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Inflammation can have social consequences, which may be relevant to inflammation's link with depression. The current study tests whether a typhoid vaccine increases feelings of social disconnection and avoidance behavior.In two full-day visits at least three weeks apart, 172 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence. Blood was drawn prior to the injection, as well as every 90 min thereafter for 8 h to assess the inflammatory response (interleukin-6, IL-6; interleukin-1 receptor antagonist, IL-1Ra). At both visits, women completed the Social Connection Scale at 0 and 8.5 h post-vaccination as well as implicit and explicit social avoidance tasks at 7 h post-vaccination.The typhoid vaccine triggered rises in both inflammatory markers (ps 0.01), but it did not impact feelings of social connection (p = .32), or performance on the implicit (p = .34) or explicit tasks (p = .37). Inflammatory rises did not predict feelings of social connection (ps 0.64) or performance on explicit (ps 0.73) or implicit (ps 0.88) social avoidance tasks.Milder inflammatory stimuli may not affect social processes. Higher levels of inflammation or, relatedly, more sickness symptoms may be necessary to recapitulate prior findings of social avoidance.

PURPOSE: To investigate breast cancer survivors’ inflammatory responses to typhoid vaccine as a window into their innate immune response to novel pathogens. METHODS: This double-blind crossover trial randomized 158 breast cancer survivors to either the vaccine/saline placebo or the placebo/vaccine sequence. The relative contributions of age, cardiorespiratory fitness (VO(2peak)), type of cancer treatment, central obesity, and depression to interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra), and WBC vaccine responses were assessed pre-injection and 1.5, 3, 4.5, 6, and 7.5 hours post-injection. RESULTS: The vaccine produced larger IL-6, IL-1Ra, and WBC responses than placebo, ps

Background Breast cancer survivors are prone to weakened gut barriers, allowing bacteria to migrate into the blood stream. Gut permeability fuels inflammation, which, among survivors, can elevate risk for comorbid disease development, cancer recurrence, and a poor quality of life; however, survivors’ satisfying relationships can provide health benefits. This longitudinal study used a conceptual model addressing how intimate relationships is associated with health through changes in gut permeability and inflammation. Method Breast cancer survivors (n=139, stages 0–IIIC) completed a baseline visit before treatment and two follow-up visits 6 and 18 months after treatment ended. Women who had an abnormal breast cancer test followed by a benign diagnosis completed visits within a comparable timeframe (noncancer patient controls; n=69). All women completed questionnaires assessing their relationship satisfaction and provided blood samples to assess two bacterial endotoxin biomarkers, lipopolysaccharide-binding protein (LBP) and soluble CD14 (sCD14), as well as C-reactive protein (CRP) and interleukin 6 (IL-6). Results Within-person multilevel mediation analyses showed that when a survivor’s relationship satisfaction was higher than usual, her own LBP and LBP/sCD14 were lower, which was associated with lower than her own average CRP and IL-6 (95% CIs [-0.0104, -0.0002]). IL-6 was also higher when older survivors, but not younger survivors, experienced higher than usual intestinal permeability (p=.001). These effects of satisfying relationships held after accounting for cancer-related and behavioral factors. Post-hoc analyses showed LBP, sCD14, and LBP/sCD14 were associated with CRP for the cancer survivors, but only LBP and LBP/sCD14 were linked to CRP among the noncancer control patients. Conclusion The gut environment is a new promising candidate for understanding a relationship’s long-term health impact, particularly among those with elevated health risks. Survivors may reap multiple physiological benefits from satisfying relationships.

Background The Center for Disease Control (CDC) recently named childhood abuse histories as a public health risk. Clear links between abuse histories and inflammation exist. However, it remains unknown how abuse histories impact inflammatory trajectories throughout adulthood. Accordingly, this study assessed inflammatory trajectories across three visits among healthy adults with and without abuse histories. Method In this secondary analysis of data from a longitudinal observational study of cancer survivors and noncancer controls, 157 noncancer controls (Mage = 55.8, range = 32–83) completed the Childhood Experiences Questionnaire (CTQ), providing data on physical, emotional, and sexual abuse prior to age 18. Cytokines interleukin-6 (IL-6), interleukin 1-beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) were collected at the baseline visit and two follow-up visits approximately one (M months = 11.52, SD = 4.10) and two years (M months = 23.79, SD = 4.40) later. To represent inflammatory changes, cytokine data at each visit were combined into a composite z-score. Covariates in all analyses included age, biological sex, race, income, body mass index, menopause status, psychological diagnosis history, and medical comorbidities. Results Compared to their nonabused peers, those who had experienced any type of abuse in childhood demonstrated steeper rises in inflammation across time. Inflammation rose more steeply for individuals with physical and emotional abuse histories compared to those without such histories. Conclusion Overall, these data suggest that childhood abuse histories may quicken age-related increases in inflammation, contributing to accelerated aging, morbidity, and early mortality. These findings provide mechanistic insight into why child abuse is a public health risk.

