Stress and the Immune System

http://healthresources.caremark.com/topic/stressimmune

Paige Bierma

CONSUMER HEALTH INTERACTIVE

Below:
• Stress and immunity
• Stress and premature aging
• Wound healing
• Infectious disease
• Stress and the "Big C": cancer
• Other conditions
• Was Grandma right?




The idea that psychological stress can make us -- or at least rats -- more vulnerable to illness was inadvertently proven by an eager yet clumsy physiologist back in the 1930s. Hans Selye, an Austrian-born endocrinologist working in Canada, was trying to prove that he'd discovered a new hormone by injecting lab rats daily with an ovarian extract. As the story goes, Selye was an inexperienced technician, and often dropped the rats and had to chase them around the floor with a broom in order to catch and successfully inject them.



A few months later, when the rats developed peptic ulcers and swollen adrenal glands, Selye was convinced he'd discovered a new hormone. Just to be sure, he ran a control group on more rats, injecting them with plain saline solution. The results? The control rats developed the exact same symptoms. The young scientist was forced to conclude that it was the stress of his sloppy lab-side manner that caused the rats' maladies. Selye had failed to discover a new hormone, but succeeded in proving a relationship between stress and physical disease. He went on to write more than 1,700 papers and 33 books on the subject of stress. Today, the late Hans Selye is known as "the father of the stress field."



Thankfully, most of us will never be chased around by giant hands attempting to stick us with sharp needles. But we will go through harrowing break-ups, moving days, and bad weeks at the office. Can stressful events like these actually make humans more likely to contract a disease? Can they hinder our recovery from hard-hitting illnesses like heart disease and cancer? Can they slow the healing of wounds? Increasing evidence suggests that stress may indeed affect the immune system in these and other ways. In fact, there is so much research on stress and immunity that it has its own field, called psychoneuroimmunology, complete with specialized journals and textbooks.



Stress and immunity

How exactly does stress from the mind end up affecting the immune system?



"Some kinds of stress -- very short-term, that last only a matter of minutes -- actually redistribute cells in the bloodstream in a way that could be helpful," says Suzanne Segerstrom, an associate professor of psychology at the University of Kentucky who has conducted studies on stress and the immune system. "But once stress starts to last a matter of days, there are changes in the immune system that aren't so helpful. And the longer that stress lasts, the more potentially harmful those changes are."



The fight-or-flight response (short-term stress) goes something like this: When a villager in Africa sees a lion charging at him, for example, the brain sends a signal to the adrenal gland to create hormones called cortisol and adrenaline, which have many different effects on the body, from increasing heart rate and breathing to dilating blood vessels so that blood can flow quickly to the muscles in the legs. Besides helping him run away, this type of acute stress also boosts the immune response for three to five days (presumably to help him heal after the lion takes a swipe at him).



When humans experience stress, our bodies react the same way that animals' bodies do. Once the lion is gone, a zebra or gazelle's stress level will return to normal, but humans have more trouble getting back to our routines after a stressful event, whether it's a car accident or a divorce. We'll think about it, dream about it, and worry about it for a long time, and that sets us up for long-term problems, says Robert M. Sapolsky, a Stanford University stress expert and author of Why Don't Zebras Get Ulcers.



Over time, continually activating the stress response may interfere with the immune system. How this affects your disease risk, Sapolsky suggests, depends partly on your risk factors and your lifestyle, including your degree of social support.



Stress and premature aging

The stress involved with caring for a loved one with dementia is well documented. According to the national Alzheimer's Association, 80 percent of caregivers report suffering high levels of stress, and nearly half suffer from depression. As a result, caregivers have become popular subjects for studies involving stress and the immune system.



A 2003 analysis of caregivers, for example, found that people caring for spouses with Alzheimer's disease showed a marked overproduction of an immune factor called IL-6, which is normally involved in the immune response to injury. A rise in IL-6 is associated with many age-related conditions, including cardiovascular disease, osteoporosis, arthritis, Type 2 diabetes, certain cancers, and mental decline.



