Introductory Review
Cellscience Reviews Vol 2 No.2
ISSN 1742-8130


Stress, Health and Disease


Colin R. Young 1, 2 & C. Jane Welsh 1,3

1 Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
2 Department of Psychology, College of Liberal Arts, Texas A&M University,
3 Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University

Received 26th October © Cellscience 2005


Historic Background

The definition of stress has changed over the years, but the meaning has remained the same: that many diverse agents elicit the same neuroendocrine response consisting of an elevated secretion of adrenocorticotrophic hormone (ACTH) by the pituitary leading to the enhanced release of glucocorticoids from the adrenal cortex (1, 2). The neuroendocrine products affect every organ system. Three major changes are observed: adrenal enlargement, gastrointestinal ulcers and thymolymphatic atrophy (1, 2, 3). Consequently it is possible to assess stress simply by weighing the thymus, spleen or the adrenal gland thus providing a quantitative index of the intensity of stress. These indicators were used half a century ago but now such functions of the adrenal medulla cortex, hypothalamus and pituitary can be determined by assaying catecholamine, corticoids and other hormones. Most recently, monitoring stress-related gene expression has been used as a measure of stress-evaluations (4).

Stress

Stress is a familiar aspect of modern life, being a stimulator for some, but having a negative impact for many others. Stress can be defined as a constellation of events resulting from a stimulus (the stressor), and precipitating a series of events activating physiologic response are generally adaptive in the body (the stress response, 5, 6). The physiologic response results in the release of neurotransmitters to the body. The results of the physiologic response are generally adaptive in the short-term (5), but can be detrimental when the stress is chronic and prolonged (7). There are wide variations in behavioural and biological reactions to stressful situations depending on genetic factors, gender, physiologic and psychological history (8). A great deal research remains to be carried out concerning these individual differences and how they can be recognized.
Any kind of immediate threat to a person's wellbeing is a stress-producing experience (acute) triggering a response in the body known as the fight-or-flight response. Here, both the sympathetic nervous system and the endocrine systems are involved. The sympathetic nervous system stimulates the adrenal medulla to secrete catecholamines, including adrenaline and noradrenaline. This results in an increase in respiration, heart rate, blood pressure and blood pressure and blood flow to the muscles, an inhibition of digestion and dilatation of the pupils - the flight or flight response. Once the threat is removed, the parasympathetic nervous system is activated and arousal tapers off over the next 20-60 minutes. Prolonged stress, however, follows a different route. The hypothalamus produces corticotrophin releasing hormone which, in turn, stimulates the pituitary to produce adrenocorticotropin, which then stimulates the adrenal cortex to release stress related corticosteroid hormones, the most important being cortisol. However, corticosteroids have long-lasting effects. Importantly, if stress is prolonged, persistent high levels of these hormones could be detrimental to the body systems, lowering immunity and increasing susceptibility to illnesses including infectious diseases – the subject of this review. Evidence of stress effects on health, predominantly involves a correlational analysis of stress and illness. For each of these examples there is evidence that acute or chronic stress can contribute as a risk factor to disease initiation and/or exacerbation.

The Role of Stress in Disease

Hundreds of studies over the last 25 years have shown that stress contributes to many illnesses including cardiovascular disease, cancer and endocrine disease. It has been calculated that 70-80 % of all visits to the doctor are for stress-related and stress-induced illnesses and that stress contributes to 50% of all illness in the U.S.

Chronic Stress and Disease

Chronic stress can be the result of repeated episodes of acute stress or a life condition, such as a chronic disease. In either case, the stress response remains continually activated, resulting in the normally functioning systems of the body performing sub-optimally.
Table 1. Medium-term Effects of Chronic Stress
   
 Tension, or migraine, headaches                  Difficult time going to sleep
 Upset stomach, problems retaining food      Change in appetite
 Tightness in chest, back, shoulders             Aching jaw, tight forehead
 Shortness of breath, dizziness                      Sweaty palms
 Tingling sensation in fingers, toes   Nervous tension, heart palpitations
 Diarrhea or constipation                               Constant low grade fever
 Cold, or sore throat                                      Rashes, hives, skin irritation
 Increased blood pressure                 Always tired, Fatigue
 Excessive sweating                           Sleep disturbances
 Feelings of anxiety                            Muscle tension and muscle pain
 Anger   Concentration problems
 Depression   Any number of other symptoms
 Increased appetite                            Menstrual problems, missed periods
   

Medium Term Effects of Chronic Stress and Illness

Here are some examples of how continued activation of the stress response results in decreased well-being:
* Muscle tension – Pain    Headaches   Fatigue   Upset stomach   Difficulty sleeping   Cold or sore throat

Long-Term Chronic Stress

Whereas the medium term effects of chronic stress are unpleasant, the long-term effects are dangerous and contribute to both suffering and disease:

1. Asthma
2. Diabetes
3. GI disorders – Ulcer disease
4. Myocardial Infarction
5. Cancer, breast cancer, cervical cancer
6. Viral infections
7. HIV
8. Parkinson’s Disease
9. Alzheimer’s Disease
Other Disease Conditions that have been shown to have a stress component:

1. Fatigue e.g. Adult onset diabetes
2. Chronic fatigue syndrome
3. Post-traumatic stress disorder

Table 2. All of the following disease conditions have been shown to have a stress component:

