Moisés Evandro Bauer

Stress, glucocorticoids and ageing of the immune system

Ageing has been associated with immunological changes (immunosenescence) that resemble those observed following chronic stress or glucocorticoid (GC) treatment. These changes include thymic involution, lower number of naïve T cells, reduced cell-mediated immunity, and poor vaccination response to new antigens. It follows that immunosenescence could be associated with changes of peripheral GC levels. Indeed, when compared with young subjects, healthy elders are more stressed and show activation of the hypothalamus–pituitary–adrenal (HPA) axis. However, both beneficial and undesirable effects of GCs ultimately depend on the target tissue sensitivity to these steroids. Recent data indicate that peripheral lymphocytes from elders respond poorly to GC treatment in vitro. The present review summarizes recent findings which suggest that immunosenescence may be closely related to both psychological distress and stress hormones. Furthermore, chronically stressed elderly subjects may be particularly at risk of stress-related pathology because of further alterations in GC-immune signalling. Finally, the neuroendocrine hypothesis of immunosenescence is finally reconsidered in which the age-related increase in the cortisol/DHEA ratio is major determinant of immunological changes observed during ageing.

The Role of Stress Factors during Aging of the Immune System

This manuscript reviews current evidence suggesting that aging of the immune system (immunosenescence) may be closely related to chronic stress and stress factors. Healthy aging has been associated with emotional distress in parallel to increased cortisol to dehydroepiandrosterone (DHEA) ratio. The impaired DHEA secretion together with the increase of cortisol results in an enhanced exposure of lymphoid cells to deleterious glucocorticoid actions. The lack of appropriated growth hormone signaling during immunosenescence is also discussed. It follows that altered neuroendocrine functions could be underlying several immunosenescence features. Indeed, changes in both innate and adaptive immune responses during aging are also similarly reported during chronic glucocorticoid exposure. In addition, chronically stressed elderly subjects may be particularly at risk of stress‐related pathology because of further alterations in both neuroendocrine and immune systems. The accelerated senescent features induced by chronic stress include higher oxidative stress, reduced telomere length, chronic glucocorticoid exposure, thymic involution, changes in cellular trafficking, reduced cell‐mediated immunity, steroid resistance, and chronic low‐grade inflammation. These senescent features are related to increased morbidity and mortality among chronically stressed elderly people. Overall, these data suggest that chronic stress leads to premature aging of key allostatic systems involved in the adaptation of the organisms to environmental changes. Stress management and psychosocial support may thus promote a better quality of life for elderly people and at the same time reduce hospitalization costs.

Restraint stress is associated with changes in glucocorticoid immunoregulation

Psychological stress has been associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired cell-mediated immune (CMI) responses. There is also evidence suggesting that intermittent chronic stress differentially alters CMI across different immune compartments, but the mechanisms underlying this phenomenon have not been explored in detail. In the present study, we investigated (i) acute and chronic restraint stress effects in Sprague-Dawley rats on both peripheral blood lymphocyte (PBL) and splenocyte mitogen-induced proliferation and (ii) also determined whether differential stress effects within these immune compartments might reflect alterations in lymphocyte sensitivity to glucocorticoids. It was found that while acute stress exposure significantly raised plasma corticosterone levels (1048% vs. controls, P<.001), this response was attenuated in the animals previously exposed to chronic intermittent stress (-79.66% vs. acute; P<.001). Acute stress increased phytohemagglutinin (PHA)-induced lymphocyte proliferation in the spleen (69.04%, P=.01) and suppressed PBL proliferation (-45.52%, P<.001). Neither of these changes were observed following chronic stress. We also demonstrated that reexposure to the stressor rapidly increased splenocyte sensitivity to in vitro dexamethasone (P<.05) and corticosterone (P<.05) in chronically stressed rats. Our data (1) confirm that acute stress is associated with compartment-specific changes in CMI function, (2) indicate that chronic stress is associated with habituated endocrine and immune responses and (3) that stressor exposure rapidly alters splenocyte sensitivity to glucocorticoids and we suggest that the latter may contribute to differential stress effects across immune compartments.

