Effects of Stress and Psychological Disorders on the Immune System. Rochester Institute of Technology http://www.personalityresearch.org/papers/beaton.html

8. Jones, J. (2003). Stress responses, pressure ulcer development and adaptation. British Journal of Nursing, 12, 17-23

Figures:

1.Sonrieka. The Effects of Stress. Last visited April, 11th 2010. http://sonireka.files.wordpress.com/2009/04/topic_effects-1.jpg

2. Stress. Last visited April 11th 2010.

http://spaceresearch.nasa.gov/research_projects/images/immune_12-2002_1.jpg

Special Topics in Immunology:

Reproductive Immunology

The Journal of Reproductive Immunology states that this field of study “encompasses normal and pathological processes of reproductive tracts, gametes, fertilization, implantation, gestation, parturition and lactation, including host defense to infectious disease…developmental immunology and immunology of reproductive neoplasms, as well as application of immunological techniques in elucidation of reproductive processes or dysfunction.”[i] With this definition, we can see that reproductive immunology is more than tolerance and protection of the fetus and pregnant woman. It also includes women’s diseases related to pregnancy, the defense of the reproductive systems (man and woman) and how immunological problems in those organs affect the body’s homeostasis.

One topic covered by Reproductive Immunology is investigation of causes and treatment of infertility, which is a hot topic in medicine today. The Centers for Disease Control report that about 12% of people of reproductive age are affected by infertility.[ii] The shear number and availability of infertility internet support groups is indicative of the extent of the problem. At www.sharedjourney.com you can learn about the possible causes of infertility, explore options like IVF and adoption, and read success stories from other previously infertile couples.[iii] At www.rialab.com women with immune related miscarriages can receive consultations for possible solutions.[iv] These are only two of innumerable support groups.

Figure 1 - Screenshots from Shared Journey and Reproductive Immunology Associates websites.

A condition that is more common than expected and studied by this field is Recurrent Spontaneous Abortion. Thanks to the advances in medical history documentation and detection of pregnancy at an earlier period, we know that the etiology of this condition is 1 in 300 pregnancies.[v] This condition is a classical example of immunological mechanisms gone wrong; here the mother’s immune system attacks the fetus or related structures instead of modulating to maintain pregnancy. Reproductive immunology has given the insights of the causes of this condition and is leading us to find treatment options and eventually prevention.

Figure 2 – Model for immunological basis of Recurrent Spontaneous Abortion. From www.rialab.com/miscarriages_prevented.php

Reproductive immunology is an important and expanding science that addresses many medical issues as stated in the introduction. The Clinical Cases that are presented in the next section, portray some classical examples of diseases know by the general public that are finally being understood and in some cases treated with success. But these diseases are only a fraction of conditions that are studied in the field of reproductive immunology.

Clinical Correlations

Recurrent Spontaneous Abortions

One factor related to miscarriage is the natural killer (NK) cells which seem to have a role in recurrent spontaneous abortions (RSA). The major role of NK cells is to cause an inflammatory response mainly by the release of IL-10 in the endometrial layer thereby increasing angiogenesis in the decidua. Thus, NK cells normally assist in early fetal development. Studies show that women with RSA have increased NK cell counts.[vi] Hyperactive NK cells probably cause RSA by damaging maternal endocrine cells responsible for producing and secreting the hormones essential for pregnancy. Another hypothesis that is gaining much acceptance is that involvement of the complement system, causes an inflammatory reaction that produce placental hypoxia eventually leading to abortion.[vii] (See figure 2)

Gestational Diabetes

Reproductive immunology has many areas of study, including women’s diseases related to pregnancy. For example Gestational Diabetes (GD) is an insulin intolerance that is recognized during pregnancy without previous diabetes history. Studies show that GD is related to fetal monocyte activation by the mother’s immunoglobulins against paternal HLAs, as is the case of Rh Hemolytic Disease of the Newborn and Pre-eclampsia (hypertension and generalized edema in the pregnant woman).[viii] Scientist hypothesized that by some defect in the barriers dividing the mother and fetus, the mother’s immune system come in contact with antigen particles that are really biological structures from the fetus.

