As identified in 1936 by Hans Selye, stress is shaping diseases through the induction of inflammation. But inflammation display some yin yang properties. On one hand inflammation is merging with the innate immune response aimed to fight infectious or sterile insults, on the other hand inflammation favors chronic physical or psychological disorders. Nature has equipped the cells, the organs, and the individuals with mediators and mechanisms that allow them to deal with stress, and even a good stress (eustress) has been associated with homeostasis. Likewise, societies and the planet are exposed to stressful settings, but wars and global warming suggest that the regulatory mechanisms are poorly efficient. In this review we list some inducers of the physiological stress, psychologic stress, societal stress, and planetary stress, and mention some of the great number of parameters which affect and modulate the response to stress and render it different from an individual to another, from the cellular level to the societal one. The cell, the organ, the individual, the society, and the planet share many stressors of which the consequences are extremely interconnected ending in the domino effect and the butterfly effect.

Whether peripheral immunity prospectively influences brain health remains controversial. This study aims to investigate the longitudinal associations between peripheral immunity markers with incident brain disorders. A total of 161,968 eligible participants from the UK Biobank were included. We investigated the linear and non-linear effects of peripheral immunity markers including differential leukocytes counts, their derived ratios and C-reactive protein (CRP) on the risk of dementia, Parkinson's disease (PD), stroke, schizophrenia, bipolar affective disorder (BPAD), major depressive disorder (MDD) and anxiety, using Cox proportional hazard models and restricted cubic spline models. Linear regression models were used to explore potential mechanisms driven by brain structures. During a median follow-up of 9.66 years, 16,241 participants developed brain disorders. Individuals with elevated innate immunity markers including neutrophils, monocytes, platelets, neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) had an increased risk of brain disorders. Among these markers, neutrophils exhibited the most significant correlation with risk of dementia (hazard ratio 1.08, 95% confidence interval 1.04-1.12), stroke (HR 1.06, 95% CI 1.03-1.09), MDD (HR 1.13, 95% CI 1.10-1.16) and anxiety (HR 1.07, 95% CI 1.04-1.10). Subgroup analysis revealed age-specific and sex-specific associations between innate immunity markers with risk of dementia and MDD. Neuroimaging analysis highlighted the associations between peripheral immunity markers and alterations in multiple cortical, subcortical regions and white matter tracts, typically implicated in dementia and psychiatric disorders. These findings support the hypothesis that neuroinflammation is important to the etiology of various brain disorders, offering new insights into their potential therapeutic approaches.

Chaigui granules were a traditional Chinese medicine (TCM) preparation with antidepressant effects derived from a famous antidepressant prescription. It was of great significance to clarify the antidepressant mechanism of Chaigui granules for the clinical application of this drug. In this study, a chronic unpredictable mild stress (CUMS) depression model was successfully established, and behavioral indicators were used to evaluate the antidepressant effect. Second, the CD4+, CD8+, and CD4+/CD8+ levels were detected in peripheral blood. Meanwhile, the amount of inflammatory cytokines was determined in serum. Correspondingly, LC/MS-based peripheral blood mononuclear cell (PBMC) metabolomics was used to investigate vital metabolic pathways participating in the antidepressive effects of Chaigui granules. Finally, bioinformatics technology was further employed to discover the potential antidepressant mechanism of Chaigui granules regulating the immune system. The results suggested that the administration of Chaigui granules significantly improved CUMS-induced depressive symptoms. Chaigui granules could improve immune function by regulating T lymphocyte subsets, increasing anti-inflammatory cytokine levels of IL-2 and IL-10, and reducing pro-inflammatory cytokine levels of TNF-α, IL-1β, and IL-6. In addition, metabolomics results of PBMCs showed that Chaigui granules improved 14 of the 25 potential biomarkers induced by CUMS. Metabolic pathway analyses indicated that purine metabolism was the critical metabolic pathway regulated by Chaigui granules. Furthermore, correlation analysis indicated that 13 key biomarkers were related to immune-related indicators. The metabolite-gene network of 13 key biomarkers was investigated by using bioinformatics. The investigation showed that 10 targets (5'-nucleotidase ecto; 5'-nucleotidase, cytosolic IB; 5'-nucleotidase, cytosolic II; etc.), mainly belong to the purine metabolism, might be potential targets for Chaigui granules to exert their antidepressant effects by improving immune function impairment. Together, our results suggested that Chaigui granules might exert antidepressant effects by improving immune function and regulating the purine metabolic pathway in PBMCs. This work used PBMCs metabolomics as an entry point to study the antidepressant mechanism of Chaigui granules, which provided a new way to elucidate the mechanism of a traditional Chinese medicine prescription.

Despite the high stress levels, paramedics seem to ignore or even negate the stress. This can be detrimental and lead to stress-related diseases. Therefore, we investigated the divergence between physiological and psychological stress responses of paramedics. Participants were 16 paramedics and 17 white-collar workers. We assessed psychological stress parameters, cortisol awakening response (CAR), and quantified immune parameters. In paramedics, electrocardiogram (ECG) was measured during one complete 24-hour shift. Our results revealed that CAR was higher in paramedics compared to controls. An alteration of immune parameters was observed even during days of free time. Also, ECG recordings showed acute stress in paramedics during rescue situations. Questionnaires revealed that rescue-service specific stressors affect psychological outcomes. However, paramedics reported significantly less mental stress and higher levels of depersonalization than controls. Taken together, our results suggest higher stress in paramedics compared to controls. However, paramedics negate their daily stress. Our findings underline therefore the importance to develop stress-management interventions for paramedics including sensitization for their stress reactions.