The Western diet, characterized by high intake of saturated fat, sugar, and salt, is associated with elevated inflammation and chronic disease risk. Few studies have investigated molecular mechanisms linking diet and inflammation; however, a small number of randomized controlled trials suggest that consuming an anti-inflammatory diet (i.e., a primarily plant-based diet rich in monounsaturated fat and lean protein) decreases proinflammatory gene expression. The current study investigated the association between everyday diet and proinflammatory gene expression, as well as the extent to which central adiposity and social involvement modulate risk. Participants were healthy middle-aged and older adults (N = 105) who completed a food frequency questionnaire and reported how many close social roles they have. Anthropometric measurements and blood samples also were collected; gene expression data were analyzed from LPS-stimulated peripheral blood mononuclear cells for interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. The inflammatory potential of each participant’s diet was calculated using the Dietary Inflammatory Index (DII®). Participants with higher DII® scores, indicating a more proinflammatory diet, had greater IL-6 (b = −0.02, SE = 0.008, p = .01), IL-1β (b = −0.01, SE = 0.006, p = .03), and TNF-α (b = −0.01, SE = 0.005, p = .04) gene expression if they had a smaller sagittal abdominal diameter (SAD); effects were not seen among those with higher SADs. Social involvement served a protective role, such that participants with smaller SADs had greater IL-6 (b = 0.01, SE = 0.004, p = .049) and IL-1β (b = 0.01, SE = 0.003, p = .045) gene expression only if they had less social involvement; there was no effect of diet on gene expression among those who reported greater social participation. Results are the first to demonstrate a link between self-reported diet and proinflammatory gene expression. Importantly, the effect of diet on gene expression depended upon both body fat composition and social participation, both of which have previously been linked directly with proinflammatory gene expression and inflammation.

Many breast cancer survivors experience improvements in depression, fatigue, and inflammation after cancer treatment, but a subset of survivors experience persistent symptoms years after treatment ends. Prior cross-sectional research indicates that childhood adversity predicts elevated symptoms one year following cancer treatment; however, studies have not assessed whether adversity produces differential symptom change over longer periods of time. The current study assessed childhood maltreatment as a risk factor for poorer short-term and long-term recovery during survivorship. In a parent study, breast cancer survivors stages 0-IIIC (N = 118) provided data prior to primary cancer treatment (i.e., surgery, radiation, or chemotherapy) and 6 and 18 months post-treatment. Women who reported clinically significant physical abuse (p = .029) and emotional neglect (p = .027) demonstrated smaller decreases in CRP from baseline to 6 months post-treatment compared to women who reported less severe or no adversities. Women who reported childhood physical abuse also had greater increases in fatigue (p = .013) from baseline to 18 months post-treatment, and women reporting physical abuse (p = .030) and emotional neglect (p = .047) had smaller decreases in depressive symptoms over the same time frame. These data suggest that childhood adversity has lasting effects on depression, inflammation, and fatigue which may persist up to 18 months post-treatment, long after the physical and psychological repercussions of cancer treatment are expected to dissipate.

Lonely people’s heightened risks for chronic health conditions and early mortality may emerge in part through cellular aging. Lonelier people have more severe responses to acute stress, increasing their risk for herpesvirus reactivation, a possible path to shorter telomeres. Lower parasympathetic activity may modulate this risk. To examine the associations among loneliness, parasympathetic activity, herpesvirus reactivation, and telomere length, 113 healthy men and women ages 40–85 provided blood samples that were assayed for telomere length, as well as the latent herpesviruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV). They also provided heart rate variability (HRV), a measure of parasympathetic activity, and reported on their feelings of loneliness. Lonelier people with lower HRV (i.e., lower parasympathetic activity) had greater CMV reactivation and shorter telomeres compared to their less lonely counterparts, above and beyond demographics, health behaviors, resting heart rate, and social network size. However, loneliness was not associated with viral reactivation or telomere shortening among those with higher HRV. In turn, greater CMV and EBV reactivation was associated with shorter telomeres. Taken together, these data implicate parasympathetic function in a novel route through which loneliness may accelerate cellular aging and hasten mortality.

