Case 3: Stress and the Immune System

CASE 3: STRESS AND THE IMMUNE SYSTEM

 

In case 3 we have KL, a medical student, who is always under stress and is recurrently sick. This is the typical picture where stress is one of the main causations of a depressed immune system. As a result, KL’s body is more susceptible to any type of pathogen that would normally present no harm to him but his body is not being able to mount an effective immune response because it is under stress. KL symptoms include dry cough and unusual tiredness, but he has no fever and his roommate has not acquired the symptoms. KL had a routine blood work and a chest radiograph. The results from these tests came normal, which suggests that these symptoms are not produced by an outside pathogen but most likely by a depressed immune system that is not being able to perform its normal function.

 

It is a well-known fact that stress causes our immune system to be depressed and more susceptible to different kinds of symptoms. Even though everyone is well aware of these facts, many still do not know the mechanism by which our state of mind influences our immune response. Based on different studies, it has been reported that stress influences the signaling pathway between the immune system and the brain. These signaling pathways are mediated strongly by the endocrine system. Two important factors of these interactions are the production of stress hormones by the Hypothalamic-Pituitary-adrenal  (HPA-chronic stress response) axis and the Sympathetic- adrenal-medullary (SAM-acute stress response) axis. The interaction between immune cells also takes place through the production of cytokines. Hormones modulate immune function by binding to its receptors, which are present on almost every type of immune cell. The modulation of cytokines has been proven to feedback to the brain. This feedback produces changes to the HPA axis, as well as inducing sickness behavior such as fever, loss of appetite, changes in sleep patterns and depression. One of these feedbacks loops is the one involving interleukin-1 (IL-1) on the production of corticotropin releasing hormone (CRH) by the hypothalamus. The production of CRH affects the HPA axis by producing an increase in cortisol, the stress hormone, levels. After this initial spike in cortisol levels, when stress is prolonged its levels decrease to an alarming level. The HPA is the main stress management system, which responds to maintain the body’s homeostasis by controlling its levels of cortisol.  Under prolonged stress this pathway is disrupted and cortisol levels drop.  Cortisol is a hormone that normally influences the immune response causing inflammation. Normally under acute stress cortisol levels would tend to spike but under prolonged stress there is a negative correlation between stress and this hormone.  This negative impact on cortisol causes inflammation to get out of control and promote disease.  The second pathway is the Sympathetic-adrenal-medullary (SAM), which mediates acute stress response. This pathway is activated by an immediate danger, and it s followed by a quick increase in heart rate, breathing rate, sweating, butterflies in the stomach, nausea, dilated pupils, etc. These reactions are caused primarily by sympathetic nerves that produce a direct stimulation of the body’s organs through the effect of noradrenaline synapses and a slow release of adrenaline from the adrenal medulla. After analyzing different studies, it can be concluded that there is a direct correlation between stress levels and the immune system. When we expose ourselves to prolonged stress, one of the areas that suffers is our immune system and as a result it is our body that endures the consequences.

 

There are various immunological explanations for the patient’s symptoms. Lack of sleep and a hard courseload are both stress-inducing factors. Such stressful situations have been shown to increase the incidence as well as the severity of illness in patients (S. Cohen, Doyle, & Skoner, 1999). In particular, studies have shown that patients under chronic stress have fewer natural killer cells, and thus less ability to fight tumors and viral infections, such as the upper respiratory infection that the subject in this case presents with (S. Segerstrom, 2004).

 

Generally high cytokine and antibody response (protein response) infers a strong immune system, with the exception of Il-6 and TNF-a. High Il-6 is indicative of increased inflammation and a decreased immune system response. It has recently been proven that stress actually increases IL-6 production due to the fact that glucocorticoids stimulate the release of this cytokine (S. Cohen, Doyle, & Skoner, 1999).  It has also been demonstrated that Il-6 concentration in nasal secretions is associated with upper respiratory symptoms, which the cytokine helps to aggravate (F. Hayden et al., 1998). Extremely low gamma interferon levels and lack of T-cell response have also been reported in stress-induced infections (S. Segerstrom, 2004).

 

Mechanistically speaking, the connection between stress and the immune system is direct and great. Chronic Stress leads to a decrease in TSH and thyroid function, a decrease in Growth Hormone and Insulin Growth Factor-I, a decrease in Growth and Differentiation, and a decrease in GnRH which leads to a decrease in Reproductive Function.  Additionally stress leads to an increase in HPA & SNS which lead to an increase in Cortisol and Catecholamines. This shift in turn leads to an increase glycogenolysis, gluconeogenesis, increase in Lipolysis and an increase in muscle proteolysis & bone reabsorption.

