The "widowhood effect" (i.e., morbidity/mortality in recently bereaved spouses) may be related to changes in immune function, but little is known about the impact of bereavement on gene transcription in immune cells. This study examined how Complicated Grief and Non-complicated Grief responses to bereavement differentially affect leukocyte gene expression. Genome-wide transcriptional profiling and bioinformatic analyses were completed on 63 older adults. Thirty-six of them had lost their spouse/partner on average 2years ago, and 27 were nonbereaved, married controls. Twelve of the bereaved participants met criteria for Complicated Grief. Compared to nonbereaved controls, bereavement (both Complicated Grief and Non-complicated Grief) was associated with upregulated expression of genes involved in general immunologic activation and a selective downregulation of genes involved in B lymphocyte responses. However, Complicated Grief and Non-complicated Grief differed markedly in their expression of Type I interferon-related transcripts, with Non-complicated Grief subjects showing substantial upregulation relative to nonbereaved controls and Complicated Grief subjects showing substantial downregulation. Bereavement significantly modulates immune function gene expression. The magnitude of bereavement-related distress (i.e., Complicated Grief vs. Non-complicated Grief) is linked to differential patterns of transcription factor activation and gene expression involved in innate antiviral responses. These findings provide a molecular framework for understanding the health effects of bereavement, as well as new insights into the particular gene modules that are most sensitive to the individual's psychological response to loss.

Adverse social conditions have been linked to a conserved transcriptional response to adversity (CTRA) in circulating leukocytes that may contribute to social gradients in disease. However, the CNS mechanisms involved remain obscure, in part because CTRA gene-expression profiles often track external social-environmental variables more closely than they do self-reported internal affective states such as stress, depression, or anxiety. This study examined the possibility that variations in patterns of natural language use might provide more sensitive indicators of the automatic threat-detection and -response systems that proximally regulate autonomic induction of the CTRA. In 22,627 audio samples of natural speech sampled from the daily interactions of 143 healthy adults, both total language output and patterns of function-word use covaried with CTRA gene expression. These language features predicted CTRA gene expression substantially better than did conventional self-report measures of stress, depression, and anxiety and did so independently of demographic and behavioral factors (age, sex, race, smoking, body mass index) and leukocyte subset distributions. This predictive relationship held when language and gene expression were sampled more than a week apart, suggesting that associations reflect stable individual differences or chronic life circumstances. Given the observed relationship between personal expression and gene expression, patterns of natural language use may provide a useful behavioral indicator of nonconsciously evaluated well-being (implicit safety vs. threat) that is distinct from conscious affective experience and more closely tracks the neurobiological processes involved in peripheral gene regulation.

Late life insomnia may increase risk for accelerated biological aging. Intervening to treat insomnia may provide protection from biological aging by reducing the prevalence of senescent cells in the immune system, as indicated by gene expression of a marker of cellular senescence, p16INK4a. In the present study, we determine whether treatment of insomnia in older adults with cognitive behavioral therapy for insomnia (CBT-I) would reduce p16INK4a gene expression in peripheral blood mononuclear cells (PBMC), compared to a sleep education therapy (SET), an active comparator condition. Secondly, we investigate the relationship between sustained insomnia remission and reduced expression of p16INK4a. Participants 60 + years old with insomnia were enrolled in a randomized controlled trial and assigned to CBT-I or SET. Analyses of 231 older adults (CBT-I = 119; SET = 112) examine baseline, post (2 months), and 24 months gene expression of p16INK4a. Compared to baseline, expression of p16INK4a increased in the SET group over 24 months (P = 0.03), but showed no change in the CBT-I group. Those who received CBT-I and experienced sustained remission of insomnia had a significant decline in p16INK4a expression by 24 months compared to baseline (P = 0.02). Individuals not sustaining remission of insomnia exhibited overall increase expression of p16INK4a by 24 months (P = 0.03). In older adults with insomnia, p16INK4a increases over 24 months, while CBT-I treatment of insomnia mitigates the increase in p16INK4a. Further, sustained remission of insomnia using CBT-I leads to a decrease in p16INK4a. These results suggest that behavioral interventions that are effective at treating insomnia might reduce the population of senescent cells in circulating blood.

To define the cellular mechanisms of up-regulated inflammatory gene expression and down-regulated antiviral response in people experiencing perceived social isolation (loneliness), we conducted integrative analyses of leukocyte gene regulation in humans and rhesus macaques. Five longitudinal leukocyte transcriptome surveys in 141 older adults showed up-regulation of the sympathetic nervous system (SNS), monocyte population expansion, and up-regulation of the leukocyte conserved transcriptional response to adversity (CTRA). Mechanistic analyses in a macaque model of perceived social isolation confirmed CTRA activation and identified selective up-regulation of the CD14(++)/CD16(-) classical monocyte transcriptome, functional glucocorticoid desensitization, down-regulation of Type I and II interferons, and impaired response to infection by simian immunodeficiency virus (SIV). These analyses identify neuroendocrine-related alterations in myeloid cell population dynamics as a key mediator of CTRA transcriptome skewing, which may both propagate perceived social isolation and contribute to its associated health risks.