Wound healing

In another study, dental students volunteered to receive small cuts on the roofs of their mouths on two occasions: once during summer break and again six weeks later, during exams. The students' wounds took 40 percent longer to heal when they were under the stress of exams. In addition, the students' levels of a protein called IL-1, which summons other immune cells to battle, were found to be two-thirds lower when the students were in exams than in the summer.



A similar study found that marital discord was also associated with the healing of wounds. In the 2005 study published in the Archives of General Psychiatry, couples whose behavior was rated as "hostile" toward each other had a wound-healing rate that was 60 percent of the rate of couples with gentler relations.



Infectious disease

A handful of vaccine studies have also found that the immune system of highly stressed individuals have sluggish responses to challenges. In one study, published in the journal Psychosomatic Medicine in 2000, a pneumonia vaccine was administered to 52 older adults, including 11 people caring for spouses with dementia. After just six months, the levels of antibodies produced against pneumonia in the caregivers had dropped off, while the non-caregivers' levels remained stable. A similar study in which 32 caregivers were given the flu shot in 1995 also found that caregivers received less protection from the vaccine than did a control group of non-caregivers.



If you're stressed out, you're more likely to get sick -- at least it seems that way. A 1991 study in the New England Journal of Medicine actually found that higher psychological stress levels resulted in a higher likelihood of catching the common cold. The researchers accounted for many variables -- including the season; alcohol use; quality of diet, exercise, and sleep; and levels of antibodies before exposure to the virus -- and concluded that higher stress was to blame for lowered immunity and higher infection rates.



Stress and the "Big C": cancer

The relationship between stress and the big daddy of all diseases -- cancer -- has also been the subject of much research. "Our studies have shown that stress can adversely affect components of the immune system involved in fighting diseases like cancer," says David Spiegel, MD, a psychiatrist and researcher at Stanford University. The number of natural killer or NK cells -- cells that kill undesirables like bacteria and cancer cells -- has been found to be lower among people who are suffering from chronic stress, says Spiegel, who also directs Stanford's Center for Integrative Medicine.



Spiegel, among others, has conducted a number of studies that indicate that group counseling and stress-management techniques offered to people who have already been diagnosed with cancer may help boost their immune systems. For example, a study of 103 women with metastatic breast cancer (cancer that has spread beyond the breast) examined how much support from family and friends the women had to help them deal with their diagnosis and treatment. The study, published in the journal Psychosomatic Medicine in 2000, found that women who had greater social support displayed lower levels of cortisol in their saliva than the women who had less support. Lower levels of cortisol, says Spiegel, indicate a healthier immune system functioning.



But the evidence linking stress and cancer is murky at best. As Sapolsky points out in his book Why Zebras Don't Get Ulcers, none of the cancer studies out there is able to directly link lower levels of stress with longer survival rates for cancer victims. And certainly, none of them can prove that stress causes any type of cancer in the first place.



"We must be careful not to blame the victim," Spiegel says. "We get cancer because we are biological creatures, not because we didn't handle stress right. Stress is just one variable among many."



Other conditions

Stress acts on the body through the immune system, and in recent years we have been learning that chronic inflammation -- the immune system's response to injury or irritation -- may be involved in everything from heart disease and diabetes to Alzheimer's disease and other dementia. So, indirectly, a stress-related imbalance in the immune system may have a wider-ranging effect than originally suspected.



Was Grandma right?

As we’ve seen, many studies show that stress can impact different facets of the immune system. Some suggest that stress slows recovery from illness or makes us more likely to catch colds. But can stress actually make us sick, or shorten our lifespans? Our immune systems are so complicated, and a person's immune response affected by so many factors, it's understandably a difficult area of study. In addition, it's hard to find stressed-out volunteers willing to expose themselves to viruses to see if they'll get sick or not.