Among breast cancer survivors, a subset experiences persistent post-treatment fatigue and diminished quality of life. Chronic inflammation underlies fatigue, and mechanistic studies have demonstrated a link between proinflammatory dietary components (e.g., refined starches, sugar, trans-fats) and systemic inflammation. The Dietary Inflammatory Index predicts inflammation and some disease-related inflammatory outcomes. Secondary analysis of a randomized controlled trial examined whether a yoga intervention shielded breast cancer survivors from the fatigue and poorer quality of life associated with a proinflammatory diet. Breast cancer survivors (N = 170) were randomized to either a 12-week, biweekly, 90-min hatha yoga intervention (n = 84) or a waitlist control group (n = 86). Women completed the Food Frequency Questionnaire at baseline and the Rand Health Assessment (SF-36) at baseline and a three-month follow-up. Controlling for age, sagittal abdominal diameter, chemotherapy treatment, yoga class cohort, and baseline values of outcome variables, an interaction emerged such that yoga negated the deleterious effects of a proinflammatory diet on fatigue (p = 0.025) and on mental health (p = 0.07). In the control group, women with a proinflammatory diet reported greater fatigue (p = 0.025) and poorer mental health (p = 0.024) compared to their peers with a less inflammatory diet; however, a proinflammatory diet was not associated with fatigue (p = 0.45) or mental health (p = 0.94) in the yoga group.

An unhappy marriage increases disease and mortality risks. Discordant couples exhibit stronger links to their partner’s autonomic fluctuations–that is, stronger covariation–than do satisfied couples, but whether this physiological signature plays a role in marriage’s health effects is unknown. To examine associations between couples’ heart rate variability (HRV) covariation during conflict and their inflammation levels, 43 married couples engaged in a marital problem discussion while wearing heart rate monitors and provided blood samples throughout the day. Multilevel models treated log-transformed interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS) stimulated IL-6 and TNF-alpha, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) as outcomes, accounting for morning baseline HRV levels, age, gender, trunk fat, marital satisfaction, hostility observed during the problem discussion, and study design features. Couples whose moment-to-moment HRV changes tracked more closely together during conflict had higher serum IL-6 ( p = 0.04), LPS-stimulated IL-6 ( p = 0.02), VCAM- 1 ( p = 0.01), and at a trend level, LPS-stimulated TNF-alpha ( p = 0.06) across the day. Thought to result in part from couples’ exchange of negative emotion during disagreement, stronger HRV covariation predicted a heightened inflammatory profile beyond the roles of general marital quality and observed negativity. These data highlight partners’ conflict-related HRV linkage as a novel social-biological mechanism explaining marital discord’s connection to inflammation-related disease.

Depression is a risk factor for morbidity and mortality, and immune dysregulation may be partially responsible for this link. Proinflammatory cytokines such as interleukin 6 (IL-6) are reliable predictors of quality of life, morbidity, and many causes of mortality. The current study evaluated relationships between depressive symptoms, as assessed by the CES-D, and stress-induced inflammation. The participants, 138 healthy adults, were evaluated at rest, and after a standardized laboratory speech and mental arithmetic stressor. Compared with individuals with fewer depressive symptoms, those with more depressive symptoms produced more IL-6 in response to the stressor, as well as significantly higher levels of IL-6 both 45 minutes and 2 hours after the stressor. These findings add to our emerging understanding of the complex interactions among stress, depression, and immune dysregulation, and provide one potential pathway to explain relationships between depressive symptoms and disease.

Shorter telomeres have been associated with poor health behaviors, age-related diseases, and early mortality. Telomere length is regulated by the enzyme telomerase, and is linked to exposure to proinflammatory cytokines and oxidative stress. In our recent randomized controlled trial, omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation lowered the concentration of serum proinflammatory cytokines. This study assessed whether n-3 PUFA supplementation also affected leukocyte telomere length, telomerase, and oxidative stress. In addition to testing for group differences, changes in the continuous n-6:n-3 PUFA ratio were assessed to account for individual differences in adherence, absorption, and metabolism. The double-blind four-month trial included 106 healthy sedentary overweight middle-aged and older adults who received (1) 2.5g/day n-3 PUFAs, (2) l.25g/day n-3 PUFAs, or (3) placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Supplementation significantly lowered oxidative stress as measured by F2-isoprostanes (p=0.02). The estimated geometric mean log-F2-isoprostanes values were 15% lower in the two supplemented groups compared to placebo. Although group differences for telomerase and telomere length were nonsignificant, changes in the n-6:n-3 PUFA plasma ratios helped clarify the intervention's impact: telomere length increased with decreasing n-6:n-3 ratios, p=0.02. The data suggest that lower n-6:n-3 PUFA ratios can impact cell aging. The triad of inflammation, oxidative stress, and immune cell aging represents important pre-disease mechanisms that may be ameliorated through nutritional interventions. This translational research broadens our understanding of the potential impact of the n-6:n-3 PUFA balance. ClinicalTrials.gov identifier: NCT00385723.

There is considerable evidence that stressful early life events influence a variety of physical health problems later in life. Childhood adversity has been linked to elevated rates of morbidity and mortality from a number of chronic diseases. Immune dysregulation may be one potential pathway that explains this link. In this mini-review, we summarize human studies demonstrating that severe early life stressors have lasting immune consequences. We propose a model outlining potential biobehavioral pathways that explain how early life stressors leave people vulnerable to these maladaptive outcomes. Finally, we suggest ideas for future work to test different aspects of this model.