 

The net effect of these physiological and hormonal shifts result in a myriad of changes in the body.  Some of the physical manifestations of these shifts are immunosuppression of the body, insulin resistance and decrease of lean body mass.  Stress causes changes in the immune system by increasing the production of cytokines which increases an individual’s propensity to inflammation. This can adversely impact the individual towards numerous medical illnesses (e.g. cardiovascular disease, arthritis, osteoporosis) and an up-regulation of the production of Interleukin–6 which is associated with cardiovascular disease, Type II Diabetes and certain cancers.   Acute Stress stimulates the immune system (i.e. evolutionary adaptation, e.g. Fight or Flight Mechanism) where as chronic stress suppresses the immune system as measured by all immune systems that can be examined. Chronic stress includes bereavement which decreases NK cell cytotoxicity. Trauma decreases numbers of T cell  and decreases cortisol production. Loss (bereavement) is commonly associated with increased cortisol production

The patient has chronic stress that result in an excess of glucocorticoids that results in immunosuppression leading to an increase in susceptibility to viral infections. Glucocorticoids are effective anti-inflammatory agents. Glucocorticoids alter leukocyte trafficking and migration of some cell types to areas of inflammation and inhibit cellular functions. This helps to avoid the effects of stress or prepare the immune system for an encounter with antigens and pathogens. Glucocorticoids inhibit IL- 12 production but increase IL-10 production by monocytes and T cells. This makes the immune response to suppress a Th1 cells (production of IL-12, IFN-γ) that supports cellular immunity essential for viral clearance and may predispose to virus reactivation. Stress,  chronic “cortisol mediated” as opposed to acute “adrenalin mediated”, is one factor associated with reactivation, and there have been considerable speculation linking stress and the appearance, duration, and intensity of herpes virus infections. Recently, it has been demonstrated that Eipstein Barr Virus-transformed B- lymphocytes express glucocorticoid receptors and that glucocorticoid hormones, adrenocorticotropic hormone, and corticotropin-releasing factor can reactivate latent Eipstein Barr Virus in vitro (S. Agarwal & Marshal, 2001). An immunoassay is the biochemical test that measures the presence or concentration of a macromolecule in a solution through the use of an antibody or immunoglobulin in this case is the technique used to determine the levels of glucocorticoids in blood, urine and saliva. A concentration of cortisol or glucocorticoid measurement can be assayed in the saliva with commercial ELISA kits and read on the Multiscan MS Plate Reader according to the manufacturers’ recommendations.

The acute stress response (known normally as Fight or flight) is a defense mechanism in which the sympathetic autonomic nervous system activates the release of hormones in response to acute stress. The specific mechanism in which stress activates a response is transmission of the sensory information to the reticular system, the reticular activating system stimulates the limbic system which is the site of emotions and the hypothalamus, finally the hypothalamus activates the endocrine system by releasing hormone stimulating factors (CRF, TRF) which stimulate the pituitary glands to secrete (ACTH and TRH) finally stimulating the secretion of thyroid and adrenal hormones, the hypothalamus is also responsible of secreting its own hormones (ADH, Oxytocin) which affect blood volume, and muscle contractions. Other hormones released are specifically catecholamines (norepinephrine, epinephrine) and cortisol from the adrenal glands, and thyroid hormones that affect metabolism. The main structures associated in acute stress response are the sympathetic nervous system, the anterior pituitary, thyroid, and adrenal glands. The hormones released produce their effects through various sites of our body, which include the heart (by action of catecholamines), bone (anterior pituitary hormones), and the respiratory (catecholamines), reproductive (anterior pituitary hormones), cardiovascular (by action of catecholamines) immune systems. The immune system is directly involved in stress response due to fact that, acute stress response stimulates the release of cortisol which in fact is a stress hormone, cortisol release has very strong immunosuppressive effects specifically preventing inflammation, and down regulating IL-2 receptor on helper T cells which results in TH1 cellular dominance and low TH2 response. On the other hand there are studies that present an acute stress response or short stress burst as an immune system enhancer, unlike the chronic stress response, which is known to be a potent immune suppressor due to high cortisol release.

 

Questions:

Are there any immunological explanation for the patient’s symptoms?

 What is the connection between stress and immune system?

How do you evaluate the immune function in the patient?

What are the main systems/structures related with responses in acute stress?

CLINICAL CORRELATION 1: INCREASED IL-6 AND DECREASED IL-10 INDUCED BY STRESS CAUSES DEPRESSIVE SYMPTOMS

Recent studies have found that stress-induced levels of IL-6 and IL-10 (both inflammatory cytokines) are associated with depression (J. Vorhees et al., 2013). The pro-inflammatory cytokine IL-6 is used as a biomarker for depression, while IL-10 is now thought to offset pro-inflammatory cytokine behavior and decrease depressive-like symptoms. IL-6 stimulates the HPA axis and increases both tryptophan levels and serotonin metabolism in the brain- both of which are risk factors for a depressive mood. Therefore, if stress increases IL-6 production then it also increases the chances for depression.  Depression has not been reported to occur, however, without the concurrent decrease in IL-10 levels. Research has proven that inflammation in the cortex and the hippocampus is directly correlated with mood disorders and major depression (J. Loftis, Huckans, & Morasco, 2010). This inflammation was caused not by increased IL-6, but by decreased expression of IL-10 mRNA found in the cortex and hippocampus during the stressed state of the subject, which remained decreased after the stress was gone. Chronic stress decreases IL-10 levels while increasing IL-6 levels, thus inducing depressive like behavior and other behavioral defecits (J. Vorhees et al., 2013). This knowledge is being used to administer IL-10 dosages as an anti-depressant treatment.

