San Juan Bautista School of Medicine
Caguas, PR


Nadya Dávila, John Hernández, Wilfred Hernández, Xyomara Jiménez, Gisela Puig, Caroline Toro, Mary-Tere Zamora
Immunology 156
May 20, 2008.

Stress and Immune Response

I. Summary

Stress is “the generalized, non-specific response of the body to any factor that threatens to overwhelm the body’s ability to maintain homeostasis”. (Stanford) Stressors can be physical, such as heat or cold; chemical, such as no oxygen; physiological, such as exercise; psychological or emotional, such as fear or anxiety; and social, such as personal conflicts. When a stressor takes place the human body reacts in the following physiological reactions, faster and shallower breathing, increased heart rate, shut-down of immune system, disrupted digestion, and by overstimulation of the sympathetic nervous system.

When the human body senses stress it can have a specific or non-specific response. The specific response depends on the stressor type. For example, when the stressor is heat the body reacts by sweating. The non-specific response is generalized and does not depend on the type of stressor; this is the fight or flight response accomplished by the sympathetic nervous system. In addition, the stress response functions in such a way that it diverts energy away from processes such as digestion or the immune system.

Stress experiments have demonstrated that epinephrine and norepinephrine are the catecholamines that increase the most under stress. These increases can suppress phases of immune function, including natural killer cell activity. Increases in catecholamines may also hastily alter cell numbers through redistribution. In fact, changes in epinephrine levels are thought to reflect lymphocyte migration from bone marrow, the extremities, and the thymus to other areas of the body. Other studies have revealed that psychological stressors induce cell division among CD8 cells, by this means increasing the number of CD8 cells and suppressing immune function.

Moreover, when a stressor takes place the endocrine system reacts by increasing the secretion of epinephrine, cortisol, glucagon, angiotensin, and vasopressin. Also, it reacts by decreasing the secretion of insulin. This reaction of the endocrine system has an effect on the immune system. For example, CRH-mediated release of glucocorticoids and catecholamines negatively regulates inflammation. The processes by which glucocorticoids and catecholamines negatively regulate inflammation is by inhibiting pro-inflammatory cytokines (IL-12, TNF-α, IFN-γ) and IL-12 receptor, stimulating anti-inflammatory cytokines (IL-10, IL-4, TBF-β), and downregulating cell adhesion molecules by regulating AP-1 and NF-κB). “The stress hormones released by the adrenals during episodes of fear and anxiety also affect white blood cells. Initially, the surge of brain and adrenal hormones that accompanies stress causes an increase in circulating white blood cells. When cortisol remains high, however, white blood cell numbers are reduced.” (Onconurse) In conclusion, glucocorticoids and catecholamines shift the immune response from TH1 to TH2.

All in all, stress does have a substantial effect on the immune system. It increases CD8 levels and catecholamines, which represses the immune system. When a person is stressed the body is going to increase the secretion of stress hormones (cortisol, glucagon, angiotensin, vasopressin, etcetera) and these molecules will send a signal to the immune system that says to stop fighting. Therefore, in circumstances of persistent stress the immune system is less able to respond to a pathogen like a virus or a bacterium.

II. Clinical Applications

A. Multiple Sclerosis (MS)

MS is an autoimmune disease affecting the central nervous system. It is characterized by demyelination of the brain and the spinal cord that leads to a wide variety of physical and mental symptoms.

At the present there is no specific cause for this disease although T cells have been associated in the development of MS, triggering the inflammatory process. Other factors, such as emotional and physical stress, have been strongly related in the exacerbation and further attacks of this illness. Also viral infections, heat, and trauma have been implicated in the progression of MS.

B. Rheumatoid Arthritis (RA)

RA is an autoimmune disease that causes chronic inflammation of the joints, can also cause inflammation of the tissue around the joints (such as the tendons, ligaments, and muscles) or other organs in the body. Inflammation of rheumatoid arthritis causes swelling, pain, stiffness, and redness in the joints. This illness can last for years; patients may experience long periods without symptoms. RA is a progressive illness that ultimately leads to joint destruction (causing deformity of the joints) and functional disability.

The Sympathetic Nervous System, which is involved in the stress response, somehow seems to have a protective role in this matter because catecholamines are known to stimulate and propagate the Sympathetic Nervous System. In patients with Rheumatoid arthritis, more inflammation is found in the areas with reduced sympathetic nerve fibers.

