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Attachment theory provides a framework for understanding individual differences in chronic interpersonal stress. 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. We investigated whether attachment anxiety was related to the expression of a latent herpesvirus, Epstein-Barr virus (EBV), when individuals were being tested for breast or colon cancer and approximately 1 year later. Participants (N=183) completed a standard attachment questionnaire and provided blood to assess EBV viral capsid antigen (VCA) IgG antibody titers. Individuals with more attachment anxiety had higher EBV VCA IgG antibody titers than those with less attachment anxiety. The strength of the association between attachment anxiety and antibody titers was the same at both assessments. This study is the first to show an association between latent herpesvirus reactivation and attachment anxiety. Because elevated herpesvirus antibody titers reflect poorer cellular immune system control over the latent virus, these data suggest that high attachment anxiety is associated with cellular immune dysregulation., (Copyright © 2014. Published by Elsevier Inc.)

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 min and 2 h 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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Adverse pregnancy outcomes, including preterm birth, are markedly higher among African-Americans versus Whites. Stress-induced immune dysregulation may contribute to these effects. Epstein-Barr virus (EBV) reactivation provides a robust model for examining cellular immune competence. This study examined associations of EBV virus capsid antigen immunoglobulin G (VCA IgG) with gestational stage, race, and racial discrimination in women during pregnancy and postpartum., Methods: Fifty-six women (38 African-American, 18 White) were included. African-Americans and Whites did not differ in age, education, income, parity, or body mass index (ps ≥ .51). During the 1st, 2nd, and 3rd trimester and ~5 weeks postpartum, women completed measures of racial discrimination, perceived stress, anxiety, depressive symptoms and health behaviors. EBV VCA IgG antibody titers were measured via ELISA in serum collected at each visit., Results: In the overall sample, EBV VCA IgG antibody titers were lower in the 3rd versus 1st trimester (p=.002). At every timepoint (1st, 2nd, 3rd trimester and postpartum), African-American women exhibited higher serum EBV VCA IgG antibody titers than Whites (ps<.001). This effect was most pronounced among African-Americans reporting greater racial discrimination [p=.03 (1st), .04 (2nd), .12 (3rd), .06 (postpartum)]. Associations of race and racial discrimination with EBV VCA IgG antibody titers were not accounted for by other measures of stress or health behaviors., Conclusions: Compared to Whites, African-American women showed higher EBV VCA IgG antibody titers, indicative of impaired cellular immune competence, across pregnancy and postpartum. This effect was particularly pronounced among African-American women reporting greater racial discrimination, supporting a role for chronic stress in this association. In women overall, EBV antibody titers declined during late as compared to early pregnancy. This may be due to pregnancy-related changes in cell-mediated immune function, humoral immune function, and/or antibody transfer to the fetus in late gestation. As a possible marker of stress-induced immune dysregulation during pregnancy, the role of EBV reactivation in racial disparities in perinatal health warrants further attention., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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 (mean(age)=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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Psychological stress-associated immune dysregulation has been shown to disrupt the steady-state expression and reactivate latent herpes viruses. One such virus is the Epstein Barr virus (EBV), which is associated with several human malignancies. EBV infects >90% of people living in North America and persists for life in latently infected cells. Although several studies have shown that glucocorticoids (GCs) can directly induce reactivation of the latent virus, the mechanism of stress hormone involvement in the control of EBV gene expression is not well understood. In this study, we tested the hypothesis that GCs can induce the latent EBV genome to lytically replicate through the induction of the EBV immediate early gene BZLF1 which encodes the lytic transactivator protein ZEBRA. We show a dose-dependent upregulation of BZLF1 mRNA expression by hydrocortisone (HC) and dexamethasone (Dex) in Daudi cells, an EBV genome positive Burkitt's lymphoma cell line, and Dex-induction of the early gene products BLLF3 (encoding for the EBV dUTPase) and BALF5 (encoding for the EBV DNA polymerase). We show that Daudi cells express glucocorticoid receptors (GR) that mediate Dex-dependent upregulation of BZLF1 mRNA levels. This effect was inhibited by both the glucocorticoid receptor antagonist RU486 and by cycloheximide. The results suggest that GCs, in addition to inducing stress-related immune dysregulation, can mediate latent EBV reactivation through the induction of the BZLF1 gene., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: Stress and depressive symptoms predict exaggerated inflammatory responses to a biological challenge in nonpregnant humans and animals. The extent to which these findings generalize to pregnancy is unknown because the immune system exhibits substantial changes to support pregnancy. Notably, inflammatory responses to infectious agents play a causal role in the development of gestational hypertension as well as risk for preterm birth. Thus, depressive symptoms may increase susceptibility to these outcomes via sensitization of inflammatory processes. The current study was designed to test the hypothesis that depressive symptoms would predict an exaggerated proinflammatory response to an in vivo antigen challenge, influenza virus vaccination, among pregnant women., Method: Twenty-two pregnant women completed two study visits: baseline and 1week after receiving influenza virus vaccination. Depressive symptoms were measured with the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline. Serum levels of macrophage migration inhibitory factor (MIF) were determined using a high sensitivity immunoassay at both study visits., Outcomes: Analyses demonstrated that, as compared to those in the lowest tertile of CES-D scores, those in the highest tertile exhibited significantly higher levels of MIF 1week after influenza virus vaccination (p=.035)., Conclusions: Depressive symptoms predicted exaggerated MIF production following influenza virus vaccination during pregnancy. These data support the hypothesis that depressive symptoms are associated with sensitization of the inflammatory response during pregnancy. Thus, women with greater depressive symptoms may be more vulnerable to negative sequelae of infectious illness during pregnancy.