Nonhuman primates from domestic sources constitute a small, but critical, proportion of animals studied in research laboratories. Many of these nonhuman primates are raised at one facility and subsequently transported/relocated to another facility for research purposes. We examined the effects of transport, relocation, and acclimation on the phenotype and function of peripheral blood mononuclear cells (PBMCs) in a group of rhesus monkeys that were transported by road for approximately 21 hours from one facility to another. Using a panel of human antibodies and a set of standardized human immune assays, we evaluated the phenotype of lymphocyte subsets by flow, mitogen-specific immune responses of PBMCs in vitro, and levels of circulating cytokines and cortisol in plasma at various time points including immediately before transport, immediately upon arrival, and after approximately 30 days of acclimation. Analyses of blood samples revealed that CD3+ T-cell and CD20+ B-cell populations had decreased significantly immediately after relocation but had recovered within 30 days after arrival at the new facility. Similarly, circulating cortisol and cytokine levels in plasma were significantly higher immediately after relocation; and by the 30-day time point, these differences were no longer significant. However, immune assays of PBMCs indicated that mitogen-specific responses for proliferation, interferon γ (IFN-γ), and perforin were significantly higher after relocation and 30 days of acclimation. These findings have implications on the research participation of transported and relocated nonhuman primates in immunologic research studies, suggesting that 30 days is not sufficient to ensure return to baseline immune homeostasis. These data should be considered when planning research studies in order to minimize potential confounding factors associated with relocation and to maximize study validity.

This study investigated the effects of a temporally confined naturalistic stressor (academic stress) on immune functions. Furthermore, moderating influences of a number of psychological variables were assessed. Five blood samples were obtained from 20 students during an observation period of 8 weeks, starting 4.5 weeks before an exam period up to 1 week following the last exam. The analysis of 45 immune parameters revealed several time-dependent changes attributable to examination stress. We observed a reduction in the absolute numbers of natural killer (NK) cells and monocytes in peripheral blood and a shift towards more immature and naïve cells within NK and T cell populations. In addition, IL-6 and TNF-α production by LPS-stimulated monocytes was increased. Psychological variables were grouped by means of factor analyses into two factors. One factor, which was interpreted as an indication of chronic stress, moderated the relationships between academic stress and percentages of mature CD57+ NK cells. This chronic stress factor was also associated with an increase in memory and a decrease in naïve CD8 T cells and increased serum levels of IL-17. The present study identifies important potential psychological mediators of stress-induced changes in specific immunological parameters.

Clinical and basic studies of functional interactions between adaptive immunity, affective states, and brain function are reviewed, and the neural, humoral, and cellular routes of bidirectional communication between the brain and the adaptive immune system are evaluated. In clinical studies of depressed populations, lymphocytes-the principal cells of the adaptive immune system-exhibit altered T cell subtype ratios and CD4+ helper T cell polarization profiles. In basic studies using psychological stress to model depression, T cell profiles are altered as well, consistent with stress effects conveyed by the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. Lymphocytes in turn have effects on behavior and CNS structure and function. CD4+ T cells in particular appear to modify affective behavior and rates of hippocampal dentate gyrus neurogenesis. These observations force the question of how such actions are carried out. CNS effects may occur via cellular and molecular mechanisms whereby effector memory T cells and the cytokine profiles they produce in the blood interact with the blood-brain barrier in ways that remain to be clarified. Understanding the mechanisms by which T cells polarize and interact with the brain to alter mood states is key to advances in the field, and may permit development of therapies that target cells in the periphery, thus bypassing problems associated with bioavailability of drugs within the brain.

Only recently, the scientific community gained insights on the importance of the intestinal resident flora for the host's health and disease. Gut microbiota in fact plays a crucial role in modulating innate and acquired immune responses and thus interferes with the fragile balance inflammation versus tolerance.

Correlations between gut bacteria composition and the severity of inflammation have been studied in inflammatory bowel diseases. More recently similar alterations in the gut microbiota have been reported in patients with spondyloarthritis, whereas in rheumatoid arthritis an accumulating body of evidence evokes a pathogenic role for the altered oral microbiota in disease development and course. In the context of dysbiosis it is also important to remember that different environmental factors like stress, smoke and dietary components can induce strong bacterial changes and consequent exposure of the intestinal epithelium to a variety of different metabolites, many of which have an unknown function. In this perspective, and in complex disorders like autoimmune diseases, not only the genetic makeup, sex and immunologic context of the individual but also the structure of his microbial community should be taken into account.

Here we provide a review of the role of the microbiota in the onset, severity and progression of chronic inflammatory arthritis as well as its impact on the therapeutic management of these patients. Furthermore we point-out the complex interwoven link between gut-joint-brain and immune system by reviewing the most recent data on the literature on the importance of environmental factors such as diet, smoke and stress.

The intent of the study was to evaluate immune system changes during 12 weeks of abstinence in heroin users. We recruited men (N = 65) aged 18-45 years and collected demographic and heroin use pattern data. Serum blood levels of total interleukin 2 (IL-2), interferon γ (IFN-γ), immunoglobulin (Ig) A, IgG, and IgM were assessed at five time points. The IL-2 level was increased on day 84 as compared to that in healthy controls. The IFN-γ level was higher in heroin users than in healthy controls between days 0 and 28, and was decreased on day 84. IgG and IgM levels in heroin users were higher than those in healthy controls in our 12-week study, and were in positive correlation with the way of using the drug, duration of heroin dependence, and daily heroin intake. Our data revealed that the immune system was not restored during the 12 weeks of heroin withdrawal.

We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is 'what is the source of this chronic low-grade inflammation?'

This review explores the role of inflammation and oxidative and nitrosative stress as possible mediators of known environmental risk factors in depression, and discusses potential implications of these findings. A range of factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency.

The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder.