C. Diabetes Mellitus

The big deal with Diabetes Type 1 is that your pancreas has under gone an autoimmune attack of the beta cells in the pancreas; therefore the body can’t synthesize insulin, which comes from these cells. If insulin is not available, glucose can’t be used by the tissues because insulin is, generally speaking, a transport protein mediating glucose into the cells. Moreover, there are two types of diabetes, the other denoted as type 2 Diabetes where the tissues are resistant to the insulin that is effectively produced. Patients affected with diabetes either type 1 or 2 have to maintain blood glucose levels on a tight rope by self testing themselves periodically and ingesting a well balanced diet. Nevertheless, blood glucose is not only increased by ingestion of carbohydrates but also by other factors such as stress. Stress induces an increase in blood sugar levels by stimulating the release of sympathetically activated hormones form the adrenal glands, specifically glucocorticoids. These function through specific pathways on the liver by increasing glucolysis more specifically in the fasting state. Apart from being a physiologic factor, stress can influence diabetes because the person may be susceptible to an increased ingestion of alcohol and a decreased mode of activity further decreasing the utilization of energy.

III. Discussion Questions

1) Different pro-inflammatory cytokines are inhibited during stress response, and some anti-inflammatory cytokines are stimulated. Mention at least two of each group and explain what its function is.

2) Explain the process in which the stress response causes a revert from TH1 to TH2 in the immune system.

3) Tumors in parts of kidney can stimulate the adrenal gland to overproduce cortisol, a hormone release during fearful episodes. Explain how cortisol works in our body.

IV. Multiple Choice Questions

1) You have three individuals, a New York Stock Exchange broker, an emergency room surgeon in a field hospital in Irak and a college graduate, an aspiring NBA player in the midst of summer training camp tryouts. Which of these individuals will be more susceptible to infection on contact with Rhinovirus sp.?
a. NYSE broker
b. ER surgeon
c. NBA player
d. A and B
e. B and C
ab. All of the above
ac. None of the above

2) Which of these situations will make a person more prone to immunological suppression?
a. Eating with a metal fork and spoon
b. Eliminating orange juice from the diet for three months
c. Participating in a boxing tournament with fights posted 5 times a week
d. Sitting at home in a dusty sofa watching television after playing soccer

3) Non specific stress response can be characterized by:
a. Increase in blood pressure because of a high tension situation
b. Activation of sweat glands because of increased room temperature
c. Redirection of blood towards contracting muscles of the legs when running away from the cops
d. Contraction of blood vessels of the skin to retain heat.

Key:

1. ab
2. c
3. c


References

Definition of Autoimmune Disease. Medicine Net Web site. http://www.medterms.com/script/main/art.asp?articlekey=2402. Accessed May 16, 2008.

Rheumatoid Arthritis. Medicine Net Web site. http://www.medicinenet.com/rheumatoid_arthritis/article.htm.%20Accessed%20May%2016, 2008.

Stress and the Immune Response. Standford University Web site. http://www.stanford.edu/~gheffner/315/stress.pdf.%20Accessed%20May%2016, 2008.

Stress and the Immune System. Oncourse Web site. http://www.onconurse.com/factsheets/stress_immune.pdf.%20Accessed%20May%2016, 2008.

Stress and the Autoimmune Disease. Suite 101 Web site. http://www.suite101.com/article.cfm/womens_thyroid_disease/80441.%20Accessed%20May%2016, 2008.

Immunostimulants

 Fig.1 Gram positive bacteria
Immunostimulants are boosters of the immune system that help with the body’s resistance to cope with viral and bacterial infections. Their aim is to help bacterial killing at the primary focus of infection, “to prevent the development of nosocomial infections and to prevent the reactivation of dormant viruses”1. This immunostimulants can also be used to help with the treatment of immunosupressed patients as in the case of AIDS and SARS.


The origin of immunostimulants are varied. They can be found in bacteria, nutritional supplements or could be synthesized for immunotherapy, as in the case of levamisole, an antineoplastic medication.

Polybacterial immunostimulants are mostly used to treat or prevent infection of the respiratory and urinary system. They are composed of gram-positive and gram-negative bacterial bodies and freeze-dried lysates. The gram-negative bacteria contain LPS endotoxins and lipoproteins that stimulate macrophages, NK cells, B-lymphocytes, production of antibodies and release of α and γ-interferon, IL-2 and IL-6. Gram-positive bacteria contain muramildipeptide, lipotheichoic acids and peptidoglycans, which also stimulate phagocytosis, T-cell and B-cell function.


Some examples are Respivax, Urostim and Dentavax. Respivax is composed of freeze-dried lysate and killed bacteria utilized to treat non-specific infections of the respiratory system, tonsillitis and pharyngitis. Urostim, also with freeze-dried lysate, is utilized to treat acute recurrent or chronic non-specific infections of the urinary tract in children and adults, such as cystitis and bateriuna. Dentavax it’s used to treat inflammatory and infectious diseases of the oral cavity2.