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-h 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.

Psychosocial stress and depressive symptoms are associated with increased risk of negative perinatal outcomes including preterm delivery and gestational hypertension. Inflammation is a likely mechanism by which distress may promote these outcomes. It is well-established that stress and depressive symptoms are associated with elevated serum inflammatory markers in nonpregnant populations. However, the immune system exhibits significant changes during pregnancy. Thus, the extent to which these findings extend to pregnancy is largely unknown. The current study examined associations among perceived stress, depressive symptoms, and serum inflammatory markers in a sample of 60 pregnant women. Fifty seven percent were African-American, 82% had completed high school or less education, and 63% reported an annual family income below $15,000. Participants completed the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression Scale (CES-D). Serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were determined using high sensitivity immunoassays. Regression analyses demonstrated that after controlling for pre-pregnancy Body Mass Index (BMI), higher scores on the CES-D were related to significantly higher levels of IL-6 (beta=.23, p=.05) and marginally higher TNF-alpha (beta=.24, p=.06). Perceived stress was not significantly related to serum levels of IL-6 or TNF-alpha. In sum, these results indicate that depressive symptoms are associated with higher levels of maternal serum inflammatory markers during pregnancy. These data are consistent with the contention that depressive symptoms may contribute to negative perinatal outcomes via inflammatory pathways.

Studies suggest that stress can be a co-factor for the initiation and progression of cancer. The catecholamine stress hormone, norepinephrine (NE), may influence tumor progression by modulating the expression of factors implicated in angiogenesis and metastasis. The goal of this study was to examine the influence of NE on the expression of VEGF, IL-8, and IL-6 by the human melanoma cell lines, C8161, 1174MEL, and Me18105. Cells were treated with NE and levels of VEGF, IL-8, and IL-6 were measured using ELISA and real-time PCR. The expression of beta-adrenergic receptors (beta-ARs) mRNA and protein were also assessed. Finally, immunohistochemistry was utilized to examine the presence of beta1- and beta2-AR in primary and metastatic human melanoma biopsies. We show that NE treatment upregulated production of VEGF, IL-8, and IL-6 in C8161 cells and to a lesser extent 1174MEL and Me18105 cells. The upregulation was associated with induced gene expression. The effect on C8161 cells was mediated by both beta1- and beta2-ARs. Furthermore, 18 of 20 melanoma biopsies examined expressed beta2-AR while 14 of 20 melanoma biopsies expressed beta1-AR. Our data support the hypothesis that NE can stimulate the aggressive potential of melanoma tumor cells, in part, by inducing the production VEGF, IL-8, and IL-6. This line of research further suggests that interventions targeting components of the activated sympathetic-adrenal medullary (SAM) axis, or the utilization of beta-AR blocking agents, may represent new strategies for slowing down the progression of malignant disease and improving cancer patients' quality of life.