Stress is a common occurrence in everyday life and repeated or traumatic stress can be a precipitating factor for illnesses of the central nervous system, as well as peripheral organ systems. For example, severe or long-term psychological stress can not only induce depression, a leading illness worldwide, but can also cause psychosomatic diseases such as asthma and rheumatoid arthritis. Related key questions include how psychological stress influences both brain and peripheral systems, and what detection mechanisms underlie these effects? A clue is provided by the discovery of the pathways underlying the responses to host "danger" substances that cause systemic diseases, but can also contribute to depression. The inflammasome is a protein complex that can detect diverse danger signals and produce the accompanying immune-inflammatory reactions. Interestingly, the inflammasome can detect not only pathogen-associated molecules, but also cell damage-associated molecules such as ATP. Here, we propose a new inflammasome hypothesis of depression and related comorbid systemic illnesses. According to this hypothesis, the inflammasome is a central mediator by which psychological and physical stressors can contribute to the development of depression, and as well as a bridge to systemic diseases. This hypothesis includes an explanation for how psychological stress can influence systemic diseases, and conversely how systemic diseases can lead to psychiatric illnesses. The evidence suggests that the inflammasome may be a new target for the development of treatments for depression, as well as psychosomatic and somato-psycho diseases.

Stress and depression consistently elevate inflammation and are often experienced simultaneously, which is exemplified by people in troubled relationships. Troubled relationships also elevate inflammation, which may be partially explained by their ability to engender high levels of stress and depression. People who are stressed, depressed, or in troubled relationships are also at greater risk for health problems than their less distressed counterparts. Inflammation, a risk factor for a variety of age-related diseases including cardiovascular disease, Type II diabetes, metabolic syndrome, and frailty, may be one key mechanistic pathway linking distress to poor health. Obesity may further broaden the health implications of stress and depression; people who are stressed or depressed are often overweight, and adipose tissue is a major source of proinflammatory cytokines. Stress, depression, and troubled relationships may have synergistic inflammatory effects: loneliness, subclinical depression, and major depression enhance inflammatory responses to an acute stressful event. The relationship between distress and inflammation is bidirectional; depression enhances inflammation and inflammation promotes depression. Interesting questions emerge from this literature. For instance, some stressors may be more potent than others and thus may be more strongly linked to inflammation. In addition, it is possible that psychological and interpersonal resources may buffer the negative inflammatory effects of stress. Understanding the links among stress, depression, troubled relationships, and inflammation is an exciting area of research that may provide mechanistic insight into the links between distress and poor health.

Our studies explore the changes of blood corticosterone (CORT), adrenocorticotropic hormone (ACTH), interleukin (IL)-1β, IL-2, IL-6 concentrations and the pituitary ACTH expression in rats after water floating in the presence or absence of following high-intensity exercise. The rats were randomly assigned into three groups. Group A served as control; Group B received 180 minutes water floating and psychological (fear) stimulation; Group C received the same treatment as Group B in addition and 120-minutes non-stop running. Compared to Group A, Group B showed a significant increase of IL-2 (19.91 ± 2.52 vs. 13.09 ± 3.13 ng/ml, P < 0.05), and IL-6 (0.18 ± 0.08 vs. 0.12 ± 0.05 ng/ml, P < 0.05); Group C demonstrated a significant increase of CORT (977.22 ± 207.36 ng/ml vs. 434.58 ± 110.45 ng/ml, P <0.01) and IL-1β (0.21 ± 0.04 vs. 0.16 ± 0.06 ng/ml, P < 0.05), IL-2 (20.29 ± 4.23 vs. 13.09 ± 3.13 ng/ml, P < 0.05), and IL-6 (0.19 ± 0.03 vs. 0.12 ± 0.05 ng/ml, P < 0.05) levels, and a significant decrease of ACTH (16.95 ± 5.46 vs. 22.96 ± 7.32 pg/ml, P = 0.03). Immunohistochemical staining showed the decreased number of pituitary ACTH-positive cells in both Groups B and C (P < 0.05) as compared to Group A. These results have lead us to believe that acute psychological stress can activate the pituitary-adrenal axis and lead to elevation of serum IL-2, IL-6 concentrations. Combined with high-intensity exercise, it can result in the increase of serum CORT, IL-1β, IL-2, IL-6 levels, and the suppression of ACTH.

Phenomena of autoimmunity are frequent among psychiatric patients, but we don't know yet if they should be considered primary and linked to the pathophisiology of the disorder, or aspecific and associated to a general immune system activation. Paraneoplastic Cerebellar Degeneration (PCD) represents a well known model of specific autoimmunity. In order to better understand the abovementioned issues, we used this condition to compare a set of immune dysfunctions found in a group of psychiatric patients. For this reason we tested sera from 48 psychiatric patients (24 schizophrenics, 17 bipolars and 7 obsessive-compulsive), 22 PCD patients and 52 healthy controls for the presence of anti-Purkinje autoantibodies and of some natural autoantibodies (ANAs, AMAs, APCAs, ASMAs). Psychopatological status of the psychiatric patients was assessed with BPRS, SANS, SAPS, HAM-D, CGI-S. In the psychiatric group anti-Purkinje autoantibodies were identified in 11/48 (22,9%) patients, while they were present in 22/22 (100%) PCD patients and in 0/52 (0%) healthy controls. Among all anti-Purkinje autoantibody positive patients (in the PCD and psychiatric samples), only those belonging to the psychiatric sample, but not those with PCD, were frequently found positive also for natural autoantibodies, that are considered good markers of aspecific immune activation. In these patients, both anti-Purkinje and natural autoantibodies were found associated with acute/positive psychopathological symptoms. These results seem to point out that some phenomena of auto-immunity described in psychiatric patients could be aspecific, unrelated to the pathophysiology of the concomitant mental disorders and could be more frequent during phases of acute/positive symptoms.

The effects of stress, which varies throughout an academic year, on proinflammatory and antiinflammatory cytokines were examined in 44 medical students. This was tested by comparing stimulated cytokines during a baseline period, stress period, and poststress vacation period. During the stress period, compared with the baseline period, levels of IL-6 were reduced, while levels of IL-10 were elevated. During the poststress vacation period, compared with the stress period, levels of IL-6 and TNF-α were increased. However, the changes in stress-related psychological and physiological variables were not significantly associated with changes in levels of proinflammatory and antiinflammatory cytokines. These results suggest that vacation is more likely to have a counterstress effect on proinflammatory cytokines than on an antiinflammatory cytokine and that a stressor may affect changes in immune function independently of self-reported stress.