Anti-Sperm Antibodies

As part of fertilization and conception problems, one of the targets in recent studies is the Anti-Sperm Antibodies (ASA). These antibodies can impair the fertilizing capacity of human spermatozoa, acting negatively on sperm motility, cervical mucus penetration and in vitro gamete interaction. These have also been linked to semen hypersensitivity, a condition in which the woman experiences the symptoms of any other allergy. Few treatments are thought to be successful. Treatment options focus on decreasing ASA production and removing ASA already bound to sperm. The first is based on a treatment with corticosteroids, and the other by in vitro capacitation of sperm where it is possible to remove the entire immune complex without damaging the cell.[ix]

However, some cytokines are released within the sperm that help to regulate the immune system preventing a response against the embryo. Studies conclude that TGF is a potent immune-deviating cytokine with pivotal roles in inducing active immune tolerance in mucosal and peripheral tissues. Seminal TGF deposited in the female tract at insemination is activated and interacts with female tract cells to elicit an inflammatory cascade. It is reasonable to postulate that seminal antigens are shared by the conceptus, seminal TGF may act to facilitate induction of maternal immune tolerance to conceptus antigens and thereby promote implantation success.[x]

Discussion Questions

1. What is the role of antisperm antibodies in infertility?

2. What other immune related conditions or cytokines might cause infertility?

3. What about immunosuppression in pregnant women? How are women immunosuppressed and why is this important to the health of the fetus?

Multiple Choice Questions

1. What is true about NK cells function in pregnancy?
1. NK cells play an important role in the 3^rd trimester.
2. NK cells are hypersensitive in pregnant women.
3. NK cells have no role in normal pregnancy
4. NK cells are important in preparing the endometrial layer for implantation.

2. According to the CDC, what percentages of people in reproductive age are affected by infertility?
1. 15
2. 7
3. 39
4. 12

3. What article would you find classified as a study of reproductive immunology?
1. Toll like receptor signaling and pre-eclampsia
2. Hepatitis B-related events in autologous hematopoietic stem cell transplantation recipients
3. Women with Multiple Implantation Failures and Recurrent Pregnancy Losses have Increased Peripheral Blood T Cell Activation
4. CD57+ Cells and Recurrent Spontaneous Abortion

---

References

[i] About Journal of Reproductive Immunology. Journal of Reproductive Immunology: The International Journal for Clinical and Clinical Reproductive Immunobiology. Available at: http://www.journals.elsevierhealth.com/periodicals/jri. Accessed April 11, 2010.

[ii] Assisted Reproductive Technology: Home. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/art/. Accessed April 11, 2010.

[iii] Shared Journey. Shared Journey: Your path to fertility. 2010. Available at: http://www.sharedjourney.com/index.html. Accessed April 11, 2010.

[iv] Reproductive Immunology Associates. 2010. Available at: http://www.rialab.com/ Accessed April 11, 2010.

[v] Berek, Jonathan, & Novak, Emil. (2007). Berek & Novak's Gynecology. Hong Kong: Lippincott Williams & Williams.

[vi] Kwak-Kim, J and Gilman-Sachs, A. Clinical Implication of Natural Killer Cells and Reproduction. Am J Reprod Immunol. 2008; 59: 388-400.

[vii] Hahn, Sinuhe, Anurag Kumar-Gupta, Carolyn Troeger, Corinne Rusterholz, and Wolfgang Holzgreve. "Disturbances in placental immunology: ready for therapeutic interventions?." Springer Semin Immun. 2006.27 (2006): 477-493. Print.

[viii] Steinborn A., Saran G, Schneider A, Fersis N, Sohn C, Schmitt E. The Presence of gestational diabetes is associated with increased detection of anti-HLA-class II antibodies in the maternal circulation. American Journal of Reproductive Immunology, 2008: 56, 124-134.

[ix] Lombardo, F, L Gandini, and A Lenzi. "Antisperm immunity in assisted reproduction." Journal of Reproductive Immunology. 2004.62 (2004): 101-109. Print.

[x] Robertson S.A., Ingman Wendy V., O’Leary Sean, Sharkey David J., Tremellen Kelton P. "Transforming growth factor β—a mediator of immune deviation in seminal plasma"
Journal of Reproductive Immunology, Volume 57, Issue 1, Page 109

Immunology and Ageing

Guide Questions:

As a guide for the reader, we have posted this guide questions to help in the understanding of the topic and the focus of the subject.