 Arrhythmia  Alcoholism  Allergies
 Angina pectoris  Arteriosclerosis  Asthma
 Atherosclerosis  Birth defects  Breast cancer
 Bruxism  Burnout  Cancer
 Carpal tunnel syndrome  Cholesterol levels elevated  Chronic backache
 Chronic fatigue syndrome  Shingles  Chronic tension headaches
 Chronic tuberculosis  Cold sores  Common cold
 Coronary heart disease  Coronary thrombosis  Depression
 Diabetes  Eczema  Epileptic attacks
 Erection problems  Fertility problems  Fibromyalgia
 Gastritis  Gastroesophageal reflux  Headaches
 Heart disease  High blood pressure  HIV
 Hives  Hypertension  Hyperthyroidism
Immune system disturbances  Impotence  Infertility
 Insomnia  Irritable bowel syndrome  Kidney disease
Loss of interest Many autoimmune problems Many endocrine problems
Memory loss Menstrual problems Migraine headache
Multiple sclerosis Myasthenia gravis Night eating syndrome
 Obsessive-compulsive disorder  Rheumatoid arthritis  Pancreatitis
 Premature aging  Psoriasis  Raynaud's disease
 Respiratory ailments  Premenstrual dysphoric disorder  Chronic obstructive pulmonary disease (COPD)

Stress and the Immune Response

Studies on stress-associated immune dysregulation have interested both clinicians and scientists in the field of psychoneuroimmunology (PNI). As the name implies, PNI encompasses interactions between the central nervous system, the endocrine system and immune system, and the impact that effects have on the health of the individual (9). The hypothalamic (HPA) and the sympathetic-adrenal medullary (SAM) axes are the two major pathways which alter the immune function. Lymphocytes, monocytes, macrophages and granulocytes express receptors for the products of both the HPA and SAM axes (10), such as cortisol and catecholamines. Binding of these products can result in dramatic changes in cell-trafficking, proliferation, cytokine secretion, antibody production and cytolytic activity (11). A pertinent example showing such changes is treatment of peripheral blood leukocytes with catecholamines causes the suppression of Interleukin-12 (IL-12) and an increase in IL-10 production (12). This change can shift the phenotype of CD4+T-helper (Th) cells from a Th1 profile to a Th2 profile. This change in the Th profile can have profound effects since Th1 cells are involved in cell-mediated immune activities, whereas Th2 cells are involved in antibody production.
Numerous animal studies over the past 30 years have clearly shown that a vast array of stressors can alter many aspects of the immune response. Such stressors include acute exposure to electric shocks, social defeat, maternal separation, rotation, the odor of a stressed conspecific, immersion in cold water, handling and loud noise (13). These stressors have all been shown to suppress some aspect of immunity. Chronic stressors such as crowding have also been investigated (14). Multiple aspects of immunity have been shown to be altered by some stressor, including the following; functions of specific cell types such as macrophages, the secretion of interleukins and the migration pattern of immune cells (14).
Acute stressors in humans such as final examinations (15), battle task vigilance (16) and sleep deprivation (17) have also been shown to have an impact on immune parameters. Studies in humans have clearly shown that stress hormones also inhibit the trafficking of neutrophils, macrophages, antigen-preventing cells as well as natural killer (NK) cells and T and B lymphocytes. Data from both human and animal studies have demonstrated that changes at any level of the stress response can lead to physiological imbalances in the body which in turn may result in increased-susceptibility to infection and inflammatory or autoimmune disease.

Stress and Infectious Disease

Many animal models indicate a link between stress and infectious disease. For example, psychological stress such as crowding prior to and following tuberculosis infection affects disease outcome (18). Psychological stress can inhibit natural killer cell lysis, T-cell responses and antibody production both in vivo and in-vitro (19). However, the degree of suppression of the immune system necessary to allow for severe infections is not fully understood.

Stress and the Immune Response to Viruses

A recent study examined whether stressful negative life events and pessimism were associated with lower natural killer cell cytotoxicity (NTCC) and T cytotoxic suppressor cell (CD8+CD3+) percentage in black women co-infected with human immunodeficiency virus Type 1 (HIV-1) and human papillomavirus (HPV), a viral initiator of cervical cancer. It was found that a greater pessimism was related to lower NKCC and cytotoxic/suppressor cells after controlling for the presence/absence of HPV Types 16 or 18, behavioral life style factors, and subjective impact of negative life events. Thus a pessimistic attitude may result in poorer control of HPV infection and increased risk for advancement of cervical dysplasia to invasive cervical cancer in HIV positive minority women co-infected with HPV (20).
The role of stress in influencing host resistance to upper respiratory tract infections induced by exposure to 5 different strains of rhinovirus and to respiratory syncytial virus has been investigated in human subjects. Following inoculation, subjects were monitored to determine whether they developed infections and cold symptoms. One third of those subjects exposed to 1 of these viruses developed clinical illness (21). Patients were then either given questionnaires or interviews related to their stress status. In the first study, higher scores on questionnaires about stressful life events, were associated with an increased likelihood of developing clinical illness or developing a 4-fold increase in antibody titers (22). In the second study, an interview replaced the questionnaire. This technique allowed the specification of the type of stressful events that increase risk, such as chronic social conflicts and underemployment of unemployment (22). The results taken together show that there is a relationship between psychological stress and susceptibility to several cold viruses. Social disruption in mice causes reactivation of latent herpes simplex virus (23). Stress has also been shown to enhance reactivation of latent herpes viruses such as Epstein-Barr virus in human subjects (24).
Social disruption in mice causes reactivation of latent herpes simplex virus (23). Stress has also been shown to enhance reactivation of latent herpes viruses such as Epstein-Barr virus in human subjects (24).