Depression is accompanied by an inflammatory reaction and activation of cell mediated immunity (CMI) and stressors may induce the cytokine network in humans. The proinflammatory cytokine interleukin-18 (IL-18) is less investigated in depression but highly relevant since it is produced by activated macrophages and expressed in the brain.

The distribution of six polymorphisms in IL10, IL18 and NF was compared between patients with a single episode of depression either preceded by a stressful life event (n=182), or occurring without a prior stressful life event (n=106) and a group of healthy control individuals (n=335).

The major C allele of the IL18 rs187238 and the major G allele of rs1946518 had a significantly higher prevalence among the patients with a stressful life event prior to onset of disease than both patients without a stressful life event and compared with the healthy controls individuals. None of the examined IL10 or NF alleles were differently distributed among these groups.

Data are nominally significant and not resistant to correction for multiple testing.

The major C allele of the IL18 rs187238 and the major G allele rs1946518 have previously been associated with higher expression of IL-18 mRNA. Our data suggest that this genetic trend towards higher IL-18 production may increase the susceptibility to depression in response to stressful life events.

Stress not only activates the SAM system and the hypothalamic-pituitary-adrenal axes, but also the immune system. The aims of this study are to assess the physiological variations in saliva (cytokines, cortisol and alpha-amylase) and perceived stress in professors when they had to lecture to 200 students. A total of eight unstimulated saliva samples were collected from nine professors: four on a working day that included the lecture and four controls on a working day without a lecture. The professors also rated subjective stress on a seven-point scale 5 min before the lecture, immediately after the lecture and at the same times on the control day. The lecture elicited substantial increases in subjective stress ratings, with the values on the lecture day significantly higher than those on the control day. Lecturing resulted in significant increases in Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-2 and IL-4 concentrations, but did not affect the IL-10 values. These changes appeared to be concomitant with changes in the concentrations of the stress markers, alpha-amylase and cortisol. The mechanisms by which psychosocial stress can induce cytokine changes and modify the activity of salivary alpha-amylase are not entirely understood, and further research is thus warranted.

We investigated the effects of the neuroendocrine modulator hydrocortisone (HC) on Th2 differentiation of human naive CD4+ T cells with and without CD28 co-stimulation. Human naive CD4+ T cells were isolated and purified from umbilical cord blood mononuclear cells from full-term newborn infants. CD4+ T cells were treated with different concentrations of HC under Th0 or Th2 culture conditions. Th0 conditions included stimulation by immobilized monoclonal antibodies (mAbs) against CD3 and CD28; Th2 conditions were the same + rhIL-4. Parallel cultures excluded the CD28 mAb. Th1 (IL-2, INF-γ)- and Th2 (IL-4, IL-5)-type cytokines were quantified in culture supernatants by ELISA and within cells by flow cytometry. For both Th0 and Th2 culture conditions, HC significantly inhibited Th1 cytokines' release (IL-2 and INF-γ). For Th0 culture conditions, HC slightly increased IL-4 expression (Th2 cytokine). However, for Th2 culture conditions, HC inhibited the IL4-induced production of IL-4. Although the absolute cytokine amounts were decreased, absence of CD28 co-stimulation did not alter these 'trends'. Our findings indicate that HC can alter the Th1/Th2 balance by inhibiting the production of Th1-type cytokines. HC can also diminish the extensive Th2 differentiation induced by IL-4.

The objective of this study was to determine the longitudinal effects of a series of stressful gross anatomy tests on the immune system. Thirty-six freshman occupational therapy students completed a written stress evaluation survey, and saliva samples were obtained at baseline and prior to each of three timed-practical gross anatomy tests. Cortisol, secretory IgA (sIgA), and IL-12 concentrations were measured within the salivary samples by enzyme-linked immunosorbent assay. The total scores from the stress surveys were used as markers for environmental stress. Data were compiled for each student at baseline and prior to each examination and were compared by repeated-measures MANOVA and Pearson's correlation test. Following normalization for protein concentration and flow rate, the concentrations of IL-2, IL-6, IL-12, and sIgA progressively increased from baseline to the third test. Cortisol concentrations, following normalization for flow rate, were highest prior to the first test and became significantly reduced prior to second and third test. Prior to second and third test, salivary concentrations of IL-6, IL-2, IL-12, and sIgA were significantly correlated (P < 0.05). In contrast, prior to third test, there was a negative correlation between salivary concentrations of cortisol and IL-12 (P < 0.05). Progressive increases in salivary sIgA, IL-6, IL-2, and IL-12 concentrations from the first to the third test coincident to decreased salivary cortisol suggest that the initial examination stressors precede significant effects on the immune system. These data suggest that there may be latent effects of examination stress on the immune system and that saliva can be used to predict these effects.

This is the final article in a four part series reviewing the influence of humor and laughter on physiological and psychological well-being. This final article reviews the evidence for the effect of sense of humor, exposure to a humor stimulus and laughter on various immune system components, with a focus on the effects of laughter on natural killer cell cytotoxicity.

The stress system co-ordinates the adaptive responses of the organism to stressors of any kind. Inappropriate responsiveness may account for increased susceptibility to a variety of disorders, including asthma. Accumulated evidence from animal models suggests that exogenously applied stress enhances airway reactivity and increases allergen-induced airway inflammation. This is in agreement with the clinical observation that stressful life events increase the risk of a new asthma attack. Activation of the hypothalamic-pituitary-adrenal (HPA) axis by specific cytokines increases the release of cortisol, which in turn feeds back and suppresses the immune reaction. Data from animal models suggest that inability to increase glucocorticoid production in response to stress is associated with increased airway inflammation with mechanical dysfunction of the lungs. Recently, a growing body of evidence shows that asthmatic subjects who are not treated with inhaled corticosteroids (ICS) are likely to have an attenuated activity and/or responsiveness of their HPA axis. In line with this concept, most asthmatic children demonstrate improved HPA axis responsiveness on conventional doses of ICS, as their airway inflammation subsides. Few patients may experience further deterioration of adrenal function, a phenomenon which may be genetically determined.