1. Ageing and COPD:

a. Discuss the immunological events in the elderly make it harder for them to fight infection as opposed to a young adult.

2. Thymic Involution:

a. Discuss and propose a theory on how thymic involution might compromise our immune system as we age.

3. Smoking and Ageing:

a. Discuss another example of how smoking indirectly affects immunosenescence.

Immunology and Ageing
The number of people aged 60 years or older exceeded 635 million in 2002, and is expected to grow to nearly 2 billion by 2050.¹ These numbers have great repercussions on the importance of the immune system as it ages. The immune system loses its ability to fight off infections, as an individual grows older. This increases the risk of getting sick, and may make immunizations less effective. The immune system's ability to detect and correct cell defects also declines. Later in life, the immune system seems to become less tolerant of the body's own cells and sometimes an autoimmune disorder develops.²

A marked difference has been observed between young and old subjects in the subpopulations of naive (mature cells, part of the immune system that has not yet had their first encounter) and memory T cells (cells of the immune system, that have already had their first encounter, and thus are more competent to a specific antigen). The elderly have almost no naive T cells at all, since as the thymus (region of the body where T cells mature) progressively deteriorates with age. Consequently, the population of naive T cells becomes depleted and the aged immune system cannot respond as well as a young person to a "new" antigen.³

Aged T cells do not display the CD28 antigen, a molecule critical for signal transduction (cascade of events that lead to proper function) and T cell activation, on the cell surface. Without this protein, T cells remain quiescent and do not respond to foreign pathogens.³

This reduced function of T cells in the elderly also affects B cell function because T cells act in concert with B cells to regulate the production of antibodies. T cells induce B cells to hypermutate immunoglobulin genes, which in turn create the antibody diversity necessary to recognize a wide range of antigens. Aged helper T cells cannot interact as effectively with B cells, and so in the elderly, the potential antibody repertoire is more restricted than the antibody repertoire of younger people.³

During infection, IgM is the first class of antibodies to respond. The inability to ward off infections could be linked to the diminishing IgM response characteristic of elderly. Ageing B cells show decreased gene expression in the areas of lineage commitment and differentiation, resulting in reduced clonotypic diversity.⁴ Having fewer mature B cells contributes to the observed decrease in the amount of antibody produced in response to infection. As a repercussion, antibody responses to vaccines are slower and not as strong as in younger people, (vaccine efficacy 17-53% in elderly population).⁵

Aged T cells are more susceptible to apoptosis, or programmed cell death, due in part to the gradual loss of telomeres that cap the ends of the chromosomes to prevent DNA degradation, thus it seems that T cells have a limited lifespan, and immunosenescence (changes in the immune system associated with age) is genetically programmed.⁶

Thymic Involution

Thymic epithelial cells constitute the major subcomponent of the thymic stroma that encourages T-cell development but, with age, there is a decrease in the thymic epithelial space with reduced T-cell output. CD8+ as well as CD4+ T-cells have a low count believed to be due to shorter telomeres in older individuals.⁷ Treatments with IL-7, IL-15, IGF-1, and GH have shown to develop thymopoiesis but not to the point of fully recovering the thymus.⁸ Regeneration is also observed in the absence of sex hormones, although this was shown by castration or ovariectomy of mice. Thymic transplantation is another alternative in restoring immune function but tissue rejection has to be kept in mind, too, due to the limited tissue transplantation. Even though these treatments are at an early stage, it should be noted that more research in this matter could permit the restoration of the thymus in immuno-impaired individuals.⁹

Ageing and COPD

When an individual ages, the immune system starts to lose its ability to carry out phagocytosis and chemotaxis, as well as maintain the robust population of leukocytes from earlier years. When examining the effects on lung tissue, as shown in the figure above, Sharma compares the effects of ageing to chronic obstructive pulmonary disease (COPD), and shows how in both there is a rise in CD 4, CD 8 T-cells, and pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α. Physical changes noted in ageing, which parallel COPD include hyperinflation, loss of both lung function and elastic recoil.¹⁰

Smoking and Ageing

Ageing is affected both genetically and environmentally. Smoking is considered an ageing accelerator both directly, though triggering inflammatory responses, and indirectly through favoring diseases in which smoking is a risk factor.

