# Critical role of mast cells in inflammatory diseases and the effect of acute stress.



## eric (Jul 8, 1999)

FYIJack Wood, PhDProfessor of Physiology and Internal MedicineChairman Emeritus, Department of PhysiologyThe Ohio State University College of Medicine Dr. Wood was the first to use microelectrodes to record the electrical and synaptic behavior of neurons in the enteric nervous system. He coined the term "brain-in-the-gut" in view of emerging evidence that the enteric nervous system had neurophysiological properties like the brain and spinal cord. In recent years he has focused on signaling interactions between the enteric immune system and the brain-in-the-gut during infectious enteritis and food allergy. In this lecture he shows how the central nervous system, enteric nervous system and intestinal immune system are integrated during physical and emotional stress to produce irritable bowel symptoms of diarrhea and abdominal pain and discomfort. http://www.conference-cast.com/ibs/Lecture...cfm?LectureID=7 Nigel Bunnett, PhDUniversity of California School of MedicineDepartment of Surgery and PhysiologyAccumulating evidence indicates that sensory nerves play a major role in inflammation of multiple tissues, and that communication between the nervous system and mast cells is of particular importance. Dr. Bunnettï¿½s lecture will highlight recent experimental evidence that mast cell proteases signal to sensory nerves through novel receptors that couple to the release of proinflammatory peptides, and that defects in this mechanism result in uncontrolled inflammation and disease. Dr. Bunnett will present evidence that therapies designed to block signaling by neuropeptides and proteases are attractive treatments for inflammation. Inflammation: Role of Sensory Nerves and Mast Cell Mediators http://www.conference-cast.com/ibs/Lecture...dRegLecture.cfm J Neuroimmunol. 2004 Jan;146(1-2):1-12. Related Articles, Links Critical role of mast cells in inflammatory diseases and the effect of acute stress.Theoharides TC, Cochrane DE.Department of Pharmacology and Experimental Therapeutics, Tufts-New England Medical Center, Boston, MA, USAMast cells are not only necessary for allergic reactions, but recent findings indicate that they are also involved in a variety of neuroinflammatory diseases, especially those worsened by stress. In these cases, mast cells appear to be activated through their Fc receptors by immunoglobulins other than IgE, as well as by anaphylatoxins, neuropeptides and cytokines to secrete mediators selectively without overt degranulation. These facts can help us better understand a variety of sterile inflammatory conditions, such as multiple sclerosis (MS), migraines, inflammatory arthritis, atopic dermatitis, coronary inflammation, interstitial cystitis and irritable bowel syndrome, in which mast cells are activated without allergic degranulation.PMID: 14698841 FYIHarvard healthThe Mind and the Immune Systemï¿½Part IOne of the standing mysteries of medicine is the relationship between the mind and physical healthï¿½how feelings, thoughts, attitudes, and behavior are related to physical illness, how psychological and social stress affect the likelihood of developing a disease or the ability to resist it, and how counseling for emotional problems can aid recovery from illness. One of the clues to this mystery lies in the immune system, the network that defends us against microbes and other invaders. Interest in the connections between the brain and the immune system has given birth to the discipline of psychoneuroimmunology. These systems communicate through the sympathetic nervous system and the endocrine glands, especially the hypothalamic-pituitary-adrenal (HPA) axis. Like the immune system, both are dedicated to the defense of the body against stress and danger, and both are directed from the same part of the brain, the hypothalamus. All threeï¿½the immune system, sympathetic nervous system, and HPA axisï¿½respond to some of the same transmitter chemicals. The sympathetic nervous system is part of the autonomic nervous system, which controls involuntary functions like heart rate, digestion, and breathing. The sympathetic nerves serve as an emergency response network, heightening the bodyï¿½s readiness to accept a challenge or escape in the face of danger. The sympathetic nerves are connected to various organs of the immune system, such as the thymus gland, the bone marrow, the spleen, and lymph nodes. Immune cells, including T cells, monocytes, and B cells, have receptors for the neurotransmitters released by sympathetic nerves. Damage to the hypothalamus and loss of sympathetic transmitters impairs the functioning of the immune system. An injection of antigens (foreign substances that activate the immune system) affects the concentration of sympathetic neurotransmitters in the brain. Immune LearningAnimal experiments show that the immune system can ï¿½learnï¿½ by association. In one experiment, rats