The counter-stress effects of relaxation on proinflammatory and anti-inflammatory cytokines were examined. From 36 medical students, 18 were randomly assigned to the relaxation group, and 18 were randomly assigned to the non-relaxation group. Relaxation lasted for four weeks. The levels of stimulated production of IL-6, TNF-alpha, and IL-10, and blood pressure were measured during the non-examination period (baseline period) and the pre-examination period (stress period). The levels of perceived stress were assessed by the Global Assessment of Recent Stress (GARS) scale, the Stress Response Inventory (SRI) and the Symptom Checklist-90-Revised (SCL-90-R) anxiety subscale. Repeat measure ANOVA revealed that the SRI total score, scores of the SCL-90-R anxiety subscale and diastolic blood pressure were significantly higher during the stress period than during the baseline period regardless of groups. The level of IL-6 production was significantly lower but the level of IL-10 production was significantly higher during the stress period than during the baseline period. Significant reduction in the delta (stress period value minus baseline period value) in the total GARS score, systolic and diastolic blood pressure, the levels of IL-6 and TNF-alpha production but significant enhancement in the delta in the level of the IL-10 production were found in the relaxation group compared with the non-relaxation group. These results suggest that relaxation is associated with reduction in stress-induced psychological or physiological responses and proinflammatory cytokine alterations but with enhancement in stress-induced anti-inflammatory cytokine alteration. Therefore, relaxation is more likely to have counter-stress effect on proinflammatory cytokines than on anti-inflammatory cytokine.

The present study examined how cardiovascular and salivary cortisol responses varied in response to an acute challenge in medical students under exam stress versus those not under exam stress. One hundred and twenty-nine medical students were randomly assigned to undertake a CO2 inhalation test either prior to an examination period (exam group) or during a regular academic period (non-exam group). Heart rate (HR) and blood pressure (BP) were measured for 5 min before and 5 min after the task, and salivary cortisol samples were collected 1 min before and 10 and 30 min after the CO2 inhalation test. Participants also completed a questionnaire measuring self-reported perceived stress. The exam group exhibited significantly higher HR reactivity following the CO2 inhalation test and slower systolic blood pressure (SBP) recovery compared with the non-exam group. The exam group also reported higher perceived stress and higher stress scores were related to higher HR reactivity following CO2 inhalation. Female students across both groups exhibited significantly lower SBP reactivity compared with male students. Salivary cortisol levels were consistently lower in the exam group. These findings indicate that ongoing natural stress alters cortisol secretion and cardiovascular responses in the face of an acute stress challenge.

Asthma, a chronic inflammatory disease of the airways, is greatly influenced by psychosocial factors and stress. This review looks at clinical studies that have shown strong associations between psychological stress and asthma to identify potential mechanisms for these interactions. Furthermore, we review animal studies involving stress and airway inflammation or airway hyperresponsiveness, and discuss possible mechanisms of stress action in asthma. In conclusion, further research, both in humans and in animal models, into the mechanisms of stress-induced changes in asthma exacerbation are required to help better understand the complex makeup of asthma and assist in the development of therapies directed at the interplay between the nervous system and airway inflammation.

The purpose of this study was to examine the direct and stress-buffering effect of optimism and satisfaction with social support on immune responses in women with breast cancer. Participants were 54 post-operative (M = 19 days) breast cancer patients who completed questionnaires on stress, optimism, and satisfaction with social support and provided blood to measure natural killer cell activity (NKCA) and interferon-gamma (IFN-gamma) from whole blood. Higher levels of stress were associated with decrements in NKCA and IFN-gamma. Optimism moderated the relationship of stress on NKCA but was not related to IFN-gamma. Satisfaction with social support was unrelated to immune responses. Results suggest that interventions aimed at reducing stress and enhancing optimism in women with breast cancer might promote optimal immune response.

Both aging processes and psychological stress affect the immune system: Each can dysregulate immune function with a potentially substantial impact on physical health. Worse, the effects of stress and age are interactive. Psychological stress can both mimic and exacerbate the effects of aging, with older adults often showing greater immunological impairment to stress than younger adults. In addition, stressful experiences very early in life can alter the responsiveness of the nervous system and immune system. We review the unique impact of aging and stress on immune function, followed by evidence of interactions between age and stress. Further, we suggest that prenatal or early life stress may increase the likelihood of maladaptive immune responses to stress in late life. An understanding of the interactive effects of stress and age is critical to efforts to determine underlying mechanisms, clarify the directionality of effects, and develop effective interventions in early and late life.

The combined effects of stress and antigen on interleukin-1beta (Il-1beta) have rarely been studied locally at the site of microbial challenges in vivo, so far. We here propose a model for the analysis of such effects in humans and examine its utility for acute stress trials. Twelve students (6 male, 6 female) refrained from oral hygiene in two antagonistic quadrants for 28 days to allow for increasing bacterial stimulation of the respective gingival sites due to accumulation of microbial plaque. Good oral hygiene was maintained in the remaining quadrants. At day 27 and 28 students were subjected to either stress ('public speech') or a control condition, in a cross-over design. Samples of gingival crevicular fluid (GCF) which emerges between the tooth surface and the gingival epithelium as transudate of healthy and exudate of inflamed gingival tissue, were taken immediately after stress and 60 min later for Il-1beta analysis. Salivary cortisol was assessed to prove the validity of the stress protocol. Stress induced a profound increase of salivary cortisol (p=.001). Repeated measures (stress x time x hygiene) ANOVA with gender as between factor revealed significant stress (p=.014) and hygiene (p=.038) effects on GCF-Il-1beta concentrations and tentatively significant hygiene x time (p = .097) and stress x time x hygiene x gender (p=.107) interactions. Stress induced an increase of Il-1beta as did plaque accumulation. The merits of the proposed model are discussed. It is concluded that it is well suited for the assessment of the effects of stress on inflammatory responses in vivo in humans.