Stress and Human Immunodeficiency Virus

Several studies have been undertaken to examine the effects of stress on disease progression in patients with acquired immunodeficiency syndrome (AIDS). Studies in California showed that depression predicted CD4+ T-lymphocyte decline (25) and mortality (26). Conversely, another study failed to detect an association between depression and the decline of CD4+ T lymphocytes, disease progression or death (27). Other studies have found significant associations between immunological parameters and psychosocial factors, particularly denial (28) and concealment of homosexual identity (29). HIV infection advanced more rapidly in a dose-response relationship to the degree participants concealed their homosexual identity (29). Theses results are consistent with hypothesis about the health effects of psychological inhibition, but further research is required to identify the psychosocial behavioral and physiological mechanisms underlying these findings.
HIV infection advanced more rapidly in a dose-response relationship to the degree participants concealed their homosexual identity (29). Theses results are consistent with hypothesis about the health effects of psychological inhibition, but further research is required to identify the psychosocial behavioral and physiological mechanisms underlying these findings.

Effects of Combined Stress and Training on Respiratory Infections

A recent study examined immune and humoral changes and their relationship with upper respiratory tract infections (URTIs) during 3 weeks of military training followed by a 5-day combat course with energy restriction, sleep deprivation and psychological stress (30). After the combat course, total leukocyte and neutrophil counts were significantly elevated whereas total lymphocyte counts were unchanged. NK cells were reduced whilst CD4+ and CD19+ (B) cells were increased. Levels of IL-6 were elevated, while levels of IL-1 beta and IL-10 were unchanged. It was found that the incidence of URTI increased during training, and that after training there was a significant correlation between URTIs and NK cells. There studies concluded that NK cell levels are related to increased URTIs during physical training in a multi stressor environment (30).

Stress and the Immune Response to Viral Vaccine in Alzheimers

To determine whether chronic stress may influence the immune response to a viral vaccine, Alzheimer's disease caregivers and well-matched non-caregivers received the vaccine. It was found that caregivers had poorer cellular and humoral immune responses to the vaccine than controls (31,32). This suggests that chronically stressed subjects might have suppression (s) of the immune response to a vaccine. This data confirms reports demonstrating that acute stress can suppress the virus-specific antibody and T-cell responses to hepatitis B-vaccine (33, 34, 35). These finding are important in older adults who demonstrate poorer immune responses to vaccines, and additionally have higher rates of clinical illness including viral infections (36).

Stress Gastrointestinal Disorders

The past 30 years have seen a rapid advancement in our knowledge of how stress affects the GI tract (37).

Stress and Gastro Esophageal Reflux Disease

Up to 64% of subjects with stress and gastro esophageal reflux disease (GERD) reported that their symptoms were aggravated by stress and that stress diminution resulted in a subjective improvement (38, 39). It is unknown how stress aggravates GERD, but it has been shown that short-term psychological stress inhibited the esophageal sphincter and increased tonic and phasic crural diaphragm contractions (40). However, the rate of stress is only minor, and it seems likely that stress leads to an abnormal perception of the acid refluxater rather than an increase in volume. Consequently stress may play a role in patients with non erosive disease (37).

Stress and Peptic Ulcer Disease

The first report documenting an association between peptic ulcer disease and stress was reported in 1962 (41). Since then, numerous reports have demonstrated that chronic stressors and episodes of personal threat are associated both with the onset and relapse of duodenal ulcers (42, 43).
Societal stress derives from event(s) affecting a larger part of society, and if stress plays a role, then such events should increase ulcer rates in the population. Indeed increases in the numbers of perforated ulcers have been reported in times of war (44) and natural disasters such as earthquakes (45). Stress as a key factor may explain the increase in peptic ulcer disease – seen since the turn of the 19th Century, especially those whose ulcers were non-helicobacter pylori in origin.

Stress and Irritable Bowl Syndrome

Stress is an important causative factor in irritable bowel syndrome (IBS). Recent studies have examined the effect of acute physical and psychological stress on autonomic innervation and visceral sensitivity in healthy volunteers and patients with IBS. It was found that acute stress elevated anal perception thresholds in patients with IBS but not controls (46). Acute stress alters gut-specific efferent autonomic innervation both in controls and patients with IBS. In contrast, only patients with IBS showed heightened visceral sensation (46), suggesting involvement of a different regulatory mechanism(s).

Stress and Inflammatory Bowel Disease

Both forms of inflammatory bowel disease (IBS), Crohn’s disease (CD) and ulcerative colitis (UC), are believed to result from interactions of both genetic, immune and environmental factors (47). There is a long but inconsistent history of observations suggesting psychological stress contributes to both UC and CD (48). However, stress is more likely to modulate disease severity rather than being an initiating factor. Exacerbations of clinical disease are associated with sustained but not short-term stress (49). The precise mechanism(s) underlying this exacerbation are unknown, but a complex interplay of nervous, endocrine and immune interactions is implicated (50). There is limited evidence that the temperature stress in colder temperatures, induces the release of substance P of other tachykinins by the enteric nervous system, and improvement of gut inflammation can be achieved by an NK-1 receptor antagonist. Additionally, stress can reactivate chemically-induced colitis, but only when memory CD4+ T cells are present. The contribution of stress is more obvious in IBD animal models then in human IBD.
In an experimental rat model of colitis, the effects of prior exposure to immobilization stress were examined. Specifically, it was determined whether this stress modifies susceptibility to oxidative damage in colonic mucosa (51). Stress induced in the oxide synthase activity and immunochemical expression. Their findings indicated that previous exposure to stressful stimuli is a factor in susceptibility to oxidative change in experimental colitis. Additionally, their findings support a possible protective rather than deleterious, effect of treatment of stress before and during the development of inflammation of the colon (51).