One possible direct mechanism is oxidative stress caused by the free radicals in cigarette smoke that activate inflammatory cells with inflammatory mediator production and further oxidative damage. Another mechanism is thought to be that tobacco smoking enhances telomere shortening in circulating lymphocytes, which increases immunosenescence. This occurs at a critical minimum length of telomeres, which triggers cell cycle arrest, or senescence of the cell.¹¹

Indirectly, smoking increases the deterioration of the immune system by making the body more susceptible to disease. For example, the oxidative damage causes endothelial dysfunction, which induces arteriosclerosis. This is caused by changes in cellular redox status and the production of high levels of pro-inflammatory cytokines.¹²

Even though ageing is multifactorial, the environmental aspect has a profound effect on the change in immunosenescence characteristics that are seen in ageing. In order to attain longevity, smoking cessation is encouraged to delay the ageing process and appearance of diseases.¹³

Assessment quiz:

1. Which of the following is NOT a result of the involution of the thymus?

a) Impairment of chemotaxis

b) Stimulation naïve CD4 T cells

c) Immunosuppression

d) Impairment of phagocytosis

Answer is B. The inhibition, not stimulation, of naïve CD4 T cells is a result of the involution of the thymus.

2. Thymic involution is thought to result from high levels of:

a. Low levels of circulating CD4 cells in plasma during puberty

b. High levels of circulating CD8 cells in plasma during puberty

c. Circulating sex hormones in particular during puberty, lower population of precursor cells from the bone marrow and changes in thymic microenvironment.

d. Amount of free radicals as we begin to age.

e. Reactive C-proteins causing damage to the thymus as we age.

Answer is C.

3. How does tobacco smoking activate the inflammatory response?

a. Destroys T cells receptors

b. Decreases macrophages

c. Releases free radicals

d. Reduces IgG response

e. Increases complement system

Answer: C. The free radicals in cigarette smoke activate inflammatory cells with inflammatory mediator production and further oxidative damage.

Works Cited

1. Editorial. Aging in the 21st Century: A Call for Papers . Arch Neurol. 2002;59:518-519.

2. Langan M. Aging Changes in immunity. MedlinePlus Medical Encyclopedia. Available at: . Accessed April 28 2010.

3. Whitman DB. The Immunology of Aging. ProQuest. Available at: http://www.csa.com/discoveryguides/archives/immune-aging.php#g23. Accessed April 28, 2010.

4. Dicarlo, Al., et al. Aging in the context of immunological architecture, function and disease outcomes. Trends. Immunol. 2009; 7:293-297.

5. Goodwin K, Vibound C, and Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006;24:1159-1228.

6. Vasto S, Malavolta M and Graham P. Age and immunity. Immunology & Ageing. 2006;3:1186-1196.

7. Dorshkind K, Montecino-Rodriguez E and Singer RA. The ageing immune system: is it ever too old to become young again? NatRev Immunol. 2009; 9:57-62.

8. Caruso C, Buffa S, Candore G, et al. Mechanisms of immunosenescence. Immunity & Ageing. July 22, 2009:6-10.

9. Danielle AW, Silva AB and Palmer DB. Immunosenescence: emerging challenges for an ageing population. Immunology. 2007; 120:435-446.

10. Sharma G, Hanania NA. and Shim YM. The Aging Immune System and Its Relationship to the Development of Chronic Obstructive Pulmonary Disease. The Proceedings of the American Thoracic Society. 2009;6:573-580.

11. Kaszubowska L. Telomere shortening and ageing of the immune system. J Physiol Pharmacol. 2008;9:169-86.

12. Wilson, S. and Mazzatti DJ. Current status and future prospects in the search for protein biomarkers of immunosenescence. Expert Rev Proteomics. 2008;5:561-570.

13. Nicita-Mauro V, Basile G, Maltase G, et al. Smoking, health and ageing. Immunity & Ageing. Available at: http://www.immunityageing.com/content/5/1/10. Accessed April 28, 2010.