Reduced natural killer cell activity in patients with dementia of the Alzheimer type

We examined the natural killer (NK) cell activity in 50 patients with dementia of the Alzheimer type (DAT) and 37 age-matched normal controls. The NK cell activity in DAT was significantly lower than in the normal controls. The NK cell activity induced by either interferon-alpha (IFN-alpha) or interleukin-2 (IL-2) in DAT was also significantly lower than in the normal controls. There were no significant differences in the level of serum IL-2 and IFN-alpha between the two groups. As regards NK cell subsets, two-color flow cytometric analysis showed no significant differences between the percentages of Leu-11+ Leu-7- cells, Leu-11+ Leu-7+ cells and Leu-11- Leu-7+ cells in the two groups. Our results suggest that NK cells in DAT may have functional abnormalities and may provide important clues to fundamental cellular and molecular aberrations in DAT.     

Depression, natural killer cell activity, and cortisol secretion

Natural killer (NK) cell activity was evaluated in 34 ambulatory patients with Major Depressive Disorder (MDD) and 21 healthy controls. No mean differences between the groups were found. However, female depressives (n = 19) exhibited higher NK activity than female controls (n = 14). The relationship between cortisol secretion and NK activity was examined using an integrated cortisol value derived from multiple blood samples taken between 1:00 and 4:00 PM. This comprehensive assessment of cortisol secretion circumvents spurious "single stick" cortisol values and provides a more accurate determination of hypercortisolemia than the dexamethasone suppression test. NK activity in depressives with cortisol hypersecretion (greater than 11 micrograms/dl) (n = 7) was no different than NK activity in depressives and controls with normal cortisol secretion. Furthermore, there was no correlation between cortisol secretion and NK activity in any of the groups. These results indicate that decreased NK activity is not a consistent finding in MDD and cannot be predicted by the presence of hypercortisolemia in these patients.     

Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity

The importance of environment in the regulation of brain, behaviour and physiology has long been recognized in biological, social and medical sciences. Animals maintained under enriched conditions have clearly been shown to have better learning abilities than those maintained under standard conditions. However, the effects of environmental enrichment (EE) on immunity and emotionality have been less documented and remain questionable. Therefore, we investigated the effect of EE on natural killer (NK) cell activity, psychological stress responses and behavioural parameters. Male C3H mice were housed either in enriched or standard conditions for 6 weeks. Behaviour was then examined by the grip-strength test, staircase and elevated plus maze, and corticosterone levels and NK cell activity were measured. Furthermore, animals exposed to the stress paradigm, achieved by electric shock with reminders, were tested for freezing time in each reminder. Corticosterone levels were also measured. The EE mice showed decreased anxiety-like behaviour and higher activity compared to standard mice, as revealed by a greater percentage of time spent in the open arms of the elevated plus maze, and a higher rate of climbing the staircase. A shorter freezing time in the stress paradigm and no corticosterone level reactivity were measured in EE mice. In addition, NK cell activity in spleens of EE mice was higher than that demonstrated in those of standard mice. Thus, EE has a beneficial effect on anxiety-like behaviour, stress response and NK cell activity. The effect on NK cell activity is promising, due to the role of NK cells in host resistance.     

Emotional stability, anxiety, and natural killer activity under examination stress.

This study was performed to evaluate the relation between a stable personality trait, a mood state and immune response to an examination stress. A self-reported measure of emotional stability (BFQ-ES scale) was obtained in a sample (n = 39) randomly selected from 277 cadets; this personality trait was also investigated by completing a neuroticism scale (Eysenck personality inventory) and a trait-anxiety scale (STAI). Natural killer (NK) cell activity was measured at baseline, long before the examination time and the examination day. The state-anxiety scale evaluated the response to the stressful stimulus. Taking subjects all together, the academic task did not result in significant modification over baseline in NK cell activity. Subjects were then divided into three groups based on emotional stability and state-anxiety scores: high emotional stability/low anxiety, medium, and low emotional stability/high anxiety. Examination stress induced significant increases in NK cell activity in the high emotional stability/low anxiety group, no effect in the medium group, and significant decreases in the low emotional stability/high anxiety group. The repeated-measure ANOVA revealed a significant interaction of group x period (baseline vs. examination) for both lytic units and percent cytolysis. The results did not change after introducing coffee and smoking habits as covariates. Our findings suggest that the state-anxiety acts in concert with a stable personality trait to modulate NK response in healthy subjects exposed to a psychological naturalistic stress. The relation between anxiety and poor immune control has been already described, whereas the ability of emotional stability to associate with an immunoenhancement has not yet reported. The peculiarity of our population, a very homogeneous and healthy group for life style and habits, can have highlighted the role of emotional stability, and may account for the difference with other studies.     