High conflict and low warmth in families may contribute to immune cells developing a tendency to respond to threats with exaggerated inflammation that is insensitive to inhibitory signaling. We tested associations between family environments and expression of genes bearing response elements for transcription factors that regulate inflammation: nuclear factor kappa B (NF-κB) and glucocorticoid receptor. The overall sample (47 families) completed interviews, questionnaires, and 8-week daily diary assessments of conflict and warmth, which were used to create composite family conflict and warmth scores. The diaries assessed upper respiratory infection (URI) symptoms, and URI episodes were clinically verified. Leukocyte RNA was extracted from whole blood samples provided by a subsample of 42 children (8-13 years of age) and 73 parents. In children, higher conflict and lower warmth were related to greater expression of genes bearing response elements for the proinflammatory transcription factor NF-κB, and more severe URI symptoms. In parents, higher conflict and lower warmth were also related to greater NF-κB-associated gene expression. Monocytes and dendritic cells were implicated as primary cellular sources of differential gene expression in the sample. Consistent with existing conceptual frameworks, stressful family environments were related to a proinflammatory phenotype at the level of the circulating leukocyte transcriptome.

Background

Social environmental influences on human health are well established in the epidemiology literature, but their functional genomic mechanisms are unclear. The present study analyzed genome-wide transcriptional activity in people who chronically experienced high versus low levels of subjective social isolation (loneliness) to assess alterations in the activity of transcription control pathways that might contribute to increased adverse health outcomes in social isolates.

Results

DNA microarray analysis identified 209 genes that were differentially expressed in circulating leukocytes from 14 high- versus low-lonely individuals, including up-regulation of genes involved in immune activation, transcription control, and cell proliferation, and down-regulation of genes supporting mature B lymphocyte function and type I interferon response. Promoter-based bioinformatic analyses showed under-expression of genes bearing anti-inflammatory glucocorticoid response elements (GREs; p = 0.032) and over-expression of genes bearing response elements for pro-inflammatory NF-kappaB/Rel transcription factors (p = 0.011). This reciprocal shift in pro- and anti-inflammatory signaling was not attributable to differences in circulating cortisol levels, or to other demographic, psychological, or medical characteristics. Additional transcription control pathways showing differential activity in bioinformatic analyses included the CREB/ATF, JAK/STAT, IRF1, C/EBP, Oct, and GATA pathways.

Conclusion

These data provide the first indication that human genome-wide transcriptional activity is altered in association with a social epidemiological risk factor. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of subjective social isolation.

Background

Psychological stress and poor sleep are associated with a wide range of negative health outcomes, which are thought to be mediated in part by alterations in immune processes. However, the molecular bases of links among stress, sleep, and immune processes are not completely understood, particularly during adolescence when sensitivity to stress and problems with sleep tend to increase. In the current study, we investigated whether various stressors (daily stress, major life events, perceived stress), sleep indices (duration, efficiency), and their interactions (e.g., moderating effects) are associated with expression of genes bearing response elements for transcription factors that regulate inflammatory and anti-viral processes.

Method

Eighty-seven late adolescents completed daily checklists of their social experiences across a 15-day period and reported on their major life events during the previous year. They also completed actigraphy-based assessments of sleep quality and duration during 8 consecutive nights. An average of 5.5 months later, participants reported on their global perceptions of stress during the previous month and provided blood samples for genome-wide expression profiling of mRNA from peripheral blood mononuclear cells (PBMCs).

Results

Higher levels of daily interpersonal stress and shorter sleep duration were associated with upregulation of inflammation-related genes bearing response elements for proinflammatory transcription factor nuclear factor kappa B (NF-κB). Shorter sleep duration was also linked to downregulation of antiviral-related genes bearing response elements for interferon response factors (IRFs). Lastly, there was a significant interaction between daily stress and shorter sleep duration, such that the association between daily stress and inflammation-related gene expression was exacerbated in the context of shorter sleep duration. Results were independent of sex, ethnicity, parent education, body mass index, and smoking and alcohol history.

Conclusion

Everyday interpersonal stress and shortened sleep can be consequential for upstream NF-κB signaling pathways relevant to inflammatory processes during late adolescence. Notably, the occurrence of both may lead to even greater activation of NF-κB signaling.

