Case 1: Depression and the Immune Response

Case 1: Depression and the Immune Response

A 48 y/o woman who suffers of pulmonary tuberculosis is receiving antibiotic therapy.

Her physician refers her to the psychiatrist because loss of interest in activities or pleasure, anorexia, weight loss, insomnia, fatigue, sense of worthlessness, loss of the ability to concentrate and thoughts of death for the last two months.

Summary

In the case shown above, it is clear that the patient presents with depression. Recently, researchers have shown that there is a definite correlation between depression and the body’s immune response; the correlation that has been found deals with the release of cytokines during an immune response. Cytokines are considered signaling peptides used by a diverse group of cells within the body to communicate. When the body is immunologically compromised (in this case, pulmonary tuberculosis), numerous cytokines are released in an attempt to have the body working together to handle the newly introduced disease.

The overall effects of cytokines can be copious, but specifically pertaining to this case, effects include: neuropsychiatric symptoms. This can be seen as the patient deals with loss of interest, sense of worthlessness, loss of ability to concentrate and thoughts of death. It has been found that a specific cytokine, such as INF-alpha, is tied to the effect of neuropsychiatric symptoms. INF-alpha is responsible for causing fever, fatigue and lack of appetite. Depression has been linked to this and other pro-inflammatory cytokines. These pro-inflammatory cytokines are responsible for causing the symptoms associated with depression in patients who do not have prior mental disorders. After many studies, focusing on pro-inflammatory cytokines, they have shown to produce psychiatric mood disruptions in those patients who were once free of any mood disorders. The presented case shows that the tuberculosis is a full onset on the lungs making this infection a cytokine-producing organ. These cytokines are produced in a large amount that they arrive in the vascular region of the brain. In part the brains astrocytes that make up the blood-brain barrier intake cytokines as they too have receptors and produce these pro-inflammatory cytokines, which in turn have negative psycho-neuronal effects on the patients brain chemistry.

Patients with autoimmune disorders are at higher risk to potentially develop behavioral changes, mood swings and loss of interest in activities, which were once pleasurable. Autoimmune diseases can be quite detrimental in the brain and central nervous system (CNS) because of the immune response and antibodies produced. The effects of the response causes further damage to neurons and other types of brain cells. These autoimmune disorders then have the potential of affected different features of the brain and CNS such as, areas dealing with memory, behavior and mood. These disruptions will eventually produce a decreased synthesis of neurotransmitters that are important in the activity of many regions of the brain; more specifically, the immune response developed by these diseases targets degradation in the amino acid, tryptophan. It is currently known that tryptophan is the precursor to the neurotransmitter, serotonin. This decrease in neurotransmitters (serotonin) leads to presentation of behavioral changes, such as depression. Thus, it can be concluded that because of the increased levels of pro-inflammatory cytokines and the effects on the synthesis of serotonin, diseases causing a prolonged immune response (such as tuberculosis) can lead to behavioral changes, such as depression.

Clinical Applications:

1.    Probiotics as modulators of cytokine production

Probiotics: microorganisms that have a favorable influence on physiological and pathological processes of the host by their effect on the intestinal flora. Probiotics may play a role in improving human health. The most intriguing aspect of probiotic modulation of immune response is believe to work through its effects on cytokine production

Studies have shown that probiotics—which by regulating cytokine levels in the gut, can influence infection and inflammation throughout the body, and even help balance brain function and mood.

The Three Steps to Successful Use of Probiotics in Depression

• Establish that your patient is suffering from atypical depression (inflammation driven)

• Examine their levels of SIgA by salivary analysis and correcting if required.

• Use the most effective human derived strains of probiotics to suppress excess inflammatory cytokines by induction of IL-10 and regulate immune response systemicall

Beneficial effects exerted by probiotic bacteria in the treatment of human disease may be broadly classified as those effects that arise due to activity in the large intestine and are related to colonization or inhibition of pathogen growth. These effects, which arise in both the small and large intestine, are related to enhancement of the host immune response and intestinal barrier function. In a strain dependent fashion, probiotic bacteria can enhance intestinal barrier function and modulate signal transduction pathways and gene expression in epithelial and immune cells. Oral administration of live probiotics and bacterial structural components can also differentially modulate dendritic cells resulting in an increased production of IL-10 and regulatory T cells. Probiotic bacteria can modulate both innate and adaptive immune responses. The use of probiotics can modulate the amount of cytokine produced, and therefore, decrease the levels of pro-inflammatory factors; this will prevent the depression seen with increased concentration of cytokines.