Stress and Diabetes

There are differing views as to the correlation of stress with diabetes mellitus (52, 53, 54, 55). Some researchers have suggested that stress is particularly important to the exacerbation of juvenile diabetes. Conversely others have dismissed the importance of stress in diabetes (52). An increase in HPA axis activity has been reported in diabetes (56). Additionally, it has been shown that there are elevated levels of cortisol in both type I & II diabetic patients (57). Thus, there is strong circumstantial evidence that there may be a correlation between stress, plasma cortisol levels and diabetes. In support of this hypothesis, it has been reported that stress in normal non-diabetic patients, induced the delay in disposal of carbohydrate load, resulting in an elevation of blood glucose (58). Patients at onset diabetes are metabolically between the normal and diabetic status. Thus stress in such individuals could produce a transient impairment of carbohydrate metabolism in the non-diabetic, resulting in permanent diabetes (58). Other studies have indicated that physical stressors diminish diabetic control (52) and increase blood glucose, whereas the stressful effects of war resulted in the deterioration of clinical status of insulin-dependent diabetic patients (59).
In experimental animal models of diabetes, it has been shown that stress resulted in increases of serum cortisol level (SCL) compared to the levels in both diabetic and non-diabetic animals (60). Additionally stress resulted in a much higher weight loss in diabetic than non-diabetic animals (60). These authors concluded that stress caused a significant increase in blood glucose in both non-diabetic and diabetic rats; it exacerbated disease in diabetic rats; it did not produce diabetes in non-diabetic animals (60).

Stress and Cancer

Psychological stress is widely perceived to play a role in the etiology of cancer. However, the field of psychosocial cancer research is contradictory with findings varying from no associations to strong associations.
A recent study supports an overall association between stressful life events and breast cancer risk (61). The biological explanation of this association might be that stress perturbs various arms of the immune system predisposing to neoplasia. Other studies have investigated the relationship between stress at initial cancer diagnosis and treatment and subsequent quality of life (QoL). Using hierarchical multiple regressions, the authors found that stress predicted both psychological and physical QoL (62).
The role of stress in the etiology of breast cancer has been of considerable interest, partly because stress affects the hormonal system and especially oestrogen synthesis (63). The risk of breast cancer associated with acute stress has been well reported, however, less emphasis has been given to the effect of perceived daily stress (64). Prolonged low key stress of everyday life results in a persistent activation of stress hormones, which may impair oestrogen synthesis, leading to a lower risk of breast cancer. A recent very large study investigated the impact of everyday stress on the incidence of primary breast cancer among 6689 women followed up for a period of 18 years (65). They found that higher self reported everyday stress was associated with lower risk of breast cancer (65). These results are in agreement with another study showing self-reported stress was associated with a lower incidence of breast cancer (66). However, these results are at odds with other studies (64,67) in which mental stress was associated with a higher incidence of breast cancer. The reasons for these discrepancies are unclear but may relate to the later two studies included all incident cases of breast cancer whereas the large former study was restricted to the first time incidence of breast cancer. It is possible that stress activates that hypothalamic-pituitary-adrenal axis which causes inhibition of the hypothalamic-pituitary axis resulting in decreased oestrogen synthesis (68). Consequently it is hypothesized that this stress induced suppression of oestrogen secretion could explain the reduced risk of breast cancer.
Cervical intra-epithelial neoplasia (CIN) is a premalignant lesion of the cervix uteri. CIN lesions can progress to higher CIN grades (1-3) and cervical cancer, persist or regress to lower CIN grades normal cervical epithelium (69). Persistent infection with human papilloma-virus may play a central role in cervical carcinogenesis (70). Psychosocial factors may influence cervical carcinogenesis via a psychoneuroimmunology pathway (71). This hypothesis is intriguing for cervical carcinogenesis, since it is a virally induced cancer. Early studies on psychosocial factors suggested that anxiety and depression (psychosocial distress) were related to cervical cancer (72). Using a stressor-support-coping model it was predicted that negative life event stressors over the past year are associated with a higher level of distress and a greater likelihood of progression of CIN. Indeed in a recent large study, no influence of negatively-rated life events, a lack of support, coping style and the amount of perceived stress on time till progression or regression of CIN (73). These findings (73) are in agreement with the authors previous large study (74) indicating that the role of psychosocial factors in the initiation and progression of cervical cancer has not been shown. It seems unlikely that psychological interventions will play a role in prevention strategies for cervical cancer.
Chemotherapy in cancer patients generates psychological sequelae, in a high percentage of breast cancer patients (75). Clinical studies have demonstrated that the psychological distress in these patients predicts poor pathological response of tumors to chemotherapy (76). Psychological interventions that reduce this distress should therefore improve the pathological response of tumors to chemotherapy. Although the mechanisms of how this psychological stress affects chemotherapeutic efficacy in breast cancer is not clearly understood, there is some evidence to suggest that both hormonal and neuronal secretions during stress have a strong impact on the biological activities of breast cancer cells (77). Adrenaline and noradrenaline play an important role in moderating the effect of stress on target cells via adrenergic receptors (78). Additionally, highly differentiated neuroendocrine cells and their catecholamine products have been detected in breast cancer tumors (79). Catcholamines are not only regulators of cellular functions, but also are involved in alterations of gene transcription and expression (80). Consequently it is possible that psychological distress may affect the chemotherapeutic sensitivity of breast cancer cells by modulating the expression of chemotherapeutic drug resistance genes.
It has been shown for a number of years that psychological stress affects the outcome of chemotherapy in cancer patients. In an experimental mouse model of mammary carcinoma, it has been clearly shown that rotational stress decreases the anti-tumor effects of chemotherapeutic drugs (81). Also in a mouse model of lung cancer restraint stress was shown to reduce the therapeutic effect of a cytotoxic anti-tumor drug (82). However, these reports did not indicate whether stress induces chemotherapeutic resistance by directly regulating the biology of tumor cells or by indirectly modulating the anti-tumor immunity in the hosts.