Observational studies have linked lower levels of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) with inflammation and depression. This study was designed to determine whether n-3 supplementation would decrease serum cytokine production and depressive symptoms in 138 healthy middle-aged and older adults (average age=51.04, SD=7.76) who were sedentary and overweight (average BMI=30.59, SD=4.50). This three-arm randomized, placebo-controlled, double-blind 4-month trial compared responses to (1) 2.5 g/d n-3 PUFAs, or (2) 1.25 g/d n-3 PUFAs, or (3) placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Serum interleukin-6 decreased by 10% and 12% in our low and high dose n-3 groups, respectively, compared to a 36% increase in the placebo group. Similarly, low and high dose n-3 groups showed modest 0.2% and -2.3% changes in serum tumor necrosis factor alpha, compared to a 12% increase in the control group. Depressive symptoms were quite low at baseline and did not change significantly in response to supplementation. Our data suggest that n-3 PUFAs can reduce inflammation in overweight, sedentary middle-aged and older adults, and thus could have broad health benefits. These data provide a window into the ways in which the n-3 PUFAs may impact disease initiation, progression, and resolution. ClinicalTrials.gov identifier: NCT00385723.

Fatigue is a notable clinical problem in cancer survivors, and understanding its pathophysiology is important. The current study sought to determine biomarkers of fatigue that exist before cancer treatment. Relationships between the expression of latent Epstein–Barr virus (EBV) and cytomegalovirus (CMV) and fatigue were examined in 158 women newly diagnosed with breast cancer or awaiting a positive diagnostic result. Higher CMV antibody titers, but not EBV antibody titers, were associated with a greater likelihood of being fatigued. Associations between fatigue and higher CMV antibody titers remained after controlling for alcohol use, smoking, comorbidities, depressive symptoms, age, BMI, cancer stage, and sleep problems. More sleep problems and higher levels of depressive symptoms were also associated with a greater likelihood of being fatigued. CMV antibody titers, but not EBV antibody titers, were associated with higher levels of C-reactive protein (CRP), but CRP was not associated with fatigue. When the cellular immune system is compromised, reactivation of latent herpesviruses may fuel chronic inflammatory responses. Prior work has suggested that fatigue may be related to inflammation and its associated sickness behaviors; accordingly, our findings may be tapping into this same physiological substrate.

Observational studies have linked lower omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and higher omega-6 (n-6) PUFAs with inflammation and depression, but randomized controlled trial (RCT) data have been mixed. To determine whether n-3 decreases proinflammatory cytokine production and depressive and anxiety symptoms in healthy young adults, this parallel group, placebo-controlled, double-blind 12-week RCT compared n-3 supplementation with placebo. The participants, 68 medical students, provided serial blood samples during lower-stress periods as well as on days before an exam. The students received either n-3 (2.5 g/d, 2085 mg eicosapentaenoic acid and 348 mg docosahexanoic acid) or placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Compared to controls, those students who received n-3 showed a 14% decrease in lipopolysaccharide (LPS) stimulated interleukin 6 (IL-6) production and a 20% reduction in anxiety symptoms, without significant change in depressive symptoms. Individuals differ in absorption and metabolism of n-3 PUFA supplements, as well as in adherence; accordingly, planned secondary analyses that used the plasma n-6:n-3 ratio in place of treatment group showed that decreasing n-6:n-3 ratios led to lower anxiety and reductions in stimulated IL-6 and tumor necrosis factor alpha (TNF-α) production, as well as marginal differences in serum TNF-α. These data suggest that n-3 supplementation can reduce inflammation and anxiety even among healthy young adults. The reduction in anxiety symptoms associated with n-3 supplementation provides the first evidence that n-3 may have potential anxiolytic benefits for individuals without an anxiety disorder diagnosis. ClinicalTrials.gov identifier: NCT00519779.

Cancer-related distress is common among breast cancer survivors prior to treatment and is associated with adverse health effects. Moreover, many survivors continue to experience distress after treatment ends, and the impact of prolonged cancer-related distress on health is unknown. The aim of the current study was to investigate the effects of cancer-related distress on inflammation changes among breast cancer survivors. In a parent study, survivors stages 0- IIIC (N = 126 ) provided data prior to primary cancer treatment (i.e., surgery, radiation, or chemotherapy) and 18 months post-treatment. The current study utilized the Impact of Events Scale-Revised (IES-R) and proinflammatory cytokine interleukin-6 (IL-6). Cross-sectional analyses indicated that women reporting more cancer-related distress 18-months post- treatment evidenced greater inflammation compared to those with lower distress (b = 0.009 , SE = 0.004 , p = .050 ). Additionally, women who experienced greater declines in cancer-related distress evidenced smaller IL-6 increases from pre to post-treatment (b = 0.007 , SE = 0.003 , p = .041 ). Follow-up analyses indicated that changes in avoidance were related to changes in inflammation (b = 0.014 , SE = 0.005 , p = .010 ), but changes in intrusive thoughts were not (b = 0.005 , SE = 0.006 , p = .453 ). Women who experience prolonged cancer-related distress, and avoidant emotional coping in particular, may experience more persistent inflammation during survivorship, leaving them vulnerable to increased risk of recurrence and morbidity.