Another bacterial lysate treatment is Broncho-Vaxom (OM-85), used in patients with recurrent exacerbations of chronic bronchitis or mild chronic obstructive pulmonary disease (COPD). It stimulates the upregulation of secretory antibodies and activation of alveolar macrophages to influence the immune and inflammatory responses of the respiratory system. Clinical trials have demonstrated that in the setting of chronic bronchitis and mild-to-moderate COPD, OM-85 seems to protect against bronchitic exacerbations on these patients3.


A new study by Ohio State University suggests that antibody-based cancer drugs might be more effective if they are given in conjunction with immunostimulants4. For example, the drug trastuzumab may work better when it’s followed by injections of IL-2 or IL-12; substances that trigger the activity of NK cells. The combination of antibody-coated cells and IL-2 or IL-12 causes the NK cells to release substances that attract more potent immune cells, mainly killer T cells, thereby trigging a larger and more effective immune response against the tumor.
The vaccine against tuberculosis, BCG, made from attenuated Mycobacterium tuberculosis, has been used as an immunostimulant for the treatment of bladder cancer. Instillation directly into the bladder induces a variety of cytokines into the urine of patients of these patients. In addition, it may induce a cytokine-mediated antiangiogenic environment that aids in inhibiting future tumor growth and progression.5


Other potent immunostimulants are Beta-carotene and Echinacea in the form of nutritional supplements. They enhance cytokine-synthesizing capacity of macrophages; increase the number of T-helper cells and stimulates NK-cell activity. These complements must be used in addition to a balanced diet to prevent the toxic effects of over supplementation.6



Discussion Questions:


1. What are the major enviromental and Physiological problems facing immunostimulants today?

2. What does immunostimulants do and what factors of the immune system are stimulated by immunotherapy?

3. Which are the factors determining the interest to use the immunostimuants in the control of different infectious diseases?


Multiple Choice Questions:

1. Immunotherapy has a mechanism of action different from that of chemotherapy. It uses materials made by your own body or made in a laboratory to boost, direct, or restore your body's natural defenses against the tumor. What imunostimulant, commonly used for other diseases is used to treat transitional cell carcinoma?

A) Respivax
B) OM-85
C) BCG vaccine
D) Eccinacea

2. Hector recently developed a septic shock that altered his innate and adaptive immune responses leading to an impaired clearance of microorganism. What treatment will be beneficial to this patient?

A) Immunostimulants
B) Immunosuppressors
C) Radioactive immunotherapy
D) Protibiotics



3. Immunostimulants yield all of the following factors of the immune system EXCEPT:

a) phagocytosis
b) alpha and Beta interferon release
c) T and B Lymphocytes
d) protective secretory Ig M antibodies


References


1. Pugin J. Immunostimulation is a rational therapeutic strategy in sepsis. Novartis Found Symp. 2007 ; 280 :21-7; discussion 27-36. Available from: http://lib.bioinfo.pl/pmid:17380786. Accessed May 19, 2008.

2. Petrunov B, Nenkov P & Shekerdjiisky. The Role of Immunostimulants in Immunotherapy and Immunoprophylaxis.Biotechnol & Biotechnol .2007. 454 -463 http://www.diagnosisp.com/dp/journals/
view_pdf.php?journal_id=1&archive=1&issue_id=16&article_id=443&PHPSESSID=634532481
140d5ec4065231691d74d51 Accessed May 19, 2008

3. Soler M. Modulation of airway inflammation to prevent exacerbations of COPD. European Respiratory Review, 2005;14: 78-82. Available from: http://err.ersjournals.com/cgi/content/full/14/95/78#R21. Accessed May 19, 2008

4. Brown CK, Kirkwood JM. Immunotherapy of Cancer. Hor Cancer Therapeutics. 2001; 2(1): 3-23. Available from: http://www.meniscus.com/horizons/2-1.pdf. Accessed May 19, 2008

5. Bladder Cancer Web Café. BCG page. Available at: http://blcwebcafe.org/bcg.asp. Accesed May 21, 2008

6. Gleeson M. Nutritional Supplements For Sport – Immunostimulants. Available at: http://www.medicdirectsport.com/sportsnutrition/default.asp?step=4&pid=437. Accessed May 21, 2008