Low Plasma Brain-Derived Neurotrophic Factor and Childhood Physical Neglect Are Associated with Verbal Memory Impairment in Major Depression : A Preliminary Report

BACKGROUND Early life stress has been suggested to mediate vulnerability to affective disorders. Animal models of repeated maternal separation have shown reduced brain-derived neurotrophic factor (BDNF) levels in specific brain regions implicated with hypothalamic-pituitary-adrenal axis and memory formation. In addition, BDNF levels are also reduced in major depressive disorder (MDD) and bipolar disorder. The aim of this study was to investigate whether childhood physical neglect (CPN) and plasma BDNF levels would impact on memory performance in adult female subjects with recurrent major depression. METHODS Recurrent female MDD outpatients with CPN (MDD + CPN, n = 17) and without CPN (MDD, n = 17) and healthy control subjects (n = 15) were assessed for plasma BDNF content and verbal memory performance. Memory was assessed through the logical memory component of the Weschler Memory Scale-Revised for immediate and delayed recall. Brain-derived neurotrophic factor was assessed with enzyme-linked immunosorbent assays (ELISAs). RESULTS Major depressive disorder patients showed lower plasma BDNF concentrations than healthy control subjects (p < .001). Major depressive disorder + CPN had even lower BDNF levels compared with control subjects and MDD (p < .05). Brain-derived neurotrophic factor levels were negatively related to psychological morbidity and positively correlated to memory performance. Regression models showed that severity of self-reported CPN and low plasma BDNF predicted impairment on immediate verbal recall. Delayed recall impairment was predicted by severity of CPN and depression and memory retention by posttraumatic stress disorder (PTSD) severity symptoms. CONCLUSIONS Our data suggest that CPN and plasma BDNF are important factors associated with depression and verbal memory performance, particularly with encoding processes.

Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder

Bipolar disorder (BD) has been associated with a proinflammatory state in which TNF-α seems to play a relevant role. The aim of the present study was to evaluate the plasma levels of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in BD patients in mania and euthymia in comparison with control subjects. We evaluated 53 BD patients (34 in mania and 19 in euthymia) and 38 healthy subjects. All subjects were assessed by the Mini-International Neuropsychiatry Interview (MINI-Plus). Patients were also evaluated by the Young Mania Rating Scale (YMRS) and by Hamilton Depression Rating Scale (HDRS). Plasma TNF-α and its soluble receptors were measured by ELISA. The plasma TNF-α and sTNFR2 levels did not differ between groups, but higher sTNFR1 levels were found in BD patients. Of note, BD patients in mania had higher sTNFR1 levels than BD patients in euthymia and controls. The sTNFR1 and sTNFR2 levels correlated with BD duration, and sTNFR2 levels correlated with age of patients. Our data indicate a proinflammatory status in BD patients during mania and further suggest that inflammatory mechanisms may be involved with the physiopathology of BD.

Increased soluble tumor necrosis factor-alpha receptors in patients with major depressive disorder.

Aim:  Several lines of evidence suggest that major depressive disorder is associated with an inflammatory status. Tumor necrosis factor‐α has been investigated as a potential molecular target in mood disorders. Tumor necrosis factor‐α exerts its activity through binding to specific cell membrane receptors named as TNFR1 and TNFR2. The aim of the present study was to investigate soluble plasma TNFR1 (sTNFR1) and TNFR2 levels (sTNFR2) in major depressive disorder patients.

Impact of psychological and endocrine factors on cytokine production of healthy elderly people

Human ageing has been associated with immunological changes including blunted T-cell responses and increased production of pro-inflammatory cytokines. Here, we investigated the role of psychological and endocrine factors in the production of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin (IL)-6) as well as soluble IL-2Ralpha, associated with T-cell activation. Forty-six elderly subjects (60-91 yrs) and 33 young adults (20-40 yrs) were recruited accordingly the SENIEUR protocol. The emotional status was measured by structured clinical interviews. Salivary cortisol levels (9, 12 and 22 h) and serum dehydroepiandrosterone (DHEA) were assessed by radioimmunoassays. The elderly were more stressed, depressed and anxious than the young subjects. Cortisol levels were increased whereas DHEA levels were significantly reduced in the elderly. Both groups showed equivalent production of pro-inflammatory cytokines as well as soluble IL-2Ralpha. Psychological scores were positively correlated to evening cortisol levels and negatively correlated to morning DHEA levels. No relationships were noted between psychological factors and cytokines studied. However, evening cortisol levels were found positively correlated to TNF-alpha and sIL-2Ralpha levels. These data indicate that healthy ageing is associated with significant distress and activation of the hypothalamic-pituitary-adrenal axis. Our data also suggest that there are complex psychoneuroendocrine relationships involved with cytokine production during ageing.