Marital stress has been associated with immune dysregulation, including increased production of interleukin-6 (IL-6). Attachment style, one’s expectations about the availability and responsiveness of others in intimate relationships, appears to influence physiological stress reactivity and thus could influence inflammatory responses to marital conflict. Thirty-five couples were invited for two 24-hour admissions to a hospital research unit. The first visit included a structured social support interaction, while the second visit comprised the discussion of a marital disagreement. A mixed effect within-subject repeated measure model indicated that attachment avoidance significantly influenced IL-6 production during the conflict visit but not during the social support visit. Individuals with higher attachment avoidance had on average an 11% increase in total IL-6 production during the conflict visit as compared to the social support visit, while individuals with lower attachment avoidance had, on average, a 6% decrease in IL-6 production during the conflict visit as compared to the social support visit. Furthermore, greater attachment avoidance was associated with a higher frequency of negative behaviors and a lower frequency of positive behaviors during the marital interaction, providing a mechanism by which attachment avoidance may influence inflammatory responses to marital conflict. In sum, these results suggest that attachment avoidance modulates marital behavior and stress-induced immune dysregulation.

Increased levels of proinflammatory cytokines, TNF-alpha and IL-6, predict mortality and morbidity. In cardiovascular disease patients, they are observed in atherosclerotic lesions and serum. Factors behind the increased levels of these cytokines are multifaceted and may include latent herpesviruses, such as Epstein-Barr virus (EBV) that can be reactivated by stress. Previously, we showed that the EBV-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase), a protein synthesized in the early phase of virus replication, can induce human monocytes/macrophages to produce TNF-alpha and IL-6. In this study, we modeled the interactions that take place between macrophages and endothelial cells in vivo using human umbilical vein endothelial cells (HUVEC). HUVEC were stimulated by soluble factors induced by EBV dUTPase-treated monocyte-derived macrophages (MDM) that resulted in the upregulation of VCAM-1 and ICAM-1. These changes were related to MDM production of TNF-alpha following the activation of NF-kappaB. In a previous study, chronically stressed dementia caregivers had elevations in plasma IL-6 levels, a risk for cardiovascular disease. We found a relationship between plasma IL-6 levels and neutralizing antibody titers to EBV dUTPase suggesting that one source of the plasma IL-6 observed in our previous study could be related to the effect of EBV-encoded dUTPase on macrophages. The results suggest that EBV-encoded dUTPase can enhance production of proinflammatory cytokines by monocytes/macrophages in contact with endothelial cells of blood vessels, and may play a role in cardiovascular pathology and chronic inflammation.

Chronically elevated systemic inflammation has a dramatic impact on health for older individuals. As stress-related responses, both hostility and pain perception may contribute to inflammation which in turn may maintain negative emotion and pain over time. We used structural equation modeling to examine the degree to which trait hostility and pain were uniquely associated with C-reactive protein (CRP) and serum IL-6 levels over a 6-year span in a sample of older adults. The sample included 113 present or former caregivers of a spouse with dementia and 101 non-caregivers. After accounting for depression, health behaviours, and other risk factors, which were also assessed longitudinally, pain and, to a lesser extent, hostility were uniquely associated with plasma levels of CRP but not IL-6. When examined separately, the association between pain and CRP was significant only for caregivers, while the association between hostility and CRP was comparable for the two groups. These findings suggest that hostility may play a role in a cycle of inflammation among older adults, and that pain may be particularly problematic for those under chronic stress. Our results also shed light on inflammation as a mechanism underlying the effects of hostility on cardiovascular disease morbidity and mortality.

Antibodies to several Epstein-Barr virus (EBV)-encoded enzymes are observed in patients with different EBV-associated diseases. The reason for these antibody patterns and the role these proteins might play in the pathophysiology of disease, separate from their role in virus replication, is unknown. In this series of studies, we found that purified EBV deoxyuridine triphosphate nucleotidohydrolase (dUTPase) can inhibit the replication of human peripheral blood mononuclear cells in vitro and upregulate the production of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10. It also enhanced the ability of natural killer cells to lyse target cells. The EBV dUTPase also significantly inhibited the replication of mitogen-stimulated lymphocytes and the synthesis of IFN-gamma by cells isolated from lymph nodes and spleens obtained from mice inoculated with the protein. It also produced sickness behaviors known to be induced by some of the cytokines that were studied in the in vitro experiments. These symptoms include an increase in body temperature, a decrease in body mass and in physical activity. The data provide a new perspective on how an early nonstructural EBV-encoded protein can cause immune dysregulation and produce clinical symptoms observed in patients with chronic fatigue syndrome (CFS) separate from its role in virus replication and may serve as a new approach to help identify one of the etiological agents for CFS. The data also provide additional insight into the pathophysiology of EBV infection, inflammation, and cancer.

