Spousal bereavement after dementia caregiving: A turning point for immune health.

Losing a spouse can increase the risk for premature mortality, and declines in immune health are thought to play a role. Most of the supporting data have come from cross-sectional studies comparing already-bereaved individuals to matched controls, which provides valuable information about health disparities between groups but does not reveal health changes over time. Moreover, the health consequences of bereavement may be unique for dementia family caregivers, a large and growing segment of the population. The current study sought to evaluate the course of health around 52 dementia spousal caregivers' bereavement by capturing lymphocyte proliferation to Con A and PHA and self-rated health before and after spousal loss. To investigate the moderating role of the social environment, we examined associations between social ties and health trajectories before and after spousal loss. Using piecewise linear mixed models to allow for turning points in caregivers' trajectories, we found that, for the average caregiver, lymphocyte proliferation to both mitogens weakened as bereavement neared and continued to decline after the loss, but at a slower pace. In tandem, perceived health degraded as bereavement approached but rebounded thereafter. Further, we found that socially isolated caregivers showed marked declines in immune responses to Con A and PHA over time both before and after bereavement, whereas their socially connected counterparts had shallower declines to PHA and maintained a level immune response to Con A. In addition, socially isolated caregivers reported poorer health before and after bereavement compared to their counterparts, whose self-rated health declined as the loss neared but later recovered to exceed prior levels. These findings shed new light on the dynamics of immune function in response to spousal bereavement after dementia caregiving: longitudinal data reveal a pattern of health recovery following caregivers' loss, particularly among those with more robust social networks prior to bereavement.

Association of Epigenetic Age and p16INK4a With Markers of T-Cell Composition in a Healthy Cohort.

How the measurement of aging biomarkers in peripheral blood T-lymphocytes (PBTLs) is influenced by cell composition is unclear. Here, we collected peripheral blood and isolated CD3+ PBTLs from 117 healthy couples between the ages of 21 and 72. Each sample was profiled for Horvath epigenetic clock (DNAm), p16INK4a expression, cytomegalovirus (CMV) seropositivity and 74 mRNA markers of PBTL subtype, differentiation, immune checkpoints, and cytokine production. Correlations between individual aging biomarkers (DNAm or p16INK4a) and PBTL mRNAs were corrected for chronological age, sex, and couple. DNAm measurements correlated with CMV seropositivity as well as PBTL mRNAs indicative of effector function (CD8A, EOMES, TBX21, GZMB), poor proliferative capacity (KLRG1, CD57), differentiation (CD45RO, CD45RA), and immune checkpoints (PDCD1, TIGIT, LAG3, CD160, CD244). In contrast, only three PBTL mRNAs, CD28, CD244, and p14ARF, showed a significant association with p16INK4a. p16INK4a expression also showed a weaker association with immunosenescent PBTL subsets than DNAm in flow cytometry analyses. These data suggest that PBTL composition has a greater influence on DNAm than p16INK4a and link accelerated epigenetic aging to immunosenescent phenotypes.

Marital distress, depression, and a leaky gut: Translocation of bacterial endotoxin as a pathway to inflammation.

BACKGROUND: Marital distress and depression work in tandem to escalate risks for inflammation-related disorders. Translocation of bacterial endotoxin (lipopolysaccharide, LPS) from the gut microbiota to blood circulation stimulates systemic inflammatory responses. METHODS: To investigate increased gut permeability (a "leaky gut") as one potential mechanistic pathway from marital distress and depression to heightened inflammation, this secondary analysis of a double-blind, randomized crossover study examined serial assessments of two endotoxin biomarkers, LPS-binding protein (LBP) and soluble CD14 (sCD14), as well as C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) during two separate 9.5 h visits. The 43 (N = 86) healthy married couples, ages 24-61 (mean = 38.22), discussed a marital disagreement during both visits; behavioral coding of these interactions provided data on hostile marital behaviors, a hallmark of marital distress. The Structured Diagnostic Interview for DSM-IV assessed participants' mood disorder history. RESULTS: Participants with more hostile marital interactions had higher LBP than those who were less hostile. Additionally, the combination of more hostile marital interactions with a mood disorder history was associated with higher LBP/sCD14 ratios. Higher LBP and LBP/sCD14 were associated with greater CRP production; for example, only 21% of low LBP participants (lowest quartile) had average CRP across the day > 3, compared to 79% of those in the highest quartile. Higher sCD14 was associated with higher IL-6. CONCLUSIONS: These bacterial LPS translocation data illustrate how a distressed marriage and a mood disorder history can promote a proinflammatory milieu through increased gut permeability, thus fueling inflammation-related disorders.