2.     Multiple Sclerosis and Depression

Depression is very common in people with multiple sclerosis (MS). In fact, symptoms of depression severe enough to require medical intervention affect up to half of all people with MS at some point during their illness.

·         Why Do People With Multiple Sclerosis Also Have Depression

-Depression may be the result of a difficult situation or stress. It is easy to understand how patients with MS, which has its potential for progressing to permanent disability, can bring on depression. In addition, MS has the capability to destroy the insulating myelin that surrounds nerves that transmit signals affecting mood. Lastly, drugs used to treat MS have proven to have depression has a potential side effect.

·         What Are the Symptoms of Depression?

Depression is differentiated from normal every day feelings of sad or blue, because of its long lasting period. Depression can last for years and cause much suffering in the individual. More importantly, this condition eventually becomes too intense and prevents an individual from living a normal life. Depression has several key symptoms that physicians should be conscious of. Below is a list of typical symptoms seen in patients with depression.

-Sadness

-Loss of energy

-Feelings of hopelessness or worthlessness

-Loss of enjoyment from things that were once pleasurable

-Difficulty concentrating

-Uncontrollable crying

-Difficulty making decisions

-Irritability

-Increased need for sleep

-Inability to fall or stay asleep at night (insomnia)

-Unexplained aches and pains

-Stomachache and digestive problems

-Decreased sex drive

-Sexual problems

-Headache

-A change in appetite causing weight loss or gain

-Thoughts of death or suicide

-Attempting suicide

 

Questions:

 

1.    Are there any immunological explanations for the patient’s symptoms?

Taking into consideration the list of symptoms presented in the case, it can be concluded that the women presents with depression. As of late, there has been new research giving evidence of immunological factors playing a role in the exhibition of depression. The relationship between depression and the immunological response has been found to involve cytokines. Within the immune system cytokines are signaling peptides used by a diverse group of cells within the body to communicate. When the body is immunologically compromised the body releases a myriad of cytokines, which all work together to have multiple effects throughout the human body. These effects include neuropsychiatric symptoms, more specifically, INF-alpha, which is responsible for, causing fever, fatigue and lack of appetite.

            Depression, as well as other behavioral changes, has been linked to pro-inflammatory cytokines. It is thought that these pro-inflammatory cytokines are responsible for causing the symptoms associated with depression in patients who do not have prior mental disorders. This is because pro-inflammatory cytokines have been shown to produce psychiatric mood disruptions in those patients that did not have former mood disorders. Below, a summarized chart for the basis of this phenomenon is shown:

 2.    What is the connection between behavior and autoimmunity?

Autoimmunity is used to describe when an organism fails to recognize proper cells as “self” cells; this eventually leads to an immune response in which the own body attacks its “self” cells. This disrupts the normal function of the human body and puts the individual at risk for potential complications. This autoimmunity can be quite detrimental in the brain and central nervous system (CNS) because the antibody production will cause further damage to neurons, as well as other types of brain cells. These autoimmunities have the potential of affecting different features of the brain and CNS. One example would be changes in memory, behavior and mood, all of which stem from auto antigens for synaptic receptors on cell surface proteins. Disruptions such as these eventually produce a decrease in the synthesis of neurotransmitters that are important in the activity of many regions of the brain (this could include regions such as the hypothalamus-pituitary axis or parts of the limbic system). Because of the role of these regions with conduct, a change in the neurotransmitters will lead to presentation of behavioral changes, such as depression, mood swings, loss of ability to concentrate and loss of interest in activities which were once pleasurable. These areas are at risk to be affected by an autoimmune disorder.

3.    What are the main structures of the CNS involved in normal mood?

One of the major CNS systems involved in normal mood is the limbic system. The components of this system include the hippocampus and amygdala. Other key players involved in normal mood include the prefrontal cortex, nucleus accumbens and hypothalamus. The roles of each structure is described below:

 

References:

         Siegel A, Sapru H. Essentials of Neuroscience. 2nd ed.Baltimore, MD:Lippincott,    Williams and Wilkins; 2011.