In the meantime, there is enough evidence to convince us that we should find healthy ways to keep our stress levels down, which is advice we got from our grandmothers: Eat right, exercise, and get enough sleep.



"Stress is inevitable," Spiegel says. "The trick is to learn to manage it, to find some aspect of our stress and do something about it. Don't think in terms of 'all or nothing' but in terms of 'more or less.' "



-- Paige Bierma is a health and medical writer who has contributed to Hippocrates, Safety + Health magazine, and Vibe.






References


Interview with David Spiegel, MD, Stanford University

Interview with Suzanne Segerstrom, PhD, University of Kentucky

Suzanne C. Segerstrom et al. "Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry." Psychological Bulletin, Vol. 130, No. 4, 2004.

Ronald Glaser et al. "Stress-induced immune dysfunction: implications for health," Nature Reviews: Immunology, Vol. 5, March 2005.

Robert M. Sapolsky. Why Zebras Don't Get Ulcers, Third Edition. Owl Books, New York, NY. 2004.

Sephton SE, et al. "Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival," Journal of the National Cancer Institute (JNCI), Vol 92; No. 12. June 21, 2000.

Janice K. Kiecolt-Glaser et al. "Chronic stress and age-related increases in the proinflammatory cytokine IL-6," Proceedings of the National Academy of Science, Vol. 100; No. 15. July 22, 2003.

Janice K. Kiecolt-Glaser et al. "Hostile Marital Interactions, Proinflammatory Cytokine Production, and Wound Healing." Archives of General Psychology, Vol. 62, Dec. 2005.

Ronald Glaser et al. "Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine," Psychosomatic Medicine, 62:804-807 (2000).

Janice K. Kiecolt-Glaser et al. "Chronic stress alters the immune response to influenza virus vaccine in older adults," Proceedings of the National Academy of Science, Vol. 93. April 1996.

Julie M. Turner-Cobb et al. "Social Support and Salivary Cortisol in Women With Metastatic Breast Cancer," Psychosomatic Medicine, 62:337-345 (2000).

Bruce S. McEwen. "Protective and Damaging Effects of Stress Mediators." The New England Journal of Medicine, Volume 338:171-179 http://content.nejm.org/cgi/content/extract/338/3/171

S. Cohen, D.A. Tyrrell, and A.P. Smith. "Psychological stress and susceptibility to the common cold." The New England Journal of Medicine, Volume 325:606-612

http://content.nejm.org/cgi/content/abstract/325/9/606

Tim Lee, PhD and Angela McGibbon, MD. Immunology Bookcase: Immunology for Medical Students. Dalhousie University, Nova Scotia, Canada http://pim.medicine.dal.ca/home.htm

The Mayo Clinic. Stress: Why you have it and how it hurts your health. http://www.mayoclinic.com/health/stress/SR00001

Graham JE, et al. Hostility and pain are related to inflammation in older adults. Brain, Behavior, and Immunity. 2006 Jul;20(4):389-400.

Alzheimer’s Association. Fact sheet: Anti-inflammatory therapy. http://www.alz.org/Resources/TopicIn...flammatory.asp


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Reviewed by Reviewed by Michael Potter, MD, an attending physician and associate clinical professor at the University of California, San Francisco.



Our reviewers are members of Consumer Health Interactive's medical advisory board.
To learn more about our writers and editors, click here.






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First published June 1, 2006
Copyright © 2006 Consumer Health Interactive



Copyright © 2004-2006 Caremark . All Rights Reserved.

Parkinson's Disease
March 2002
WHAT IS PARKINSON'S DISEASE AND WHAT CAUSES IT?
Parkinson's disease (PD) is a slowly progressive disorder that affects movement, muscle control, and balance. Parkinson's disease is referred to as idiopathic, which means that the cause is unknown. This term distinguishes the primary disease from parkinsonism, which are the symptoms occurring from a known cause.
Parkinson's Disease and Dopamine Loss
Parkinson's disease occurs from the following process in the brain:
PD develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra .


Nerve cells in the substantia nigra send out fibers to the corpus stratia , gray and white bands of tissue located in both sides of the brain.


There the cells release dopamine, an essential neurotransmitter (a chemical messenger in the brain). Loss of dopamine in the corpus stratia is the primary defect in Parkinson's disease.


Dopamine is one of three major neurotransmitters known as catecholamines, which help the body respond to stress and prepare it for the fight-or-flight response. Loss of dopamine negatively affects the nerves and muscles controlling movement and coordination, resulting in the major symptoms characteristic of Parkinson's disease.


The disease process also may impair nerve endings in the heart that regulate the release of norepinephrine, a hormone that regulates blood pressure, pulse rate, perspiration, and other automatic responses to stress. Such effects could be responsible for the abrupt drops in blood pressure when standing that some patients experience. Further research is underway to determine if the loss of nerve terminals is confined to the heart or if it affects other organs as well.
Although it is clear that dopamine deficiency is the primary defect in Parkinson's disease, it is not clear what causes dopamine loss. The culprit is less likely to be a single cause than a combination of genetic and biologic factors, which are triggered by some environmental assault.
Biologic Factors
Abnormal Apoptosis (Programmed Cell Death). In everyone, cells in the body are programmed to naturally die through a genetically regulated process called apoptosis. In Parkinson's disease, there is some evidence that this process goes awry in nerve cells.

Proteins Involved in Parkinson's Disease Important research now suggests that three molecules are critical in the development of inherited PD: parkin, alpha synuclein (specifically alphaSp22), and ubiquitin, which all interact in the normal brain. AlphaSp22 is produced in the nerve cells involved with the dopamine pathway. Parkin normally causes alpha synuclein to bind with a molecule called ubiquitin, which then triggers apoptosis causing this compound to self-destruct. In many cases of inherited Parkinson's disease, however, parkin is abnormal and fails to bind alpha synuclein to ubiquitin. Apoptosis does not take place and, instead of dying, synuclein accumulates in Lewy bodies , deposits of fibrous tissue found in all patients with PD.

Another protein that may be critical in the disease process is beta amyloid, which builds up in the brains of Alzheimer's patients and is a major factor in that disease. Beta amyloid also increases the build-up of synuclein and may help explain the connection between Alzheimer's and Parkinson's disease in many patients.

Lewy Bodies. Fibrous deposits known as Lewy bodies are the hallmark signs of Parkinson's disease. They are found in the substantia nigra, the place in the brain where dopamine is first released. It is not clear whether Lewy bodies are the major killers of the nerve cells or whether they are simply a byproduct of the degenerative process. They are found not only in the brains of patients with Parkinson's disease, but, in rare cases, may show up in cells in other parts of the body (the heart, intestine), causing severe disabling symptoms. These substances are also present in other diseases that cause dementia, such as Alzheimer's, and can occur in people without neurologic symptoms.

Complex I and Oxygen-Free Radicals. Some research has observed that certain Parkinson's patients have a 30% to 40% reduction in an enzyme called complex I. This enzyme is found in the mitochondria, sausage-like structures in cells that generate energy. Some theories suggest that low amounts of complex I may make nerve cells vulnerable to the assault of oxygen free radicals (also called oxidants). Oxidants are unstable molecules that bind to other molecules in the body. They are normally produced by the natural chemical processes in the body. If the body is subjected to environmental stresses, however, they can be over-produced. And, in access, they can damage any cell, including nerve cells in the brain, and even interferes with their DNA.

NMDA Receptors. Also of interest in PD are processes that occur in an area of the brain called the subthalamic nucleus . Here, receptors known as glutamatergic N-methyl-D-aspartate (NMDA) become persistently overexcited and produce high levels of calcium ions within brain cells. This in turn leads to a cascade of events that trigger oxygen-free radicals and cell damage.