In recent years photopheresis has been claimed to be an effective form of immunomodulation. It has also been shown to have an effect on the disease process at the onset of type 1 diabetes. In a double-blind, placebo-controlled randomized study, we analyzed if the effect of photopheresis in children with newly diagnosed diabetes is related to changes in the balance of lymhocyte populations. We also analyzed if lymphocyte subsets were related to recent infection, mild or aggressive disease manifestations, heredity, or gender. Nineteen children received active treatment with photopheresis, while 21 children received sham pheresis (placebo group). No influence of a history of previous infection, heredity, or certain clinical parameters on lymphocyte subsets was found. At the onset of type 1 diabetes, girls showed a higher proportion and a larger number of T cells (CD3+) and T-helper cells (CD4+) and a higher proportion of naïve CD4+ CD45RA+ cells. In the placebo group, an increase in the number of subsets with the activated phenotype in both the CD4(CD29+) and the CD8 (CD11a+) compartments was noted during the course of the study. These changes did not occur in the photopheresis group. No relation between lymphocyte subsets and clinical outcome was found 1 year after the treatment with photopheresis. In conclusion, we found no major effect of photopheresis on lymphocyte populations in a group of children with newly diagnosed type 1 diabetes. However, in the placebo group the proportions of activated CD4 and CD8 cells increased over time. Since these changes did not occur in the actively treated group, our findings suggest that photopheresis may have some suppressive effects.

To review the evidence supporting a role for psychological interventions in the treatment of asthma, with particular emphasis on underlying psychobiological mechanisms.

Independent literature searches on MEDLINE, PREMEDLINE, Cochrane Library, and PSYCHINFO from their respective inception to 2003 were performed. Separate searches were performed for psychological stress and asthma, psychoneuroimmunology and asthma, stress management, relaxation, asthma, complementary and alternative medicine and asthma, and immune function and psychological intervention. The search was not limited based on language of publication.

Supportive evidence from overlapping research was included based on the expert opinion of the author and through discussions with consultants in the field.

This review first discusses human and animal studies focused on psychological stress and the effects of stress on the neuroendocrine and immune system, emphasizing the implication of these effects on asthma. Second, studies that evaluated the influence of stress reduction modalities on neuroendocrine and immune function were examined. Existing evidence from human clinical studies that explored the role of psychological interventions for asthma is reexamined in this context.

A growing appreciation of the interactions among behavioral, neural, endocrine, and immune processes suggests possible mechanisms through which psychological interventions for asthma may be operating. This review provides a framework in which we can begin to see links among these systems that might provide new insights to guide future explorations.

The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of specific immunity. Brief naturalistic stressors (such as exams) tended to suppress cellular immunity while preserving humoral immunity. Chronic stressors were associated with suppression of both cellular and humoral measures. Effects of event sequences varied according to the kind of event (trauma vs. loss). Subjective reports of stress generally did not associate with immune change. In some cases, physical vulnerability as a function of age or disease also increased vulnerability to immune change during stressors.

A suppressed immune response has been documented in students under examination stress.

The current study aimed to evaluate the effect of milk fermented with yogurt cultures plus Lactobacillus casei DN-114001 (Actimel) on the immune system of subjects under academic examination stress.

University students were allocated to one of two groups, receiving during 6 weeks (3 weeks prior to, as well as the 3-week duration of the examination period) either: a) a glass of semi-skimmed milk each day (control group, n=63) or b) two 100mL portions per day of fermented milk (treatment group, n=73). Anxiety and immunological measurements were monitored at baseline (Phase 0) and study end (Phase 1).

The results were expressed as the differences between the data obtained from Phase 0 and Phase 1. This was calculated by subtracting Phase 1 results from the Phase 0 and it is denominated "Treatment effect". Mean (+/- SE) anxiety increased significantly (P<0.05) over the 6-week study in all students, from 40.74+/-2.50 to 61.19+/-2.64 (in percentiles). There was no significant treatment effect since this increase was similar in the control and the treatment groups (21.65+/-5.09 vs 19.14+/-3.67, respectively). However, there was a significant treatment effect (P<0.05) on the mean change in absolute number of lymphocytes during the 6-week study, which decreased in the control group (-0.04+/-0.12 cells x 10(3)/mm(3)) and increased in the treatment group (0.37+/-0.11 cells x 10(3)/mm(3)). There was also a significant treatment effect (P<0.05) on the change in absolute numbers of CD56 cells during the 6-week study. Mean absolute CD56 cells significantly decreased (P<0.05) in the control group (-51.97+/-21.33 cells/mm(3)),while remaining similar in the treatment group (17.29+/-17.27 cells/mm(3)). During the study, mean serum cortisol increased 4.30+/-0.98 microg/dL in the control group, and 1.75+/-1.05 microg/dL in the treatment group and no significant differences were found between both values (P=0.062).

Milk fermented with yogurt cultures plus Lactobacillus casei DN-114001 was able to modulate the number of lymphocytes and CD56 cells in subjects under academic examination stress.

The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of specific immunity. Brief naturalistic stressors (such as exams) tended to suppress cellular immunity while preserving humoral immunity. Chronic stressors were associated with suppression of both cellular and humoral measures. Effects of event sequences varied according to the kind of event (trauma vs. loss). Subjective reports of stress generally did not associate with immune change. In some cases, physical vulnerability as a function of age or disease also increased vulnerability to immune change during stressors.