Smith R. Cytokines and Depression : How your immune system causes depression.Gilroy California;1997.

Dantzer R. From inflammation to sickness and depression: when the

immune system subjugates the brain. NIH Public Access. Available at: http://ecourses.sanjuanbautista.edu/file.php/4/Immunoblog_2012/Case_1_Group_1.pdf. Accessed May 7, 2013.

C. A. Opitz, W. Wick, L. Steinman, M. Platten.Tryptophan degradation in autoimmune diseases. Cell Mol Life Sci. 2007 October; 64(19-20): 2542–2563. doi: 10.1007/s00018-007-7140-9

Billiau, A. ; Vanderbroeck, K. INF Gamma. Rega Intitute, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Year 2000

Matsuda, T. ; Hirano, T; IL-6. Department of Immunology, Toyama Medical and Pharmaceutical University, Toyama, Japan. Year 2000

Aggarwal, B.; Samanta, A.; Feldman, M. ; TNF Alpha. Cytokine Research Laboratory, Department of Biotherapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA 2000

Cytokine Reference, A compendium of cytokines and other mediators of host defense, Vol 1: Ligands, Acadmeic Press, 2001

Michael E. Ash; A Novel Approach to Treating Depression, How probiotics Can Shift Mood by Modulating Cytokines, B.S.c. (Hons) D.O.N.D. F. Dip ION, September 2009

Brunilda Nazario M.D.; Multiple Sclerosis and Depression, Web MD Medical    Reference, @2011WebMD, LCC, Available at: http://www.webmd.com/multiple-sclerosis/guide/ms-depression

 

 

Case 2: Acute Pharyngitis

Case 2: Acute Pharyngitis (Infection of Jason Hornbuckle)

Jason Hornbuckle is not a happy little boy. For the past 12 hours he has complained of pain when he swallows, has a headache, and has vomited twice. His mother decides to take the seven-year-old to his pediatrician. He is febrile (temperature 40.3 degrees centigrade) with tender, bilateral, cervical lymphadenopathy (enlarged lymph nodes). A Complete Blood Count (CBC) performed on a sample of Jason’s blood reveals: WBC: 14000/mm3, 90% PMNN, 8% lymphocytes, monocytes 2%.  Sedimentation rate: 85/mm3. 

His mother is concerned because the patient is sleeping more than usual.

Summary

Acute bacterial pharyngitis is caused by Group A Streptococcus.  Streptococcus is the most common cause of bacterial pharyngitis in children and accounts for 15 to 30 percent of all cases of pharyngitis in children between the ages of 5 and 15 years. ⁸ Viral pharyngitis is more common than bacterial infection; that is why in order to make an accurate diagnosis, a throat culture must be taken. ¹⁰

A patient will present with swollen and erythematous pharynx, tonsils, and uvula; pain when swallowing, headache, fever, lymphadenopathy, and vomiting. Further, a patient will present with white areas of exudate in the tonsils (Figure 1). A high percentage of neutrophils suggest an acute innate response to the bacterial infection.

Both inflammation and leukocytosis are due to the body’s immunological innate response. Leukocytes such as neutrophils and macrophages enter the site of infection to combat the bacteria. They begin to release various cytokines including: IL-1, IL-6, IL-8, and TNF-alpha, to promote vasodilation and recruit more neutrophils.⁵ However, if the innate response is prolonged the high levels of cytokines will eventually reach the temperature-regulating centers in the pre-optic area of the hypothalamus causing fever.⁵ These increased cytokine levels may also stimulate the liver to produce acute phase proteins, increasing the sedimentation rate.⁵ Enlarged lymph nodes are the result of lymphocyte proliferation. ⁵

On another note, there are several studies that suggest that there is a bidirectional communication between the circadian (sleep-wake) and immune systems. Kruger concluded that sleep is “a local use-dependent process” influenced by cytokines and their effector molecules such as nitric oxide, prostaglandins and adenosine.² IL-1 and TNF-alpha promote non-rapid eye movement sleep and induce symptoms such as sleepiness and fatigue.² (Figure 2) Besides acting on neurons to change input-output properties of the local network, these substances interact with multiple other substances via NFkB activation.²

 

 

   IL-6 is another factor that can affect sleep patterns.  Lorton found that certain IL- 6 levels are negatively related to the amount of nocturnal sleep.³ Exogenous injections of IL-6 into rats caused them profound somnolence and fatigue, suggesting that to have a ‘good-night sleep’ lower levels of IL-6 are required.³ However, with infection IL-6 levels increase dramatically giving the patient symptoms of sleep deprivation, resulting in the need to sleep more.