Stress and Asthma

Amongst many factors, stress has long been suspected of being a contributing factor to asthma (83). Typically, there are reports supporting the importance of stress in asthma, as well reports refuting its significance (84). It is well known that in asthmatics, stress increases shortness of breath and respiratory resistance immediately (85), and increases acute exacerbation within a few weeks (86). A recent study in South Korea clearly showed an association between stress and asthma symptoms (87). Another study showed that parental stress increases infantile wheeze in infants with family histories of atopy (88). It is unclear which mechanisms may be responsible for the relationship between stress and the appearance of asthma in asthmatics. One possible mechanism may include the immune response since: the detrimental effects of stress on viral infections could exacerbate asthma symptoms (89); stress enhances airway inflammation after antigenic challenge in asthmatics (90).

Role of Mast Cells in Inflammatory Diseases and the Effect of Acute Stress

Mast cells are involved in both allergic reactions and in a variety of neuroinflammatory disease, especially those exacerbated by stress. In these instances most cells appear to be activated through their Fc receptors by immunoglobulins other than IgE, and also by anaphylatoxins, neuropeptides and cytokines to secrete mediators without overt degranulation (91). Most cells may be involved in inflammatory diseases including multiple sclerosis (92), Migraines (93), arthritis (94), cardiovascular disease (95), interstitial cystitis of the urinary bladder (96) and irritable bowl syndrome (97).
Increasing evidence indicates that the symptoms of MS are exacerbated by acute stress (98). The blood-brain barrier (BBB) is disrupted, or displays increased leakiness, prior to many of the pathological or clinical symptoms of MS (99). Brain mast cells are partly responsible for permeability changes in the BBB (100). Brain mast cells are permeability (100). Additionally, mast cells have also been reported in MS plaques and could be directly involved in demyelination (101).
Stress is known to precipitate migraines, and recent studies have demonstrated that stress-induced neurogenic inflammation depends on NK-1 receptors and may involve a direct action of CRH on brain microvessels (102). However, delayed responses may additionally involve elevations in IL-6 and nitric oxide in dura macrophages (103). These finding have led to a model of intracranial neurogenic inflammation in which hypothalamic CRH effects the sensory nucleus of the trigeminal nerve, leading to the release of mast cell stimulation peptides which in turn may act directly on the vasculature (104).
Several reports have identified mast cells in the joints of patients with inflammatory arthritis (105). Also it has been shown that mast cells are required for autoimmune arthritis (106). Interestingly, mast cells in rheumatoid arthritis joints express CRH receptors (107). Furthermore, CRH urocortin and CRH receptors are elevated in RA patients whose symptoms are exacerbated by stress (108). Thus, proteases released from mast cells can stimulate protease-activated receptors on other immune cells thereby triggering a release of inflammatory molecules. Indeed, it has been demonstrated the cells obtained from arthrosynivitis joints express RANTES and MCP-1 (109), both chemokines being mast-cell chemo-attractants.
There is increasing evidence that cardiac mast cells are involved in the development of atherosclerosis, coronary inflammation and cardiac ischemia. Cardiac mast cell-derived histamine can constrict coronary arteries and can sensitize nerve endings (110). In an experiment animal model, it has been demonstrated that acute-stress induced rat cardiac mast cell activation (111). Subsequently it has been in a mouse-model that acute stress induces histamine release from heart, and elevated levels of serum histamine and IL-6 (112). These findings are important since both histamine and IL-6 are significant risk factors of coronary disease (113).
The symptoms of interstitial cystitis (IC) worsen in premenopausal women and common factors in this triggering process include psychological or physical stress (114). IC patients with bladder inflammation show elevated levels of urinary IL-6 (115) and bladder biopsies show an elevated number of activated mast cells (116). These bladder mast cells are positive for IL-6 (117), and furthermore bladder biopsies show higher expression of NK receptors (118). These mast cells had ultra structural signs of activation without overt degranulation (119). Experimental animal studies have clearly shown that bladder symptoms could be mimicked by acute stress leading to bladder mast cell activation (120).
The role of mast cells in gastrointestinal pathology has been extensively reviewed (121). Interestingly, mast cells are located close to intestinal neurons (122). Neuroimmune interactions have been implicated in food allergies (123), IBS (124) and in cyclic (125) vomiting syndrome, both of which can be precipitated by psychological or physical stress (126). Acute stress is associated with gastrointestinal mast cell activation (127), this process being dependent upon CRH. CRH can increase intestinal mast cell degranulation leading to increased vascular permeability (128). A pertinent finding relevant to this is that mast cells are increased in the intestine of IBS patients (97, 124).