The immune system is the body's major defense mechanism against disease. However, psychosocial factors, such as stress, can modulate various immune responses. Although they have been examined in adult humans and other animals, sex differences in immune responses and immune reactivity to stress have rarely been examined in adolescents, particularly comparing healthy and asthmatic adolescents. In 151 healthy and asthmatic high school adolescents (91 females and 60 males), natural killer cell (NK) cytotoxicity, polymorphonuclear leukocyte (PMN) superoxide release, lymphocyte proliferative responses, and CD subsets were measured twice: once during mid-semester and again during final examinations. There was little difference in these measures between healthy and asthmatic adolescents. Similarly, only sex difference was noted in NK cytotoxicity at a 25:1 effector-to-target cell ratio, with males showing significantly higher responses than females. For PMN superoxide release, females significantly increased their responses during final examinations, whereas males demonstrated no changes. For lymphocyte proliferative responses, both females and males increased their responses during final examinations, but the magnitude of increase was much greater in males. Furthermore, racial comparisons indicated that African American adolescents (n = 16), as compared with Caucasian adolescents (n = 128), had significantly higher responses in PMN superoxide release to N-Formyl-Met-Leu-Phe (FMLP) activation during mid-semester and lymphocyte proliferative responses at both time points. Nevertheless, the overall findings indicate limited differences in immune responses and immune reactivity to stress in adolescents between males and females, healthy and asthmatic adolescents, and Caucasians and African Americans. However, further investigations with larger samples are warranted.

Cigarette smokers frequently fail multiple attempts to quit smoking, often because of the unpleasant symptoms that accompany quitting. Similar unpleasant symptoms accompany inflammatory responses during infection and autoimmune disease. The hypothesis that smoking abstinence induces inflammation was tested. Eighteen smokers (n = 18) were evaluated while smoking freely and after 24 h of nicotine abstinence. Immune, cardiovascular and psychological measures were collected. Hunger, nervousness, anxiety, restlessness and irritability increased during abstinence (p < 0.05); systolic blood pressure and heart rate levels decreased (p < 0.05). Analysis demonstrated a split among smokers in response to abstinence compared with smoking freely; some smokers (n = 10) displayed increased C-reactive protein (CRP, p < 0.05) whereas others (n = 8) responded with decreased CRP (p < 0.05). An increase in symptoms of depressed mood and a fall in heart rate occurred only in those who displayed increased CRP with nicotine abstinence ( p < 0.05), while systolic blood pressure fell only in those whose CRP levels decreased with abstinence ( p < 0.05). Interleukin-1 and interleukin-6 did not change with abstinence. The results suggest that 24 h nicotine abstinence does not stimulate inflammation among all smokers, but that a sub-group of smokers do demonstrate an inflammatory response with significant negative psychological and physiological symptomatology.

This study investigated the relationships between a mindfulness-based stress reduction meditation program for early stage breast and prostate cancer patients and quality of life, mood states, stress symptoms, lymphocyte counts, and cytokine production.

Forty-nine patients with breast cancer and 10 with prostate cancer participated in an 8-week MBSR program that incorporated relaxation, meditation, gentle yoga, and daily home practice. Demographic and health behavior variables, quality of life (EORTC QLQ C-30), mood (POMS), stress (SOSI), and counts of NK, NKT, B, T total, T helper, and T cytotoxic cells, as well as NK and T cell production of TNF, IFN-gamma, IL-4, and IL-10 were assessed pre- and postintervention.

Fifty-nine and 42 patients were assessed pre- and postintervention, respectively. Significant improvements were seen in overall quality of life, symptoms of stress, and sleep quality. Although there were no significant changes in the overall number of lymphocytes or cell subsets, T cell production of IL-4 increased and IFN-gamma decreased, whereas NK cell production of IL-10 decreased. These results are consistent with a shift in immune profile from one associated with depressive symptoms to a more normal profile.

MBSR participation was associated with enhanced quality of life and decreased stress symptoms in breast and prostate cancer patients. This study is also the first to show changes in cancer-related cytokine production associated with program participation.

The study aimed to analyse (a) whether the effects of psychological stress and of experimental gingivitis on interleukin-1beta (Il-1beta) described before are compensated by concomitant increases in Il-1 receptor antagonist (Il-1ra), and (b) whether there do exist any gender differences in the Il-1 responses to experimental gingivitis and to psychological stress.

Thirteen medical students participating in a major academic exam (seven males, six females) and 14 medical students without academic stress (eight males, six females) refrained from oral hygiene in two antagonistic quadrants for 28 days (plaque) while they maintained oral hygiene in the remaining quadrants (hygiene). Weekly crevicular fluid samples of plaque and hygiene sites were assayed for Il-1beta and Il-1ra.

Neither stress nor experimental gingivitis exerted significant effects on Il-1ra. In controls, we observed significant gender and gender x time effects on Il-1beta; comparing stress groups, gender x time and stress x gender x time interactions became significant. Women show a reduced Il-1beta response to plaque at rest and an increased response under stress. Similar results were found with respect to bleeding on probing.

Gender must be controlled in studies on periodontal responses to pathogens. Stress plays a role in these responses.

Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor kappaB (NF-kappaB). Therefore, NF-kappaB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-kappaB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-kappaB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-kappaB-controlled beta-globin transgene were stressed by immobilization. Immobilization resulted in increased beta-globin expression, which could be reduced in the presence of the alpha1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-kappaB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-kappaB and NF-kappaB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by alpha(1)- and beta-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-kappaB in vitro and in vivo. Activation of NF-kappaB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.

To determine the effect of hypnotic-guided imagery on immune function and psychological parameters in patients being treated for Stage I or II breast cancer.

To determine the effects of hypnotic-guided imagery on immune function and psychological parameters, the following study was undertaken. Psychological profiles, natural killer (NK) cell number and activity were measured at baseline, after the 8-week imagery training program and at the 3-month follow-up.

There were significant increases in improvement in depression (P<.04) and increase in absolute number of NK cells, but these were not maintained at the 3-month follow-up. Hypnotic-guided imagery did cause some transient changes in psychological well-being and immune parameters. However, these changes were not retained after the treatment ended.