The invitation to present the Norman Cousins Memorial Lecture to the Psychoneuroimmunology Research Society is a distinct honor; this recognition is clearly shared by my primary collaborator, Ronald Glaser, who has had equal responsibility for the design of our studies and whose laboratory generated most of the immunological data I will describe. We have addressed a number of questions since we initiated our joint research program in 1982: How do commonplace, everyday stressors affect the immune response? What are the health consequences of stress-related immunological changes? Does a chronic stressor promote persistent immunological dysregulation? Does age pose an additional risk factor? I will address each of these topics briefly; however, as a clinical psychologist, the studies of greatest interest to me are those that have examined the links between close personal relationships and immune responses and, in turn, how these elements are translated into important health outcomes. Thus, these issues will be my primary focus.

Telomeres, the caps found at the ends of chromosomes, have clinical significance for health: a growing literature links shorter telomeres with depression, poor health behaviors, age-related diseases, and mortality (Epel et al., 2010; Lin et al., 2012). Elegant prior work by Cohen and his colleagues clearly demonstrated that psychological stress and socioeconomic status (SES) alter infectious disease risk (Cohen et al., 2013). In their newest paper, Cohen and colleagues show that adults with lower SES during childhood had shorter telomeres on CD8+CD28− T-cells and were more likely to develop the common cold than adults with a higher childhood SES (Cohen et al., in press). The authors argue that lower childhood SES speeds the progression to replicative senescence in CD8+CD28− T-cells, an important T-cell subset because of its role in cancer and viral illnesses; shorter CD8+CD28− telomeres reflect greater senescence (Cohen et al., in press). Accordingly, childhood SES could have a far-reaching impact on disease susceptibility. Inflammation may be one mechanism linking lower childhood SES to shortened telomeres; inflammation triggers T-cell proliferation, one known cause of telomere shortening (Kiecolt-Glaser et al., 2013). Indeed, converging evidence suggests that other forms of childhood adversity, such as abuse or neglect, are linked to elevated levels of inflammation and shortened telomeres. For example, adults who experienced more early life adversity had higher inflammation and shorter telomeres than adults who experienced less early life adversity (Kiecolt-Glaser et al., 2011). Importantly, Cohen’s paper suggests that early childhood stressors may affect immune function throughout the lifespan (Cohen et al., in press); related work has demonstrated that adult SES also has immune consequences, potentially because low SES adults report high levels of stress and depression (Jaremka et al., 2013). For instance, adults with lower subjective SES had stronger inflammatory responses to a laboratory speech task than those with higher subjective SES, and tended to rate the task as more threatening and less manageable (Derry et al., 2013). Taken together, previous research and the new Cohen paper suggest that low SES and early life stress elevate inflammation, thereby shortening telomeres and increasing infectious disease susceptibility during adulthood. Prior work investigating the links among SES, early life adversity, inflammation, and disease susceptibility often utilized relatively healthy adult samples. Indeed, Cohen and colleagues tested their hypotheses with a unique sample of extremely healthy adults (Cohen et al., in press); their volunteers were free from major medical comorbidities and were not taking medication other than birth control. Furthermore, their average age was 29.8, with a range from 18 to 55. The odds of needing prescription medication for one or more chronic conditions rise steeply during middle age, and thus their sample represents the very best case scenario in terms of physical and mental health. Although telomere attrition is an important correlate of aging, health status affects this relationship. For example, healthy centenarians had longer telomeres than centenarians who had two or more chronic health conditions (Terry et al., 2008). Accordingly, chronic illness may further accelerate age-related telomere shortening. Indeed, many chronic diseases, including cancer, have inflammatory correlates or consequences (Jaremka et al., 2013). In this context, elevated inflammation among cancer survivors carries clear risks for accelerated aging. The tissue damage resulting from surgery, chemotherapy, and radiation may evoke inflammatory responses and thus shorten telomeres. Furthermore, many people reduce physical activity and gain weight during cancer treatment; low physical activity and adiposity are risk factors for higher inflammation and shorter telomeres, placing cancer survivors at further risk of accelerated aging. Depression, which affects a subset of cancer survivors, promotes inflammation and the premature aging of immune cells (Hewitt et al., 2003; Jaremka et al., 2013). Accordingly, the combination of depression and inflammatory-related chronic diseases may be a particularly potent challenge to cell aging. The findings by Cohen and colleagues suggest that this accelerated cell aging may affect disease susceptibility among cancer survivors; shortened telomeres enhance risk of infectious (Cohen et al., in press) and age-related diseases (Epel et al., 2010). Indeed, cancer survivors experience higher rates of other comorbid illnesses, such as cardiovascular disease, than those who have not had cancer (Hewitt et al., 2003); infectious disease risk may also be higher. In sum, inflammation and accelerated cell aging represent important pre-disease mechanisms that may be improved or worsened through multiple behavioral and biomedical pathways (Kiecolt-Glaser et al., 2013). Because short telomeres predict early disease, slowing immune cell aging could have broad effects by slowing the onset of age-related diseases.