Stress Autoimmunity and Autoimmune Diseases

Whereas many studies have shown a connection between stress and autoimmune disease, the data indicating a correlation between stress and onset and progression of such diseases is circumstantial. An essential component of the response to stress, is a rapid increase in activity of the HPA axis. The best evidence for an effect of stress is the onset of Grave’s hyperthyroidism and major stress (129). Stress has also been shown to be involved in several other autoimmune diseases such as: the induction of arthritis in experimental animals; the modulation of acute inflammation triggered by mycobacteria; experimental autoimmune encephalomyelitis.
The effects of emotional states on the susceptibility to type II collagen-induced arthritis in rats has been examined in some detail. The effects of stress were examined on the clinical, histological and immunological aspects of the disease (130). Stress produced by exposing rats to cats, abrogated the development of type II collagen-induced arthritis, whereas the incidence of arthritis was reduced in rats stressed by transportation and handling (13). This important study clearly indicates that psychosomatic processes can influence an animal model of autoimmunity.
The effect of a single stress treatment of mice on the early cellular response of acute inflammation produced by the intraperitoneal inoculation of animals with Mycobacterium avium has been investigated. Autoimmune-prone NZB/W mice were subjected to stress produced by swimming, before or simultaneously with the induction of mycobacteria-induced inflammation (131). The authors found that: First, stress is able to modify the acute inflammatory response of mice; Secondly, autoimmune-prone mice are more sensitive to stress-induced modulation of inflammation than normal animals; Thirdly, the timing of stress with respect to initiation of the inflammatory process, is an important factor in the severity of changes produced by swimming stress in the early cellular response of acute inflammation.
Experimental autoimmune encephalomyelitis (EAE) is a model for T-cell mediated autoimmune disease (132) and shares many features in common with human multiple sclerosis (132). Corticotrophin-releasing factor (CRF) is a 41-amino acid peptide that plays a major role in the stress response by effecting the HPA axis (133), the sympathetic nervous system (134) and the immune system (135). Activation of the HPA axis and sympathetic nervous system increases the production of glucocorticoids and catecholamines, which down regulate the immune system. CRF is expressed in the brain as well as in the immune system (136). Recently it has been shown that intraperitoneal administration of CRF can prevent the development of EAE (137). This prevention is mediated not only by the adrenal corticosteroids, but also by direct effects on the immune system. Thus stress may play a critical role in the development of this autoimmune disease. Surprisingly, two neuropeptides involved in the stress response (CRF and urocortin, a neuropeptide showing 45% homology to CRF) ameliorate clinical and pathological aspects of disease in a model of cell-mediated, organ-specific autoimmunity (137).

Stress and Coronary Heart Disease

Over the past twenty years, an increasing number of reports have been published showing an association between job strain and coronary heart disease (138, 139). However, there is also convincing evidence showing that job strain is not associated with CHD risk factors in Japanese part-time female employees of a retail company (140). Additionally, a cohort study of 5577 Scottish men, with 25 years of follow-up, indicated that stress did not underlie any association with cardiovascular disease once the influence of established risk factors had been taken into account (141). Many studies provide evidence that socioeconomic conditions in both childhood are important for coronary heart disease risk in adulthood (142,143). Established risk factors did not fully account for these associations and despite many studies supporting the role of daily stress showing a link between deprived circumstances and coronary heart disease (144, 145), no evidence for such a role was found in the Japanese and Scottish studies.
The role of stress in patients exhibiting cardiac arrest with apparently normal hearts, is rarely unknown. A recent study (146) examined the role of psychosocial stress as a precipitant of cardiac arrest in patients with apparently normal hearts, termed idiopathic ventricular fibrillation (IVF). They interviewed 25 IVF survivors and 25 matched comparison group consisting of patients with angina pectoris or acute myocardial function by without cardiac arrest. Their findings showed that psychosocial stress does play a role in otherwise unexplained cardiac arrest (146).
Myocardial infarction (MI) is one of the major causes of death in the world. Psychosocial factors, such as anxiety and social isolation contribute to cardiovascular related morbidity and mortality (147). It has been shown that mental stress during daily life triggers myocardial ischemia (148). The impact of emotional stress on the heart has been documented in the West (149, 150, 151) but few studies have been carried out in developing countries. A recent study in India, however, examined life events as risk factors for MI (152). In this study, it was found that control individuals would have experienced 2.24 stressful life events during the past year without suffering any adverse physical or psychological disturbance, whereas MI patients would have experienced an average of 4.16 stressful life events during the past year. These major life events indicates that there is a period of increased risk when interventions may prevent or reduce illness (153).
Psychosocial aspects of heart disease have usually been studied in predominantly male patients. A literature survey showed that women are subject to adverse cardiac effects of stress and chronic negative effects similarly as in men (154). Interestingly, stress is perceived differently in men and women and can lead to different physiological reactions. One example of this is the “stress cardiomyopathy", an acute life-threatening illness, found mostly in women which is often triggered by sudden emotionally distress (154). Women with heart disease, report that they have more psychological distress in response to their illness than do men.
The biological pathways involved in the association between stress and coronary risk are not clearly understood, though haemodynamic, neuroendocrine, inflammatory and haemostatic pathways may contribute (155). It is possible that platelets, blood cell fragments derived from megakaryocytes in the bone marrow, may be involved in the association between stress and coronary risk. A common feature of acute coronary syndromes is coronary artery occlusion as a result of the rupture of vulnerable plaque and resultant thrombosis. Activated platelets play an important role in the formation of arterial thrombi. They deposit at sites of plaque rupture, releasing potent platelet agonists, leading to additional platelet recruitment, activation and aggregation (156). Activated platelets release an array of adhesive and pro-inflammatory factors (157). These include pro-inflammatory cytokines, chemokines, vasoactive amines and growth factors. Supporting evidence of a possible platelet-leukocyte interaction has been recently presented showing that patients with stable coronary disease had elevated circulating levels of the inflammatory markers IL-6, IL-1 receptor antagonist and C-reactive protein, which correlated with the number of platelet-leukocyte aggregates in the blood (158).
Speculation about the biological effects of stress on disease has focused on glucocorticoids which can display long-term increases in response to chronic stress (159). Glucocorticoids suppress testosterone in men (160), and low testosterone levels are a component of the chronic physical and psychological stress response in men (161, 162). A high ratio of cortisol to testosterone is indicative of chronic stress and has been used as an indicator of stress in both human and animal studies (161, 163). Indeed recently it has been reported that there is an association between cortisol: testosterone-ratio (CT ratio) and incident ischemic heart disease (IHD) in Caerphilly, South Wales (164). In this prospective study, CT ratio was positively associated with IHD incidence and mortality. Evidence suggests that high cortisol and low testosterone levels are associated with a detrimental profile of resistance syndrome components (165, 166). This suggests that protocols aimed at reducing the C/T ratio, such as testosterone administration, may improve insulin resistance and reduce the risk of CHD.