Immune Factors and the Inflammatory Response. An over-responsive immune system triggered by initial damage may also play a role in perpetuating Parkinson's disease. When the immune system becomes over-active, it produces excessive numbers of potent factors called cytokines, which cause inflammation and further injury in brain cells. Important cytokines under investigation are interleukin-1 and tumor necrosis factor.
Genetic Factors
Specific genetic factors appear to play a strong role only in early-onset Parkinson's disease. Multiple genetic factors are likely to contribute to the great majority of Parkinson's cases, which occur in older people. Nevertheless, the study of even rare genetic cases is proving to be useful in understanding the nature of degenerative nerve diseases in general.

Early Onset PD. The cases of genetic early-onset Parkinson's disease have most often been detected in specific family groups.
Defective genes that regulate the molecules alpha synuclein and parkin, which are important in the PD disease process, may be responsible for a number of early-onset cases. [ See Biologic Factors, above.] For example, genetic abnormalities the alpha synuclein protein has been detected in some early-onset Parkinson's patients of European descent.


The parkin gene may be the cause of many cases of early-onset Parkinson's in young adults. (Parkinson's cases associated with this mutation tend to progress slowly and respond well to treatment, even after years of symptoms. Dementia is also rare with this form.)
Late Onset PD. The role of genes in late-onset, the much more common form of the disorders, is not yet clear and appears to be weak. Still, some may be important:
Research published in 2001 has targeted the gene for the tau protein, which in its healthy state is important for the support structure in nerve cells that allows the flow of nutrients through them. A defective tau gene may increase susceptibility for idiopathic late-onset Parkinson's disease.


Investigators have observed iron deposits in the brains of PD patients. Animal research suggests that genetic factors that impair iron metabolism may play a role in late-onset PD.
Environmental Assaults and Oxygen-Free Radicals
Environmental toxins, infections, and other triggers can provoke excessive production in the body of oxygen free-radicals, damaging particles that may play a major role in the deterioration of nerve cells that lead to Parkinson's.

Infectious Agents. Some research has identified immune factors that suggest a viral presence in the Lewy bodies and swollen nerve pathways of Parkinson's brains. Influenza and other potent viruses have long been known to be a cause of parkinsonism. In one well-known example, a major flu epidemic causing encephalitis in the early twentieth century left many of its victims with parkinsonism.

Environmental and Industrial Chemicals. Intense exposure to certain environmental and industrial chemicals is also being studied.


Pesticides and Herbicides. Some evidence implicates pesticides and herbicides as important factors in many cases of Parkinson's disease. A higher incidence of parkinsonism has long been noted in people who live in rural areas, particularly those who drink private well water or are agricultural workers. A large 2000 study found a strong link between high exposure to insecticides and herbicides at home and a 50% to 70% increase in risk of Parkinson's. Important studies are implicating rotenone, a common organic chemical in pesticides, which may release powerful destructive oxidants that target the dopamine nerve cells that are important in PD. Rotenone is very unstable, however, and some research suggests that it becomes inactive too quickly to affect human brains.


Other Chemicals. Intense exposure to other industrial chemicals and metals (manganese, copper, lead, iron, mercury, zinc, aluminum, and others) has also been linked with parkinsonism, which is often reversible. The role of long-term exposure in the development of Parkinson's disease is unclear.
Aging Process
Most, but not all, Parkinson's victims are elderly. Some studies indicate that the very elderly are not susceptible to the disease, indicating that the aging process itself is not the major player in the disease. Aging does appear to reduce the concentration of dopamine in structures called dopamine transporters, which carry the neurotransmitter back and forth between nerve cells. Some researchers posit that any excessive stress on these transporters might trigger Parkinson's disease in the aging, and more vulnerable, brain.


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Definition and Causes of Parkinson's Disease, Symptoms, Risk Factors, Severity and Outlook, Diagnosis, Guidelines for Treating the Stages of Parkinson's Disease, Levadopa (L-Dopa) Treatment, Other Drug Treatments, Surgical Procedures, Lifestyle Changes, Support Organizations

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