Evidence for the role of Epstein Barr Virus infections in the pathogenesis of acute coronary events.

BACKGROUND: The role of viral infections in the pathogenesis of atherosclerosis remains controversial largely due to inconsistent detection of the virus in atherosclerotic lesions. However, viral infections elicit a pro-inflammatory cascade known to be atherogenic and to precipitate acute ischemic events. We have published in vitro data that provide the foundation for a mechanism that reconciles these conflicting observations. To determine the relation between an early viral protein, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), produced following reactivation of Epstein Barr Virus (EBV) to circulating pro-inflammatory cytokines, intercellular adhesion molecule-1 (ICAM-1) and acute coronary events. METHODOLOGY/PRINCIPAL FINDINGS: Blood samples were obtained from 299 patients undergoing percutaneous coronary intervention for stable angina (SA), unstable angina (UA), or acute myocardial infarction (AMI). Plasma concentrations of pro-inflammatory cytokines and neutralizing antibody against EBV-encoded dUTPase were compared in the three patient groups. AMI was associated with the highest measures of interleukin-6 (ANOVA p<0.05; 4.6 ± 2.6 pg/mL in patients with AMI vs. 3.2 ± 2.3 pg/mL in SA). ICAM-1 was significantly higher in patients with AMI (ANOVA p<0.05; 304 ± 116 pg/mL in AMI vs. 265 ± 86 pg/mL SA). The highest values of ICAM-1 were found in patients having an AMI and who were antibody positive for dUTPase (ANOVA p=0.008; 369 ± 183 pg/mL in AMI and positive for dUTPase vs. 249 ± 70 pg/mL in SA negative for dUTPase antibody). CONCLUSIONS/SIGNIFICANCE: These clinical data support a model, based on in vitro studies, by which EBV may precipitate AMI even under conditions of low viral load through the pro-inflammatory action of the early protein dUTPase that is produced even during incomplete viral replication. They further support the putative role of viral infections in the pathogenesis of atherosclerosis and coronary artery events.

How stress and anxiety can alter immediate and late phase skin test responses in allergic rhinitis.

Allergic rhinitis (AR) is the fifth most common chronic disease, and the association between allergic disorders and anxiety is well-documented. To investigate how anxiety and stressors modulate skin prick test (SPT) responses and associated inflammatory responses, 28 men and women with AR were selected by clinical history and skin test responses. The participants were admitted twice to a hospital research unit for 4h in a crossover trial. Changes in SPT wheals were assessed before and after a standardized laboratory speech stressor, as well as again the following morning; skin responses assessed twice during a lab session without a stressor and again the following morning served as the contrast condition. Anxiety heightened the magnitude of allergen-induced wheals following the stressor. As anxiety increased, SPT wheal diameters increased after the stressor, compared to a slight decrease following the control task. Anxiety also substantially enhanced the effects of stress on late phase responses: even skin tests performed the day after the stressor reflected the continuing impact of the speech stressor among the more anxious participants. Greater anxiety was associated with more IL-6 production by Con A-stimulated leukocytes following the stressor compared to the control visit. The data suggest that stress and anxiety can enhance and prolong AR symptoms.

Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients.