Stress and Multiple Sclerosis

There have been many studies examining the association between stress and the clinical course of multiple sclerosis (MS). Several other studies have demonstrated that stressful life events are associated with increased exacerbations in relapsing-remitting MS (167, 168). Conversely other studies have reported that there is no strong evidence of a relationship between psychological stress or distress and clinical exacerbation, although this same study concluded that their data support the notion that conflict and disruption in routine are related to subsequent disease activity in MS (169).
Findings by Ackerman et al., (170) suggest that stress rapidly precipitates MS exacerbations, with a mean of 14 days from stressor to exacerbation. A broad spectrum of stressors, ranging from mild to severe threat, were associated with these exacerbations. Furthermore, there was a rapid decrease in time between exacerbations as the frequency of life events increased suggesting a cumulative effect of stressful life events and MS exacerbations. In a meta-analysis of 14 empirical MS studies, it was found that stress is related to exacerbation of multiple sclerosis (171). The association between stress and exacerbation in multiple sclerosis can be demonstrated only when a clinical trial(s) of a behavioral intervention that teaches patients to reduce both the occurrence and impact of stress (171). Taken together these studies suggest that stress and the clinical course of MS are related (172, 173, 174). These studies found that MS patients had more stress prior to both disease onset or exacerbation. Although the exact mechanism of stressor-induced susceptibility to development of MS is unknown, several theories have been proposed: First, failure to eliminate auto reactive B lymphocytes; Secondly, failure to eliminate auto reactive T lymphocytes; Thirdly, alteration of cell regulation. If the hormonal response to stress alters the mechanism by which tolerance occurs, stress may increase the likelihood of MS. The hormonal response to stress may alter the function of regulatory cells, such as macrophages, CD4Th2 lymphocytes producing the cytokines IL-4 and IL-10, and CD4 Th1 lymphocytes producing interferon (175).
An interesting finding in MS patients concerns the size of patient's adrenal glands. At postmortem examination, the adrenal glands of patients with MS were 36% larger than those of patients who had amyotrophic lateral sclerosis who had comparable body weight. The adrenal-body weight ratio was 40% higher in patients with MS than in patients who died from myocardial infarction (176). This increased adrenal size in MS patients may allow excessive glucocorticoid secretion in response to stress, and thereby affect immune regulation.
It is possible that stress-related health changes in MS might correlate with altered neural immune-signaling. In order to investigate this hypothesis Hessen et al., (177) used a standardized, acute laboratory stressor and compared cytokine and neuroendocrine responses between different subject groups in MS. Significantly increased heart rate, systolic and diastolic blood pressure was noted in all stress groups, despite a decline in neuroendocrine parameters. They also reported that there were minor elevations of cortisol in physiologically stressed MS and patients (177), in line with other studies on experimental stress in MS (178, 179). Additionally, they did not find a clearly altered immune response in stress versus control MS patients. However, baseline levels for IL-6 were significantly elevated in MS patients compared to healthy controls (177). TNF levels were also shown to decrease in stressed MS patients, although not significant statistically. Since TNF might not only have a proinflammatory effect in MS but also a protective potential (180), this finding may suggest a functional TNF deficiency in MS (177).
An important question to ask here is what specific factors affect the clinical symptoms of MS patients? Common factors reported as beneficial are cannabis, cold baths, meditation and dietary factors. Adverse factors are high stress, exposure to high temperatures and viral infections (181). An additional adverse factor is solar heat and not solar light. It is possible that patients with MS may consequently risk vitamin D deficiency because of sun avoidance possible due to heat-related fatigue or intolerance. This later finding may have significance because vitamin D may have beneficial immunomodulatory properties.