Impaired natural killer cell activity during bereavement

Natural killer (NK) cell activity, a component of the immune surveillance system, was compared in women whose husbands had recently died with that found in age-matched women who had not experienced recent adverse life events. Bereaved women had significantly lower NK activity than women whose husbands were healthy. In a second study, depressive symptoms and NK activity were measured longitudinally in women before and after the death of their husbands. Our results suggest that depressive symptoms, not merely the death of the spouse, are related to a reduction in NK activity during bereavement.     

Modulation of human natural killer cell activity by exposure to uncontrollable stress.

Changes in natural killer cell (NK) activity and proportions of circulating T and NK lymphocyte subsets were assessed in adult males immediately after exposure to controllable or uncontrollable stress (noise) as well as 24 and 72 h later, in order to track the time course of the effects of stress. The role of control-relevant personality variables as moderators of the stress-immunosuppression relationship was considered. Subjects who perceived they had control over the noise as well as no-noise "control" subjects showed no reduction in NK activity. By contrast, subjects who perceived that they had no control over the stressor showed reduced NK activity immediately after the conclusion of the first 20-min stress session, and the reduced NK activity was found as long as 72 h later. Optimism and one's desire to be in control enhanced the negative impact of uncontrollable noise on NK activity. No differences between conditions were found on number of NK cells or a variety of T cell subsets. The results suggest the importance of perceived control in moderating the short- and long-term effects of stress on NK activity.     

Hypothalamic-pituitary-adrenal axis function, psychopathological traits, and natural killer (NK) cell activity in anorexia nervosa

To evaluate the role of Hypothalamic-Pituitary-Adrenal (HPA) hormones and psychoneuroendocrine modulation on NK cell activity in Anorexia Nervosa (AN) we studied in 24 patients and 20 sex- and age-matched healthy controls, the spontaneous NK activity of peripheral blood mononuclear (PBM) cells and the susceptibility in vitro to cortisol or immune interferon or interleukin-2. NK cytotoxicity of PBM cells was measured in a direct non-radiometric 4h cytolytic assay using K562 cells as targets. HPA axis function was evaluated by IV ovine Corticotropin Releasing Hormone (o-CRH) administration. We did not find clear-cut abnormalities of NK cytotoxicities either in basal conditions or after exposure to challengers. The extent of cortisol-dependent inhibition was comparable in patients and controls. Significant inverse and direct correlations were found respectively between the spontaneous NK cell activity and baseline serum cortisol at 0800h (r = −0.5; p < .02), and between IL-2 dependent boosting of NK cell cytotoxicity and ACTH, β-endorphin or cortisol responses after o-CRH, expressed as areas under the curve (AUC) (r = 0.46, p < .05; R = 0.46, p < .05; and R = −0.48, p < .05, respectively). Correlations observed with AUC ratios yielded more significant results (r = 0.62; p < .01 and R = 0.51; p < .05 respectively). These data suggest a role for Proopiomelanocortin (POMC) derived peptides in the regulation of NK cell activity in AN, and multifaceted relationships between this particular immune function, on the one hand, and certain patterns of HPA axis function on the other.     

Coping in an intermittent swim stress paradigm compromises natural killer cell activity in rats

The effects of intermittent swim stress and stressor controllability on natural killer cell activity (NKCA) was examined. Significant decreases in splenic NKCA were observed immediately post-stress, but only when the stress was controllable. Although decreased NKCA was also observed in yoked rats subjected to the same stressor, it failed to attain statistical significance. Previous results suggest these effects are not due to corticosterone. The results suggest a cost of coping on the acute, in vitro immune measure of NKCA.     

Plasma cortisol and natural killer cell activity during bereavement

Natural killer cell (NK) activity, which is important in the defense against tumors and viral infections, is reduced in women undergoing conjugal bereavement. The relationship between NK activity and plasma cortisol was investigated in three groups of subjects: women who were anticipating the death of their husbands, women whose husbands had recently died, and controls. Bereaved women showed reduced NK activity and increased plasma cortisol levels as compared to controls. Anticipatory bereaved women also showed significant reductions in NK activity, but had levels of plasma cortisol comparable to those of controls. The reduction of NK activity during anticipatory and actual bereavement cannot be explained solely on the basis of increased cortisol secretion.     

Influence of desmethylimipramine on natural killer cell activity

Mounting evidence suggests that the central nervous system (CNS) and the immune system are extensively interconnected. One question that arises is whether there is cross-reactivity between psychotropic agents, which are active in the CNS, and immune system function. To explore this notion, we examined the in vitro effect of the tricyclic antidepressant, desmethylimipramine (DMI), on human natural killer (NK) cell activity in seven separate experiments. At concentrations greater than or equal to 625 ng/ml, DMI reliably inhibited NK activity. Preincubation of lymphocytes with DMI before assay did not increase the inhibitory effect. Furthermore, removal of the drug from preincubated cells immediately before assay completely eliminated the inhibitory effect. These results demonstrate that DMI reversibly inhibits NK activity at serum concentrations that are not uncommonly found in depressed patients receiving this medication.     