CLINICAL CORRELATION 2: STRESS & ASTHMA

Studies have shown a relationship between emotion, stress and asthma. Some studies have shown that the increased psychological symptoms are a result of asthma exacerbations. On the other hand, other studies suggest that extreme emotional manifestations can worsen asthma symptoms. Recently there have been several studies demonstrating that mild to moderate asthmatic teenage subjects have immunological changes (decreased NK cell cytotoxicity and cytokine alterations) in response to exam stress. Alternatively, stress-mediated exacerbations of asthma may require multiple alterations by stress, including cytokine dysregulation and/or vagal mediated airway hyperresponsiveness. A recent intervention study suggests that psychological stress may play an important role in asthma. Asthmatics who wrote about past stressful experiences had an improvement in the predicted FEV1 compared to control groups, which was associated with decreases inself-reported distress levels. These results are provocative in that they demonstrate a relationship between psychological stress and asthma and suggest a role for stress management in the treatment of complicated asthmatics. We believe that these type-1/type-2 cytokine alterations are a major mechanism of the stress-associated increased susceptibility and/or severity of immune-based diseases.

Three factors in recent medical research and treatment have led clinicians and researchers to reconsider the role of psychosocial stress in asthma. There are many reports suggesting that stressful life events, family problems and a behavior pattern that increases psychological conflict may influence the development or relapse of asthma and influence its clinical course. Depression is known as one of the risk factors of fatal asthmatic attack. In laboratory studies, about 20% of asthmatics were considered reactors who showed an airway change after exposure to emotional stress.

CLINICAL CORRELATION 3: HEALTH PROVIDERS & THE IMMUNOCOMPROMISED PATIENT

The immune system is one of the most defenders of the body’s health. Many things can affect the efficiency and ability of the immune system. One very important factor that causes inhibition is chronic stress. This factor is especially important in a health care setting where both healthcare providers and patients are under a lot stress. A recent study by Dr. Uchakin titled “Fatigue in Medical Residents Leads to Reactivation of Herpes Virus Latency” indicates that in situations of chronic stress there is not only reactivation but active shedding of herpes virus particles. Such a relationship is extremely important because most healthcare providers suffer a large degree of stress while at the same interacting frequently with immunocompromised patients. If care is not taken by the health provider the patient can easily receive a secondary infection. Similarly work has been done on patients hospitalized for a long amount of time. Dr. Cohen mentions in the article “Physiological Stress, Immunity, and Upper Respiratory Infections” that patients likewise can suffer chronic stress associated immune inhibition. This is important because even if patients are not immunocompromised they are more prone to infection. This problematic because of the prevalence of infections such as Methycillin Resistant Staphlycoccus aurus (MRSA) and Streptococcus pneumoniae and Hemophillus influenzae. Therefore, if there is an effort to reduce unnecessary stress on both healthcare providers and long term hospitalized patients, this should lead to better overall prognoses, faster healing times, and less of a chance of a secondary infection.

REFERENCES:

 

1.     Agarwal SK, Marshal GD. Stress effects on immunity and its application to clinical immunology. Experimental Allergy. 2001; 31:25-31.

2.     Cohen S, Doyle WJ, Skoner DP. Psychological stress, cytokine production, and severity of upper respiratory illness. Psychosomatic Medicine. 1999; 61:175-180.

3.     Cohen, S. Psychological stress, immunity, and upper respiratory infections. Current Direction in Psychological Science. 1996; 5:86-89.

4.     Hayden FG, Fritz RS, Lobo MC, Alvord WG, Strober W, Straus SE. Local and systemic cytokine responses during experimental human influenza A virus infection. J Clin Invest. 1998;101:643-649.

5.     Nagata S, Irie M, Mishima N. Stress and Asthma. Allergology International. 1999; 48:231-238.

6.     Loftis JM, Huckans M, Morasco BJ (2010) Neuroimmune mechanisms of cytokine-induced depression: Current theories and novel treatment strategies. Neurobiol Dis 37: 519–533.

7.     Segerstrom SC. Psychological stress and the human immune system: A meta-analytic study of 30 years of inquiry. Psychol Bull. 2004;130:601-630.

8.     Uchakin PN, Parish DC, Dane FC, et al. Fatigue in medical residents leads to reactivation of herpes virus latency. Interdisciplinary Perspectives on Infect Diseases. 2011; 2011:571340.

9.     Voorhees JL, Tarr AJ, Wohleb ES, Godbout JP, Mo X, Sheridan JF, Eubank TD, et al. (2013). Prolonged Restraint Stress Increases IL-6, Reduces IL-10, and Causes Persistent Depressive-Like Behavior That Is Reversed by Recombinant IL-10.  [Internet]. PLoS ONE. 2013. Available from: http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058488