Stress and Méniere’s disease and Acoustic Neuroma

The relationship between stress and chronic idiopathic inner ear pathologies has not been well investigated. Patients with Méniere's symptoms display episodic vertigo which could be related to stress. Indeed it has been stated that Méniere's disease is a psychosomatic disorder (182). A recent detailed study (183) provided evidence supporting the concept that both Meniere's disease and acoustic neuroma patients have quantitative and qualitative changes in stress hormone profiles. Additionally, (183) a strong positive correlation between cortisol and ACTH was found for Meniere as well as neuroma patients, but no such correlation was observed for patients with facial spasm. This finding suggests that the Meniere and neuroma patients were in a state of chronic stress where hypothalamic-pituitary-adrenal axis is perturbed. These findings, taken together, suggest that stress hormone profiles of patients with inner ear pathologies might be useful indicators for patient management (183, 184).

Post-traumatic Stress Disorder (PTSD)

PTSD is a chronic psychiatric illness that develops in a small percentage of trauma-exposed individuals. PTSD is associated with several biopsychosocial changes which may adversely affect health. Biological changes identified in PTSD patients include an increased suppression of the hypothalamic-pituitary-adrenal (HPA) axis in response to dexamethasone challenge (185) enhanced catecholamine and emotional responses to infusion of a sympathetic agonist (186), exaggerated heart rate and blood pressure changes after witnessing trauma related material (187), and augmented thyroid-stimulating hormone responses to stimulation by thyrotropin-releasing hormone (188). Increased activity of the cellular immune system in PTSD may also raise susceptibility to autoimmune disorders (189).
It has been found that trauma exposure that leads to PTSD is associated with increased health complaints and increased visits to health specialists, whilst trauma exposure alone is not. This indicates that somatic complaints whether physiological or pathological in nature, were distressing enough to compel individuals to visit multiple health care providers. Furthermore, epidemiological studies demonstrate that negative health perceptions can exert independent effects on morbidity and mortality (190, 191). Vedantham and colleagues (192) determined that PTSD or trauma exposure without PTSD, is associated with negative health changes by comparing the health status of trauma-exposed individuals with and without PTSD with the health status of individuals who had never experienced trauma.

Stress and Alzheimer’s Disease

Chronic stress has been associated with structural changes in the hippocampus with impairment of hippocampally-mediated forms of learning and memory in animals (193) and humans (194). The association of psychological distress with hippocampal damage has led to the possibility that psychological stress may affect the risk of developing Alzheimer’s disease in old age (195). This hypothesis is interesting since evidence suggests that some of the adverse effects of chronic disease can be blocked by a variety of pharmacologic agents (196). A recent study in a cohort of older Catholic clergy members suggested that chronic psychological distress is a risk factor for AD and that this association probably reflects neurobiologic mechanisms other than the pathologic hallmarks of AD (197).
It is well established that chronic stress leads to both functional and structural changes in the nervous system, particularly along the limbic-hypothalmic-pituitary adrenal axis (198). The hippocampal formation is vulnerable to chronic stress, and consequently forms of learning and memory mediated by the hippocampus are influenced by stressful experiences (199). Depressive symptomatology, a common form of psychological distress is also associated with AD risk (200) and a decline in episodic memory. Further studies are required to further understand the neurologic basis of the association between distress proneness and clinical AD.

Stress and Back Pain

Back pain is one of the most common and costly health problems in our society (201). Although many psychosocial risk factors such as employment dissatisfaction, physical and family problems, poor self-esteem, poor health perception may play a role in the severity of acute back paid (202), stress may also play a pivotal role. An extensive study recently was carried out on lower back pain in a population of 10,321 healthy individuals (203). It was found that personal stress was significantly raised in individuals with any form of back paid. Interestingly, logistic regression analysis indicated that stress might be a significant factor for back pain of any severity (203). In another large study of workers, it was determined that individual psychological factors as well as workplace and background factors were related to back pain in the workers (204). Of the wide range and number of variables included, the individual psychological variables were most prominent and increased the risk for significant back pain by as much as 13 fold. Similarly, in the prospective study pain catastrophizing and distress were two of the best predictors (204). Since psychological variables were important risk factors. The effects of early interventions might then be improved by focusing on the psychological factors. Thus stress and the work environment may play and important role in the genesis and/or perception of back pain.

Conclusions

Hundreds of studies over the past twenty-five years have shown that stress can contribute to many illnesses and disease. Additionally, numerous animal studies over the same period have clearly shown that a vast array of stressors can alter many aspects of the immune response, much of which is mediated via the HPA or SAM axes. In this article we have reviewed the literature on the effects of stress on a wide range of different illnesses and diseases, including: The immune response to viruses; The immune response to HIV; The immune response to viral vaccines; Gastrointestinal disorders; Diabetes: Cancer; Asthma; Coronary heart disease; Multiple sclerosis; Meniere's disease; Post traumatic stress disorder; Alzheimer's disease and Back pain. Although there exists some conflicting data, the general findings are that stress contributes, in some form or other, to either the onset, severity and/or progression of these illnesses or diseases. Furthermore, some neuroimmunological mechanistic models are presented as to show how stress can produce such changes in specific diseases.

Acknowledgements

We would like to acknowledge grant funding from NIH/NINDS R01 39569 and Dana Parks for excellent secretarial assistance.


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