Electroacupuncture up-regulates natural killer cell activity Identification of genes altering their expressions in electroacupuncture induced up-regulation of natural killer cell activity

As an important cellular component of the innate immune system, NK cells constitute a first line of defense against various infections and malignancies. Previous studies have reported electroacupuncture (EA) modulation of natural killer cell (NK cell) activities. Our study confirmed that EA treatment increases NK cell activity using (51)Cr release assay. Furthermore, in order to better understand the activation mechanism of NK cell by EA, we employed a cDNA microarray technique to elucidate how EA alters gene expressions in the spleen of rats. We screened EA responsive genes using a high-throughput screening and identified 154 genes. Among those genes we selected 4 genes that are known to play a crucial role in NK cell activation and examined their mRNA expressions after EA treatment using RT-PCR. Our data shows that EA treatment increased CD94, PTK and VCAM-1 expressions while decreased PTP and SHP-1. These results imply that EA treatment increase PTK expression, which increases NK cell activity, through induction of CD94 while decreases SHP-1, which inhibits NK cell activity, simultaneously so that it activates NK cell with high efficacy. It seems that increased VCAM-1 expression is due to INF-gamma produced by activated NK cell. Increased production of VCAM-1 is expected to play an important role in binding of NK cell to the target cell. The result of our study may provide key insights in understanding the mechanisms of activation of NK cell induced by EA.     

Reduced natural killer cell activity in major depression: neuroendocrine implications

Natural killer cell activity (NKCA) was significantly reduced in a group of depressed patients, melancholic subtype, compared to sex- and age-matched controls. Corticotropin and cortisol values were significantly higher in the depressed subjects than in the controls, but no correlation between high hormone levels and low immunological activity was found in the patients.     

The stress and psychological morbidity of the Alzheimer patient caregiver.

BACKGROUND: Alzheimer's family caregivers suffer from psychological and physical morbidity associated with the care of the Alzheimer's patient. The objectives of the study were to compare stress and psychological morbidity between family caregivers of Alzheimer's disease patients and family caregivers of aged non-demented chronically ill patients and to explore the impact of cognitive and non-cognitive patient symptoms on caregivers.METHOD: Fifty-eight caregivers of Alzheimer's patients (cases) and 32 caregivers of non-demented chronically ill patients (controls) were studied. A cross-sectional case-control design was employed using validated scales to assess patient symptomatology and self-report questionnaires to measure stress and psychological morbidity in caregivers.RESULTS: Compared to controls, stress and psychological morbidity were higher in caregivers of Alzheimer's patients. Behavioral symptoms and impairment in instrumental activities of daily living were associated with caregiver stress. Length of care was associated with caregiver psychological morbidity.CONCLUSIONS: Caregiver stress may be reduced with special attention paid to the treatment and management of behavioral and functional symptoms in the Alzheimer's disease patient. Caregiver education and coping skills should also be included.     

Glucocorticoid dysregulation of natural killer cell function through epigenetic modification

It is well-established that psychological distress reduces natural killer cell activity (NKCA) and dysregulates cytokine balance. This may be mediated by stress-induced release of glucocorticoids, which have broad effects on the immune system, including the suppression of NKCA and alteration of cytokine production. The purpose of this study was to evaluate epigenetic mechanisms that may underlie the effect of glucocorticoids on NK cells, using the human NK cell line, NK92. Treatment of NK92 cells with the synthetic glucocorticoid, dexamethasone, at a concentration of 10⁻⁷ M, produced a significant reduction in NKCA. Glucocorticoid inhibition was a consequence of not only a reduced capacity of the NK cells to bind to tumor targets but also a reduced production of granule constituents (perforin and granzyme B) with no detectable effect on granule exocytosis. Glucocorticoids also reduced the constitutive and the stimulated production of the cytokines, IL-6, TNF alpha and IFN gamma, and reduced the surface expression of LFA-1. Glucocorticoid treatment also reduced global histone acetylation, the acetylation of histone 4 lysine position 8, and the accessibility of the proximal promoters of perforin, interferon gamma and granzyme B. Histone acetylation was recovered by treatment of the NK cells with a histone deacetylase inhibitor, which also restored NKCA and IFN gamma production. These results demonstrate glucocorticoids to dysregulate NK cell function at least in part through an epigenetic mechanism, which reduces promoter accessibility through modification of histone acetylation status. This epigenetic modification decreases the expression of effector proteins necessary to the full functional activity of NK cells.