Many studies during the last 15 years have demonstrated interactions between the central nervous and the immune systems. While a negative effect of stress on immune responses has been demonstrated, there have also been published reports that psychological treatments can positively alter the immune system. However, given the complexities of immune system kinetics, the transient nature of any psychological effect and the insensitivity of immune assays, our study indicates that there is a role for hypnotic-guided imagery as an adjuvant therapy.

In this report, the authors propose that underlying sex differences in the biobehavioral response to stress may contribute to the variance in prevalence of some psychiatric disorders based on sex. The authors begin with a discussion of stress physiology and review a new theory on sex differences in stress responses (ie, the "tend-and-befriend" response), which may provide a recent framework for considering sex differences in the manifestation of some psychiatric illnesses. The authors then move to a discussion of major depression and attention deficit hyperactivity disorder as examples of how sex differences in stress responses may influence the behavioral symptoms of psychiatric disorders that are more often diagnosed in one sex compared with another. The authors conclude with a brief discussion of the implications of this new perspective on treatment approaches and encourage further inquiry into the importance of sex-based differences in the behavioral manifestation of some psychiatric illnesses.

The aim of the present study was to measure interleukin-1beta, interleukin-6 and cortisol levels in the peripheral blood of periodontally diseased patients in order to record any interactions with psychosocial stress.

The test group comprised 16 patients with untreated and 14 with treated aggressive generalized periodontitis (AGP), five patients with untreated aggressive localized periodontitis (ALP) and five with chronic generalized periodontitis (CGP). The control group comprised 40 periodontally healthy probands. Blood was taken from the cephalic vein of all patients and controls at the same time (8 a.m.) each day. IL-1beta, IL-6 and cortisol levels were then measured with a sensitive ELISA, the 'Quantikine HS Immunoassay Kit' (Biermann Diagnostica, Bad Nauheim, FRG). The clinical examination covered probing depth, gingival recession, gingival index, plaque index and clinical attachment level. A questionnaire was used to ask the patients and controls about their attitude to life and the stress induced by their jobs and their families. Previous and current levels of tobacco consumption were also recorded. Statistical evaluation was based on the Mann-Whitney U-Wilcoxon test for comparison of blood serum values and clinical parameters between patients and controls, and the Kruskal-Wallis test for intergroup comparison. All data were correlated by means of Spearman's rank correlation coefficient, and significance levels relating to stress and smoking were determined with the chi-square test.

With respect to cortisol, the results showed no significant differences either between the patient groups or in comparison with the controls. IL-1beta was detected only in the AGP patients and their controls, but with no significant differences. IL-6 was detected in virtually all patients and controls, but with no significant differences. Only in the untreated AGP patients was IL-6 significantly elevated (P < 0.05) and a slight correlation with attachment loss recorded. In all AGP patients a slight correlation between IL-1beta and IL-6 was recorded. Evaluation of the questionnaire revealed a higher proportion of untreated AGP patients than of controls with a pessimistic attitude to life. In all AGP patients, family-induced stress and smoking were found to correlate with attachment loss. In the untreated AGP patients, smoking correlated with IL-1beta protein content, and in the controls there was a moderate correlation between smoking and IL-6 levels.

The present study found no correlation between the immunological mediators (IL-1beta, IL-6), glucocorticoids (cortisol) and the registered stress values. However, the patients with untreated AGP showed signs of a pessimistic attitude to life, and an elevated IL-6 level was recorded in the peripheral blood. As a restrictive factor it should be borne in mind that the number of patients investigated was too small for adequate conclusions to be drawn.

This review focuses on human psychoneuroimmunology studies published in the past decade. Issues discussed include the routes through which psychological factors influence immune function, how a stressor's duration may influence the changes observed, individual difference variables, the ability of interventions to modulate immune function, and the health consequences of psychosocially mediated immune dysregulation. The importance of negative affect and supportive personal relationships are highlighted. Recent data suggest that immune dysregulation may be one core mechanism for a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, Type 2 diabetes, certain cancers, and frailty and functional decline; production of proinflammatory cytokines that influence these and other conditions can be stimulated directly by negative emotions and indirectly by prolonged infection.

Psychological stress can lead to asthma exacerbations in some patients. It is our hypothesis that the stress effect can occur through an enhancement of allergic inflammatory response. To investigate this possibility, airway antigen challenge was evaluated in 20 college students with mild asthma during both a low-stress phase (midsemester or two weeks postfinal examination) and a stress phase (final examination week). Subjects completed questionnaires to assess psychological state and underwent inhaled antigen challenge. Sputum samples were collected before challenge, and six and 24 hours and seven days postchallenge. Leukocytes were counted and eosinophil-derived neurotoxin (EDN) was measured in sputum supernates. Sputum cells were cultured and stimulated ex vivo with phytohemagglutinin (10 microg/ml), and culture supernates were assayed for interleukin-5 (IL-5) and interferon-gamma by enzyme-linked immunosorbent assay. Sputum eosinophils and EDN levels significantly increased at six and 24 hours postchallenge and were enhanced during the stress phase (p < 0.01). IL-5 generation by sputum cells was also increased at 24 hours during stress and correlated with airway eosinophils (r(s) = 0.65, p < 0.05). Students' anxiety and depression scores were significantly higher during the examination period. Our findings suggest that stress associated with final examinations can act as a cofactor to increase eosinophilic airway inflammation to antigen challenge and thus may enhance asthma severity.

All cultures have metaphors for mental illness that define how it is diagnosed, treated, and experienced by the patient. Cultural metaphors that define mental illness have been traced predominantly to biomedical and systems models. However, the research on factors such as progression of illness, survival rates, adherence to medical regimens, level of disability, and experience of pain in chronic and acute life-threatening illnesses suggests another metaphor. This article not only explores how a constructivist metaphor makes sense of this research, but also suggests an approach to consider in helping patients and their families deal with the difficult life circumstances that illness imposes. Implications for nurses are outlined.