This interactive brain-cytokine system that alters sleep patterns is critical for an individual to efficiently respond in a coordinated manner to infectious pathogens.³ If activation of this system occurs inadvertently in vulnerable individuals can lead to sleep disturbances and other nonspecific symptoms.

Infectious diseases, as well as physical and mental disorders, are commonly associated with fatigue and sleepiness. As it was previously mentioned, cytokines released to combat the bacterial infection (IL-1, TNF- and IL-6) may induce sleep, explaining the abnormal sleeping pattern.

 

L Case Question

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

The patient suffers of a sore throat or acute pharyngitis due to streptococcal infection.  The immune Th₁ cytotoxic response produces inflammatory signs, which includes: pain, heat, redness, swelling, and loss of function that are seen in the area of the pharynx.

Another mechanism used by the body to fight an infection, is fever, due to the WBC production of cytokines and interleukins as IL-1 and IL-6. The pus is produced by the result of dead neutrophils and bacteria. Vomiting is due to the action of the Area Postrema in the medulla that does not have a blood brain barrier (BBB). The excessive sleeping is a result of the actions of cytokines and interleukins in the reticular formation nucleus of Raphe (serotonin) and Nucleus Coeruleus (NE) and the Suprachiasmatic nucleus of the hypothalamus that controls the circadian rhythm. It has been found that fever response is better while sleeping.³

What is the connection between behavior, general symptoms and acute inflammation?

      Jason’s cervical lymph nodes are enlarged because of high proliferation of lymphocytes to fight off a bacterial infection. The enlarged lymph nodes could be compressing against the cervical arteries leading to the brain, hence causing a headache due to diminished blood flow.

 Neutrophils release cytokines that amplify inflammation and cause fever. Thus, the swollen pharynx, tonsils, and uvula are a result of the neutrophil fighting off the infection and the cause of the pain he experiences when swallowing as well as vomiting. The redness seen in the mouth is a typical inflammatory response. The areas of white exudates noticeable on the tonsils indicate plasma with dead and active neutrophils.

 Evidence suggests that there is a bi-directional influence between the immune system and the circadian rhythm, which could explain Jason’s unusual sleeping pattern.⁵ 

What is the mechanism by which fever is induced and what are its benefits in terms of combating an infection?

Fever is a body temperature higher than the normal range of 36.5–37.5 °C. The mechanism that induces fever begins by neutrophil and macrophage release of cytokines: IL-1, IL-6 & TNF, to neighboring endothelial cells. Vasodilatation with increased permeability and edema occurs. The endothelial cells, in response, produce PGI2 which will dilate adjacent capillaries and arterioles; thus, increasing blood flow and allowing more WBCs to localize. With prolonged inflammation, IL-1 & TNF produce a systemic effect. These cytokines act on liver and central nervous system. IL-6 cross the BBB in the hypothalamus, and stimulate the production of local PGI2 which produce a higher temperature set point. Also act on muscle contraction to produce heat.

 This rise in temperature helps fight infections, because pathogens optimal incubation is at 37°C; high temperatures interfere with their invasive functions, making it a hostile environment for pathogens.⁵

What is the mechanism by which the number of circulating white blood cells is increased?

    In the case of Strep infection, the M protein of the surface of the bacteria are recognized by the B cells. This interaction stimulates clonal expansion in the lymph nodes where a single B cell multiplies and secretes the same specific immunoglobulin to opsonize the bacteria and enhance their destruction. Also the release of some cytokines (IL-1, IL-6, IL-8, TNF, IL-23) by macrophages aid in the increase circulating WBC and their extravasations. IL-23 is a pro-inflammatory cytokine and down regulates neutrophils phagocytosis and is a potent stimulator of TH17 CD4. IL-17 stimulates G-CSF in the bone marrow, which stimulates the proliferation of more neutrophils. IL-8 cytokine is a chemo-attractant to neutrophils to the area of infection.