drank sweetened water containing a drug that causes nausea and depresses the immune system. They became so sick that they avoided sweetened water for some time after the drug was removed. That behavioral conditioning eventually was extinguished (wore off), and they returned to drinking the waterï¿½only to start developing infections at an abnormally high rate. Apparently, by association with the immunosuppressant drug, sugared water was provoking a conditioned response that continued to suppress the ratsï¿½ immune systems even when it no longer affected their behavior. Another experiment involved mice bred to be genetically vulnerable to an autoimmune disease (one in which an overactive immune system attacks the bodyï¿½s own tissues). They were given a flavored solution containing a drug that suppresses the immune system, delaying the onset of the disease. Then most of the drug was removed, but as long as the flavor remained, the rats continued to drink the liquid and resist the disease. The immune system had learned by association to suppress itself when the animals recognized that taste. Conditioned learning can also enhance immune function, as another experiment showed. Mice were repeatedly forced to smell camphor while they were injected with a substance that stimulated the activity of natural killer (NK) cells, a type of white blood cell. When they were exposed to the smell of camphor without the injection, the activity of their NK cells still increased. Hormonal EffectsThe HPA axis regulates the bodyï¿½s activity through the circulation of the blood rather than directly through neural connections. The hypothalamus directs the pituitary gland to produce hormones that travel in the blood to the adrenal glands, where they cause the release of cortisol and other steroids as well as epinephrine (adrenaline) and its chemical relative norepinephrine (both of which also serve as neurotransmitters in the sympathetic system). These stress hormones influence the immune reaction through receptors on immune cells. Adrenaline, which prepares the body for immediate action, stimulates the immune system. One function of cortisol and related hormones (glucocorticoids) is to serve as a feedback mechanism that conserves energy by tuning down the emergency reaction when it is no longer needed. Rising cortisol levels signal the brain to shut down an immune response that threatens to become overactive. Thereï¿½s evidence that stress is associated with depressed immune function in one or another part of the system. In one study, the activity of NK cells declined in medical students preparing for an examination. Those who felt calmer and had a slower heart rate also showed fewer immune changes. In another study, unemployment slowed the multiplication of white blood cells in response to antigens. A survey found that unhappily married women had lower numbers of certain immune cells than women with happy marriages. Elderly people caring for relatives with Alzheimerï¿½s disease have higher than average levels of cortisol and low levels of antibody response to influenza vaccine. Stress delays the production of antibodies in mice infected with influenza virus and suppresses the activity of NK cells in animals inoculated with herpes simplex virus. Social stress can be even more damaging than physical stress. In a report published last year, some mice were put into a cage with a highly aggressive mouse two hours a day for six days. Other mice were kept in tiny cages without food and water for long periods. Both groups of mice were exposed to a bacterial toxin, and the socially stressed animals were twice as likely to die. Severe depression resembles a chronic stress response, and depressed patients often lack the normal daily variation in the production of cortisol. Depressed patients seem to have lower NK cell activity than healthy controls, possibly because of high cortisol levels. In one study, the lymphocytes (a type of white blood cell) of depressed and bereaved persons responded sluggishly to the substances that normally stimulate them to proliferate. Isolation can also suppress immune function. Infant monkeys separated from their mothers, especially if they are caged alone rather than in groups, generate fewer lymphocytes in response to antigens and fewer antibodies in response to viruses. Some studies have found lower NK cell activity in separated and divorced than in married men. NK cell activity also has been found to be lower in medical students who say they are lonely. In a year-long study of people caring for husbands or wives with Alzheimerï¿½s disease, changes in immune function were greatest in those who had the fewest friends and least outside help. In general, good social support is associated with better immune function in the elderly, even after correction for health habits, depression, anxiety, and life stress. The effect of traumatic stress on the immune system has been studied occasionally. According to one