Neuroendocrine and Immunological Correlates of Chronic Stress in ‘Strictly Healthy’ Populations

Background: Chronic stress has been associated with detrimental or maladaptive neuroendocrine and immunological changes. Objectives: We assessed the neuroendocrine and immunological correlates of a realistic chronic stress experienced by strictly healthy caregivers of Alzheimer’s disease patients and age-matched controls. Methods: We screened 330 caregivers and 206 non-caregivers according to the ‘strictly healthy’ conditions established by the SENIEUR protocol. Forty-one strictly healthy caregivers (60.56 ± 16.56 years) and 33 non-stressed controls (60.27 ± 14.11 years) were selected for this study. Salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed at multiple points by radioimmunoassay. Peripheral T cell proliferation and cellular sensitivity to glucocorticoids (corticosterone and dexamethasone, DEX) were evaluated by colorimetric assays. We also examined the hypothalamic-pituitary-adrenal (HPA) axis response to the administration of a low-dose DEX in vivo. Results: The caregivers were significantly more stressed, anxious and depressed than non-caregivers (all p < 0.0001), in contrast to similar cortisol levels. Caregivers had reduced DHEAS levels (–32%, p < 0.0001), an increased cortisol/DHEAS ratio (39.7%, p < 0.0001) and impaired HPA axis response to DEX intake. Caregivers had a higher T cell proliferation (p < 0.0001) and increased sensitivity to glucocorticoids in vitro (p < 0.01) as compared to non-stressed controls. Conclusions: Our results suggest that the maintenance of health in chronically stressed populations may be associated with both protective and detrimental neuroendocrine and immunological changes.

Increased Serum Levels of Inflammatory Markers in Chronic Institutionalized Patients with Schizophrenia

Activation of the cytokine systems may be involved in the neuropathological changes occurring in the central nervous systems of schizophrenic patients. However, associations between the levels of cytokines and the severity of symptoms have not been completely established. Objective: It was the aim of this study to evaluate serum levels of tumor necrosis factor (TNF)-α and their soluble receptors (sTNFR) in schizophrenic patients and healthy controls. Methods: Forty male institutionalized schizophrenic patients (mean age ± SD, 52.3 ± 9.9 years) and 20 asymptomatic matched controls were recruited. The severity of symptoms was assessed using the Brief Psychiatric Rating Scale, the Positive and Negative Syndrome Scale and the Abnormal Involuntary Movement Scale. Serum levels of cytokines were measured by ELISAs. Results: Serum levels of sTNFR1 and sTNFR2 were increased in schizophrenic patients when compared with controls (all p < 0.05), but there was no difference in TNF-α levels. There was no correlation between the length of disease/hospitalization or the severity of symptoms and the serum levels of these molecules. Conclusion: Inflammatory markers are increased in schizophrenia but they do not correlate with symptom severity.

Chronic stress and immunosenescence: a review.

This paper reviews recent work suggesting that human immunosenescence may be closely related to both chronic stress and stress hormones. The age-related immunological changes are also similarly found during chronic stress or glucocorticoid exposure. These data further suggest that endogenous glucocorticoids could be associated with immunosenescence. When compared with young subjects, healthy elders are emotionally distressed in parallel to increased cortisol/dehydroepiandrosterone ratio. Furthermore, chronically stressed elderly subjects may be particularly at risk of stress-related pathology because of further alterations in glucocorticoid-immune signaling. Age-related increase in cortisol/dehydroepiandrosterone ratio could be understood as a major determinant of immunological changes observed during aging. Strictly healthy elders are somewhat protected from chronic stress exposure and show normal cortisol levels and increased T cell function. This information adds a new key dimension to the biology of aging and stress.