Immunologic variants in children

Immunologic variants in children

The human defense system is built to allow human life to have a successful healthy progression from the mother’s womb all the way up to adulthood. This process has defined immunological steps. The many differences between an adult and a neonate will be discussed throughout this work.
First, let’s begin with the development of the cells involved in defense. At 7 weeks of gestation most of the cells in the liver are hematopoietic (60 percent). In the liver these may differentiate into neutrophills, hepatic white blood cells among other (figure 1). However, after the 24th of gestation the bone marrow becomes (and remains in adults) the major site of hematopoiesis. At the beginning, the fetal bone marrow has equal number of myeloid and erythroid cells. “However, myeloid cells predominate by 12 weeks' gestation and the myeloid-to-erythroid ratio approaches the adult level of 3:1 by 21 weeks' gestation”(1). Lymphopoesis occurs in the lymph plexuses and the thymus after 9 weeks’ gestation. “B cells with surface IgM are present in the liver, and circulating lymphocytes also are seen at 9 weeks' gestation. T lymphocytes are found only rarely before 12 weeks' gestation and 31 Lymphocyte subpopulations are detected by 13 weeks' gestation in fetal liver.

Figure 1immune system development (differentiation)

Second, the function and mechanism of the defense cells also varies as the fetus transforms to a child and then an adult. “Cellular defense mechanisms and humoral immunity of the newborn differ from those found later in life, and these undoubtedly contribute to the unusual susceptibility to infection noted in the neonatal period.” For example, monocytes in newborns are slower than monocytes in adults because they have reduced ATP production and phagocytosis. Because of these functional differences newborns are more susceptible to many kinds of infection agents.

Third, as an infant grows into an older person, some variants are observed in their immune system, specifically the cell count of white blood cells which does not necessarily mean that there is something wrong with the defense system of the developing body. For instance, higher ranges for white blood cell counts are observed among children, newborns and infants compared to adult values (2). The physician must keep in mind that these values are absolutely normal when reading the lab results of an infant patient for that this does not represent an infection (3). We must add that for the first 4-6 months of the newborn’s life, those whom are breast feed receive immunity passively conveyed by the mother that contains the immunoglobulins (Ig G and Ig A particularly) that protects to the infants against invaders during first year of life.

As we progress in age and become elderly, there is a deterioration of the immune system, including the atrophy of the thymus that compromises the defense system of the human body and causes significant variations between the immune system of children and the elderly1. Genetic mutations throughout the course of human development also cause variations at the molecular level between children and older patients that reflect on differences of the immune system among different age groups that trigger immunodeficiency or autoimmune disorders. All these differences allow us to marvel at the complexity of our immune system.


Multiple Choice Questions

1. Where is hematopoeisis taking place at week 7 of gestation?
a. Bone marrow
b. Thymus
c. Liver
d. Spleen

2. Why are monocytes in adults faster than in newborns?
a. amount of mitochondria
b. increased ATP production
c. amount of bone marrow

3. Which type of defense do children have during first year of life?
a. innate immunity and maternal immunoglobulins
b. only innate immunity
c. plasma cells

Discussion Questions

4. Discuss the consequences of an adult having monocytes like a newborn.

5. Do the differences between children and adult ranges in WBC count point to a microbial insult or not? Explain.

6. What happen if someone does not have passive immunity? Hypothetically, what is treatment you chose?

References

1. Segel GB., Palis J. Chapter 6. Hematology of the Newborn. In: Lichtman MA, Beutler E, Kipps T, eds. Williams Hematology. USA: The McGraw-Hill Companies: 2006

2. Dales Nursing Place: Common Lab Values. Available at: http://www.dalesplace.net/lab_values.php#Hematology%20Values. Accessed May 21, 2008

3. Siparsky G, Accurso FJ, Chapter 43. Chemistry & Hematology Reference Intervals. In: Hay W, Levin M, Sondheimer J, eds. Current Pediatric Diagnosis and Treatment. USA: The McGraw-Hill Companies: 2006

Figure 1 obtained at http://espanol.images.search.yahoo.com/images/view?back=http%3A%2F%2Fespanol.images.search.yahoo.com%2Fsearch%2Fimages%3Fp%3Dimmune%2Bsystem%26fr%3Dyfp-t-340%26ei%3Dutf-8%26js%3D1%26x%3Dwrt&w=400&h=400&imgurl=www.drstandley.com%2Fimages%2Fimmune.bmp&rurl=http%3A%2F%2Fwww.drstandley.com%2Fbodysystems_immune.shtml&size=157.3kB&name=immune.bmp&p=immune%20system&type=bmp&oid=3ced6bf09a97e724&no=1&tt=67.294

Reproduction immunology

http://reproductionimmunology.blogspot.com/

Group Home Work

For April 23 you are asked to submitt the group homework about Special Topics in Immunology.
The list of topics will be available at begining of the course.
The report must follow the corresponding instruction and be publisized in this blog.
Each student is resposible for read and study the blosg contents.
Final course exam will incorporate questions of information inlcuded in this discusion space.