Background

Rates of depression increase and peak during late adolescence and alterations in immune processes are thought to be both a risk factor and outcome of depression. However, few studies have examined depression-immune dynamics among adolescents. Using a functional genomics approach, the current study examined whether depressive symptoms were associated with activation of a gene expression profile, characterized by upregulated expression of pro-inflammatory-related genes and downregulated expression of antiviral-related genes in a sample of older adolescents (M_age = 18.37, SD = 0.51).

Method

Participants (n = 87) reported on their depressive symptoms during the past week using the CES-D, and provided blood samples for genome-wide transcriptional profiling of mRNA.

Results

Adolescents with clinically-significant levels of depressive symptoms (CES-D ≥ 16) exhibited upregulated expression of inflammation-related genes and downregulated expression of antiviral-related genes compared to their peers with lower levels of depressive symptoms (CES-D < 16). Bioinformatics analyses suggested that this pattern of differential gene expression was mediated by greater activity of the pro-inflammatory transcription factor, nuclear factor-kappa B (NF-κB), and reduced activity of glucocorticoid receptors (GRs) and interferon response factors (IRFs). Additional analyses implicated monocytes, B cells, and dendritic cells as primary cellular sources of the observed gene expression patterns associated with depressive symptoms.

Conclusion

Results are consistent with past work demonstrating links between depression and altered immunity. They provide a molecular basis for these associations and suggest that the underlying molecular signature may emerge as early as late adolescence when rates of depression tend to increase.

Background

Sleep disturbance is associated with activation of systemic and cellular inflammation, as well as proinflammatory transcriptional profiles in circulating leukocytes. Whether treatments that target insomnia-related complaints might reverse these markers of inflammation in older adults with insomnia is not known.

Methods

In this randomized trial, 123 older adults with insomnia were randomly assigned to cognitive-behavioral therapy for insomnia (CBT-I), tai chi chih (TCC), or sleep seminar education active control condition for 2-hour sessions weekly over 4 months with follow-up at 7 and 16 months. We measured C-reactive protein (CRP) at baseline and months 4 and 16; toll-like receptor-4 activated monocyte production of proinflammatory cytokines at baseline and months 2, 4, 7, and 16; and genome-wide transcriptional profiling at baseline and month 4.

Results

As compared with sleep seminar education active control condition, CBT-I reduced levels of CRP (months 4 and 16, ps < .05), monocyte production of proinflammatory cytokines (month 2 only, p < .05), and proinflammatory gene expression (month 4, p < .01). TCC marginally reduced CRP (month 4, p = .06) and significantly reduced monocyte production of proinflammatory cytokines (months 2, 4, 7, and 16; all ps < .05) and proinflammatory gene expression (month 4, p < .001). In CBT-I and TCC, TELiS promoter-based bioinformatics analyses indicated reduced activity of nuclear factor-κB and AP-1.

Conclusions

Among older adults with insomnia, CBT-I reduced systemic inflammation, TCC reduced cellular inflammatory responses, and both treatments reduced expression of genes encoding proinflammatory mediators. The findings provide an evidence-based molecular framework to understand the potential salutary effects of insomnia treatment on inflammation, with implications for inflammatory disease risk.

Background

Social isolation is associated with accelerated breast cancer progression and increased disease recurrence and mortality, but the underlying biological mechanisms remain poorly understood. In preclinical models, beta-adrenergic signaling from fight-or-flight stress responses can stimulate prometastatic processes in the tumor microenvironment including upregulation of M2 macrophages, epithelial-mesenchymal transition (EMT), and lymphovascular invasion. This study examines whether the same pathways are upregulated in breast tumors from socially isolated cancer patients.

Methods

EMT and M1/M2 macrophage gene expression programs were analyzed by genome-wide transcriptional profiling, and lymphatic and vascular density were assessed by immunohistochemistry in primary tumors from 56 early-stage breast cancer patients who were part of the UCLA RISE study. Social isolation was quantified by the Social Provisions Scale, and disease characteristics were assessed by medical record review. General linear models were used to quantify differential gene expression across risk factor groups. Linear regression models were used to examine associations between social isolation and lymphovascular invasion.

Results

Tumors from socially isolated patients showed upregulated expression of genes involved in EMT (average score difference = +0.080 log2 mRNA abundance ± 0.034 standard error) and M2 macrophage polarization (+0.033 ± 0.014) as well as increased density of lymphatic vessels (β= -.29) but no difference in blood vessel density. TELiS promoter-based bioinformatics analyses indicated activation of CREB family transcription factors that mediate the gene-regulatory effects of β-adrenergic signaling (log2 fold-difference in promoter binding site prevalence: mean ± standard error = +0.49 ± 0.19).

Conclusions

Primary breast tumors from socially isolated patients show multiple prometastatic molecular alterations, providing a plausible biological pathway through which poor social support may accelerate breast cancer progression and defining new targets for intervention.