Inflammation increases with age and is associated with many chronic diseases that are prevalent among older adults. Persistent pathogens such as latent herpesviruses and chronic bacterial infections can act as a source of inflammation. Herpesviruses, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV), establish latent infections following primary infection and reactivate when the cellular immune system is compromised. EBV and CMV replication can induce proinflammatory cytokine production and thus could influence systemic inflammation. The present study addressed relationships among EBV and CMV antibody titers, and levels of C-reactive protein (CRP) and interleukin-6 (IL-6) in a sample of 222 community dwelling older adults (meanage= 64.1 ± 14.1 years). Participants were divided into two groups based on whether they were EBV seropositive and CMV seronegative (EBV+CMV−), or EBV and CMV seropositive (EBV+CMV+). Among individuals who were EBV+CMV−, EBV antibody titers were not associated with either CRP or IL-6 levels. However, among those who were EBV+CMV+, higher EBV antibody titers were related to elevated levels of CRP and IL-6 in those individuals with higher CMV antibody titers; there was no relationship between EBV antibody titers and CRP or IL-6 levels in those participants with lower CMV antibody titers. These data suggest that the combination of latent EBV and CMV reactivation (indexed by antibody titers) may boost CRP and IL-6 production. Thus, reactivation of multiple herpesviruses may drive inflammation and could contribute to poorer health among older adults.

Married individuals reap many health benefits, including higher 5-year relative survival rates from cancer than unmarried individuals. We investigated whether cellular immune function differed by marital status (married vs. single vs. divorced, separated, or widowed) during the stress of cancer diagnosis. Immune dysfunction was indexed by reactivation of latent Epstein-Barr virus (EBV), and was measured using EBV viral capsid antigen (VCA) IgG antibody titers. In 393 men and women awaiting or shortly following diagnosis for breast or colorectal cancer, EBV antibody titers differed significantly by marital status, p

Attachment theory provides a framework for understanding individual differences in chronic interpersonal stress and may offer insight into the associations between interpersonal relationships and health. Attachment anxiety, a type of relationship insecurity characterized by worry about rejection and abandonment, is a chronic interpersonal stressor. Stress impacts cellular immunity, including herpesvirus reactivation. In this study, we investigated whether attachment anxiety was related to the expression of a latent herpesvirus, Epstein–Barr virus (EBV), during a stressful period when individuals were being tested for breast or colon cancer because of suspicious symptoms or a suspicious initial test, and then during a lower stress period approximately 1 year later. Participants ( n = 183) completed questionnaires and provided blood to assess EBV viral capsid antigen (VCA) IgG antibody titers. Compared with those who had lower attachment anxiety, individuals who had higher levels of attachment anxiety had higher EBV VCA IgG antibody titers, reflecting poorer cellular immune system control of the latent virus. General anxiety did not explain the association between attachment anxiety and EBV VCA IgG antibody titers. The association between attachment anxiety and EBV VCA IgG antibody titers was not more pronounced during the more stressful period compared with the less stressful period. This study adds to our growing understanding of how interpersonal relationships and chronic interpersonal stress influence immune function and health.

Although evidence suggests that attachment anxiety may increase risk for health problems, the mechanisms are not well understood. Married couples (N = 85, Mage = 38.67) provided saliva samples over three days and blood samples on two occasions. Participants with higher attachment anxiety produced more cortisol and had fewer numbers of CD45+ T cells, CD3+ T cells, CD3+CD4+ helper T cells, and CD3+CD8+ cytotoxic T cells than those with lower attachment anxiety. Higher cortisol was also related to fewer numbers of CD45+, CD3+, CD3+CD4+, and CD3+CD8+, which is mechanistically consistent with research showing that cortisol alters the cellular immune response. These data suggest that attachment anxiety may have physiological costs and provide a glimpse into the pathways through which social relationships impact health. The current study also extends attachment theory in an important new direction by utilizing a psychoneuroimmunological approach to the study of attachment anxiety, stress, and health.