Caregivers of Alzheimer's disease patients endure chronic stress associated with a decline of immune function. To assess the psychological and immunological changes of caregivers, we compared depressive symptoms, PBMC composition, in vitro activation-induced proliferation and cytokine production, and telomere length and telomerase activity of 82 individuals (41 caregivers and 41 age- and gender-matched controls). We found depressive symptoms were significantly higher in caregivers than in controls (p < 0.001). Correspondingly, caregivers had significantly lower T cell proliferation but higher production of immune-regulatory cytokines (TNF-alpha and IL-10) than controls in response to stimulation in vitro. We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 kb, respectively, p < 0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC. Finally, we showed that basal telomerase activity in PBMC and T cells was significantly higher in caregivers than in controls (p < 0.0001), pointing to an unsuccessful attempt of cells to compensate the excessive loss of telomeres in caregivers. These findings demonstrate that chronic stress is associated with altered T cell function and accelerated immune cell aging as suggested by excessive telomere loss.

Wound site neutrophil transcriptome in response to psychological stress in young men.

Communication between the central nervous and the immune system occurs through chemical messengers secreted by nerve cells, endocrine organs, or immune cells. Psychological stressors can disrupt these networks. We have previously observed that disruption of the neuroendocrine immune system adversely influences a broad range of physiological processes including wound healing. Migration of neutrophils to the wound site is an early event that induces a transcriptional activation program, which regulates cellular fate and function, and promotes wound healing. In this study, we have sought to identify stress-sensitive transcripts in wound site neutrophils. A skin blister model was used to collect wound fluid and wound site neutrophils from four young men, experiencing or not examination stress. Self-reported stress was recorded using the Beck Depression Inventory. Stress decreased growth hormone levels at the wound site and was related to impaired wound healing in all subjects. High density microarray analyses were performed using RNA from wound site neutrophils. Results show that psychological stress had an overall suppressive effect on the neutrophil transcriptome. Of the 22,283 transcripts screened, 0.5% were downregulated whereas only under 0.3% were induced by stress in all four out of four subjects. Functionally, stress tilted the genomic balance towards genes encoding proteins responsible for cell cycle arrest, death, and inflammation. Further effort to gain a more comprehensive understanding of the functional significance of such behavior-genome interaction is warranted.

Autonomic and glucocorticoid associations with the steady-state expression of latent Epstein-Barr virus.

Previous studies have demonstrated the impact of psychological stress on the steady-state expression/reactivation of latent Epstein-Barr virus (EBV). Stress-induced decrements in the cellular immune response result in less control over the expression of the latent virus, resulting in increases in antibody to the virus. In Study 1, we investigated whether the steady-state expression of latent EBV in vivo differed between high and low stress reactors, as defined by sympathetic cardiac reactivity. Autonomic activity and antibody titers to Epstein-Barr virus capsid antigen (VCA) were measured in 50 elderly women latently infected with EBV. Results revealed that women who were high stress reactors were characterized by higher antibody titers to the latent virus than low stress reactors. High reactors tended to show larger stress-related increases in cortisol than low reactors, but the differences were not significant. Daily stressors can activate the autonomic nervous system and promote the release of pituitary and adrenal hormones, especially in high reactors. Glucocorticoid hormones have been shown to reactivate EBV in vitro from cells latently infected with the virus. We hypothesized that absolute levels of plasma cortisol may not be the only explanation for stress-induced reactivation of latent EBV and that the diurnal changes in the production of cortisol may be an important factor in these interactions. To examine the feasibility of this hypothesis, an in vitro study was conducted (Study 2) to determine whether changing glucocorticoid concentrations in the medium, in which EBV latently infected cells were cultured, to mimic diurnal changes in plasma cortisol concentrations would enhance the reactivation of the latent virus. Cells latently infected with EBV were exposed to either constant or varying concentrations of the synthetic glucocorticoid hormone dexamethasone (Dex), for 72 h. Results revealed a three- to eightfold enhancement of reactivation of latent EBV in cells pulsed with varying Dex concentrations when compared with cells exposed to a constant and/or a higher mean level of one Dex concentration. Together, these studies raise the possibility that differences in the kinetics of glucocorticoid concentrations may contribute to differences in the reactivation of latent EBV.