report, four months after the passage of Hurricane Andrew in Florida, people in the most heavily damaged neighborhoods showed red uced activity in four out of five immune functions. Similar results were found in a study of hospital employees after an earthquake in Los Angeles. And a report published last year suggested that men with a history of posttraumatic stress disorder (PTSD), even long after apparent recovery, had lower numbers of various immune cells and lower levels of immune activityï¿½possibly indicating a long-lasting suppression of the system. Another study found lower lymphocyte activity in abused women. But itï¿½s not easy to generalize about the effect of stress hormones and sympathetic nervous system activity on immune functioning. Much depends on the individual, the timing, the kind of stress, and the part of the immune system under consideration. The results of studies on depression, for example, are conflicting; it does not consistently suppress any part of the immune system except NK cells. Animal experiments suggest that the nervous system responds differently to acute and chronic stress. The acute stress reaction is often a healthy response to a challenge. But chronic stress may cause the feedback controls to fail, turning the emergency response into a condition that persists when it no longer has any use. Stress hormones and sympathetic activity remain at high levels, suppressing immune function and possibly promoting illness. The immune systems of people who are under chronic stress may also respond abnormally to acute stress. The Difference it MakesWhat matters most is whether the mindï¿½s influence on the immune system has the power to raise or lower the risk of illness or injury. On that issue only a little evidence is available. Healing of injuries. One study found that the wound from a biopsy healed more slowly in women under high emotional stress. In another experiment, a wound healed more slowly in students when it was inflicted before an examination rather than just before vacation. Slow healing has also been found in people caring for Alzheimerï¿½s patients. Colds and flu. Both observation and experiments suggest that stress makes people more susceptible to colds and other respiratory infections. In a one-year study, researchers asked 100 people to keep a diary recording their feelings and events in their lives. They were examined periodically for bacteria in throat cultures and virus antibodies in the blood. Stressful events were four times more likely to come before rather than after new infections. And people who developed a cold or other infection had often been feeling more angry and tense than usual. In an English study published in 1991, 420 people were given nose drops containing a cold virus after answering questions about their personality, health practices, and behavior. They were asked about feelings of frustration, nervousness, anxiety, and depression and about events such as loss of a job or deaths in the family. When the subjects were quarantined and monitored for nine days, those under greater stress were more likely to catch a cold. Researchers have continued to confirm this connection. In a study conducted in the late 1990s at the University of Pittsburgh, 276 healthy adults were given nose drops containing a cold virus. The symptoms were most severe in those who reported a high level of stress in their livesï¿½but only when it was prolonged stress caused by such problems as unemployment and troubled marriages. Resistance to the virus was correlated with strong social support, especially a variety of contacts with family, neighbors, friends, workmates, and fellow members of voluntary organizations. This effect was independent of smoking, alcohol consumption, and quality of sleep. People with the weakest (least diverse) social ties were four times more susceptible to colds than those with the strongest ties. Stress can also interfere with the response to a vaccine. In one study, flu shots were given to 32 people under high stress and 32 under low stress, matched for age, sex, and social class. The vaccine produced higher levels of antibodies in the low-stress group, and the high-stress people were more likely to become infected. The University of Pittsburgh researchers found a close association between difficulties in coping with stress, flu symptoms, and a specific immune response. Fifty-five volunteers were given nose drops containing a flu virus after answering questions about their ability to handle stress in their lives. The people with the most stress-related problems produced higher concentrations of interleukin-6, a chemical messenger that attracts immune cells to the site of an infection. They also produced more mucus (had stuffier noses) and generally developed more serious symptoms in direct proportion to the rise in their interleukin-6 levels. http://www.health.harvard.edu/hhp/article/content.do?id=537


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