In animal studies, the neuropeptides oxytocin and vasopressin have been implicated in social behaviors. In humans, plasma levels of oxytocin covary with perceptions of relationship quality, but little is known about the association between plasma vasopressin and social behaviors in humans. The goal of this study was to evaluate the relationships among plasma oxytocin and vasopressin and self-reported social functioning. Thirty-seven couples completed measures of social functioning and provided blood samples for neuropeptide analysis during a 24-hour admission to a hospital-based research unit. Higher plasma oxytocin was associated with less hostility among men, p = .001, but not women, p = .67. Across both men and women greater levels of vasopressin were associated with larger social networks, p = .05, less negative spousal interactions, p = .03, less attachment avoidance, p = .03, more attachment security p = .04, and marginally with greater spousal social support, p = .06. Overall, higher social functioning was associated with greater plasma vasopressin levels. This study provides evidence that plasma vasopressin levels have small, but significant associations with dimensions of social functioning in humans.

Psychological stress negatively affects proinflammatory cytokine production in the local wound environment, and examination stress can delay wound healing. Relaxation interventions are commonly used to reduce stress, and appear to promote recovery in surgical care settings. This study tested the effect of relaxation training on early wound repair in medical students with an upcoming examination. Medical students (n = 47) were randomized to receive either a relaxation intervention (n = 15) or wait-list (n = 32) immediately prior to an examination. All participants received standardized blister wounds upon arrival at a hospital research unit, and fluid from the blister chambers was aspirated 4 h, 7 h, and 22 h afterward. The subsequent relaxation intervention consisted of 5–6 h long structured sessions over the course of the stay. Students with higher Impact of Events scale Intrusion scores had significantly lower levels of interleukin-6 and tumor necrosis factor alpha at the wound site at 22 h post blister wounding. This effect remained when controlling for body mass index and randomization condition. Furthermore, higher levels of intrusions were associated with higher levels of negative affect on the Positive and Negative Affect Schedule after each relaxation session. These results suggest that the ability to regulate one’s emotions affects early wound repair, and that those with poor emotional regulation may require additional intervention efforts apart from progressive relaxation under stress.

Cigarette smoking continues to be the most preventable cause of illness and death. Current smokers have dysregulated hypothalamic–pituitary–adrenal (HPA) activity and elevated levels of inflammation compared to nonsmokers. To date, data in former smokers has been limited to observing persistent inflammation even years following cessation, yet there is little published on HPA function. This study examined cortisol and interleukin-6 (IL-6) responses to a laboratory stressor in breast cancer survivors who formerly smoked compared to their counterparts who had never smoked. Participants included 90 women (age = 51.4 ± 9.4 years) who had completed treatment for stage 0-IIIA breast cancer within the past three years and were at least two months post surgery, radiation or chemotherapy, whichever occurred last. Cortisol and IL-6 were evaluated in response to a standardized laboratory speech and mental arithmetic stressor. Former ( n = 25) and never ( n = 65) smokers did not differ by cancer stage, cancer treatment, comorbidities, time since treatment, depression, or stress. Despite having similar cortisol responses to the stressor, former smokers had exaggerated IL-6 responses two hours post-stressor compared to never smokers ( p

Herpesviruses characteristically persist in a latent state in the body over the lifetime of an individual. Under certain conditions, any one of the herpesviruses can be reactivated. The mechanisms underlying the establishment of latent virus infection or viral reactivation are not well understood; however, it is known that the cellular immune response plays a very important role in the maintenance of latency and in virus reactivation. One of the factors thought to be associated with the reactivation of latent herpes-viruses is psychological stress. Using an examination stress model with medical student subjects, we previously demonstrated the reactivation of latent Epstein-Barr virus (EBV), as measured by increases in antibody titers. In this follow-up study using the same group of medical students, we found evidence for incomplete reactivation of latent EBV, with only selective expression of the latent virus genome.

This paper summarizes important methodological issues that are particularly relevant for behavioral immunology research with humans. The assessment of such salient parameters as nutrition, drug/alcohol use, physical activity, and health are discussed. In addition, a number of logistical issues are addressed.

This study used a year-long prospective design to assess linkages among distress, immunity, and illness. Serial blood samples were collected from 40 first-year medical students at the first, third, and fifth examination periods, as well as 1 month before each. There were significant decrements in the production of gamma-interferon by concanavalin A-stimulated lymphocytes obtained at the time of examinations. Antibody titers to Epstein-Barr virus (EBV) increased during examination periods, suggesting reactivation of latent EBV and therefore poorer cellular immune control of latent virus. We obtained data that suggest that T-cell killing by memory T lymphocytes of EBV transformed autologous B lymphocytes also declined during examination periods. The activity of a lymphokine, leukocyte migration inhibition factor, normally suppressed during recrudescence of herpes simplex virus type 2 infections, was altered during examination periods and an increase in both plasma and intracellular levels of cyclic AMP associated with examination stress was observed. An increase in the incidence of self-reported symptoms of infectious illness was also associated with examination periods. The data support the linkage between stress-related immunosuppression and health.