ëPhysical findings

The physical findings include the symptoms:

• Enlarged lymph nodes
• Swollen pharynx
• Tonsillitis with white pup
• Indicating elevated neutrophils
• Fever
• Nausea and Vomiting
• Sore throat while swallowing
• Headache
• Abnormal sleeping patterns

CLINICAL CORRELATIONS

      FEBRILE, HEADACHE, SORE THROAT - Can be alleviated with Aspirin or Tylenol. Prostaglandins are potent mediators of inflammation. The first and committed step in the production of prostaglandins from arachidonic acid is the bis-oxygenation of arachindonate to prostaglandin PGG2. This is followed by reduction to PGH2 in a peroxidase reaction. Both these reactions are catalyzed by cyclooxygenase, also known as PGH synthase. (Cyclooxygenase (COX) is inhibited by the family of drugs known as non-steroidal anti-inflammatory drugs or NSAIDs. Aspirin, ibuprofen, flurbiprofen and acetaminophen (trade name Tylenol) are all NSAIDs.)^7,9

 IMMUNE SYSTEM MOLECULES AND THEIR EFFECTS IN SLEEP PATTERN     Recent studies have shown that sleeping patterns are the result of the actions, in the reticular formation, of Interleukin-1 (IL-1) and tumor necrosis factor (TNF). This molecules promote non-REM sleep under normal physiological condition and also in respond of an inflammatory reaction. The reticular formation has the nucleus of Raphe (Serotonin), Nucleus Coeruleus (Norepinephrine) and the Suprachiasmatic nucleus of the hypothalamus that controls the circadian rhythm. It has been found that fever response is better while sleeping.^3,2
  THE  ERYTHROCYTE SEDIMENTATION RATE

This is a blood test that reveals inflammatory activity in the body. A high sedimentation rate reveals an increase acute phase proteins in the blood produced by the liver. Normal values are 0-10 mm/hr in children, 0-15 mm/hr in men, 0-20 mm/hr in women. This is a direct correlation with an inflammatory response.⁵

aREFERENCES:

1.     Del Mar, C. (1992). Managing sore throat: a literature review. I. Making the diagnosis. http://www.ncbi.nlm.nih.gov/pubmed/1565052. Published April 20, 1992. Accessed May 9, 2012.

2.     Krueger, James. The Role of Cytokines in Sleep Regulation. Curr Pharm Des. 2008: 14(32): 3408–3416.

3.     Lorton, D. (2006). Bidirectional Communication between the Brain and the Immune System: Implications for Physiological Sleep and Disorders with Disrupted sleep. NeuroImmunoModulation. http://www.cfids-cab.org/cfs-inform/Sleep/lorton.etal07.pdf. Published August 6, 2007. Accessed May 8, 2012.

4.     Manzar, MD., & Hussain, ME. (2012). Sleep–immune system interaction: advantages and challenges of human sleep loss model. http://www.frontiersin.org/Sleep_and_Chronobiology/10.3389/fneur.2012.00002/full. Published January 16, 2012. Accessed May 8, 2012.

5.     Murphy, K. Janeway’s  Immuno Biology. 8th edition. Garland Science, Taylor & Francis Group, LLC; NY, 2012.

6.     Marx, J. Rosen's Emergency Medicine: Concepts and Clinical Practice (7th ed.). Philadelphia, Pennsylvania: Mosby/Elsevier; 2010.

7.     Shaikh N, Swaminathan N, Hooper EG. Accuracy and precision of the signs and symptoms of streptococcal pharyngitis in children: a systematic review. J Pediatr. 2012:160(3):487.

8.     Shulman, ST., Bisno, AL., Clegg, HW., Gerber, MA., Kaplan, EL., Lee, G., Martin, JM., & Van Beneden, C. (2012). Clinical Practice Guideline for the Diagnosis and Management of Group A Streptococcal Pharyngitis: 2012 Update by the Infectious Diseases Society of America. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. http://www.ncbi.nlm.nih.gov/pubmed/22965026. Published November 15, 2012. Accessed May 8, 2012.

9.     Tsevat J, Kotagal UR. Management of sore throats in children: a cost-effectiveness analysis. Arch Pediatr Adolesc Med, 1999: 153(7):681.

10.   Wald ER, Green MD, Schwartz B, Barbadora K. A streptococcal score card revisited. Pediatric Emergency Care, 1998: 14(2): 109.

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