Certain patterns of anger expression have been associated with maladaptive alterations in cortisol secretion, immune functioning, and surgical recovery. We hypothesized that outward and inward anger expression and lack of anger control would be associated with delayed wound healing. A sample of 98 community-dwelling participants received standardized blister wounds on their non-dominant forearm. After blistering, the wounds were monitored daily for 8 days to assess speed of repair. Logistic regression was used to distinguish fast and slow healers based on their anger expression pattern. Individuals exhibiting lower levels of anger control were more likely to be categorized as slow healers. The anger control variable predicted wound repair over and above differences in hostility, negative affectivity, social support, and health behaviors. Furthermore, participants with lower levels of anger control exhibited higher cortisol reactivity during the blistering procedure. This enhanced cortisol secretion was in turn related to longer time to heal. These findings suggest that the ability to regulate the expression of one's anger has a clinically relevant impact on wound healing.

Evidence from human and animal studies support the hypothesis that psychological stress can be a co-factor for the initiation and progression of cancer. Recent work from our laboratory and others have shown that the catecholamine hormone, norepinephrine (NE), may influence tumor progression of some solid epithelial tumors including nasopharyngeal carcinoma (NPC) and ovarian cancer by modulating the expression of proangiogenic and pro-metastatic factors, such as vascular endothelial growth factor (VEGF). In this study, we determined whether NE can likewise modulate the expression of VEGF in a lymphoid tumor, multiple myeloma (MM), a cancer of plasma cells. Three MM-derived cell lines, NCI-H929, MM-M1, and FLAM-76, were studied. The presence of beta1- and beta2-adrenergic receptors (ARs) was assessed using Western blotting. Cells were treated with 0, 1, and 10 microM NE for 1, 3, 6, and 24h and the levels of VEGF in culture supernatants were measured by ELISA. Immunoblots of cell lysates revealed the presence of beta1- and beta2-ARs in all three MM-derived cell lines. However, these MM-derived cell lines exhibited varying degrees of NE-dependent regulation of VEGF expression with FLAM-76 (the only IL-6-dependent cell line among the three) exhibiting the most significant stimulation, followed by MM-M1 cells and then NCI-H929. The data suggest that the ability of NE to regulate the expression of VEGF is not limited to solid epithelial tumors and suggests a possible regulatory role of catecholamine stress hormones in MM progression.

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.

Purpose: Psychological interventions are efficacious in reducing emotional distress for cancer patients. However, it is not clear whether psychological improvements are, in turn, related to improved health. A clinical trial tests whether a psychological intervention for cancer patients can do so, and also tests two routes to achieve better health: (a) reducing patients' Emotional Distress, and/or (b) enhancing their functional immunity., Methods: Post-surgery, 227 breast cancer patients were randomized to intervention or assessment only Study Arms. Conducted in small groups, intervention sessions were offered weekly for 4 months and followed by monthly sessions for 8 months. Measures included psychological (distress), biological (immune), and health outcomes (performance status and evaluations of patient's symptomatology, including toxicity from cancer treatment, lab values) collected at baseline, 4 months, and 12 months., Results: A path model revealed that intervention participation directly improved health (p<.05) at 12 months. These effects remained when statistically controlling for baseline levels of distress, immunity, and health as well as sociodemographic, disease, and cancer treatment variables. Regarding the mechanisms for achieving better health, support was found for an indirect effect of distress reduction. That is, by specifically lowering intervention patients' distress at 4 months, their health was improved at 12 months (p<.05). Although the intervention simultaneously improved patients' T-cell blastogenesis in response to phytohemagglutinin (PHA), the latter increases were unrelated to improved health., Conclusion: A convergence of biobehavioral effects and health improvements were observed. Behavioral change, rather than immunity change, was influential in achieving lower levels of symptomatology and higher functional status. Distress reduction is highlighted as an important mechanism by which health can be improved.

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.

Historically, clinicians have suspected that both major and minor stressful events can have health implications. Observations and case reports link severely stressful life events with a sudden onset or worsening of a variety of illnesses. The immune system was quickly implicated as a means to help explain how stressful life events could produce this relationship. The field of psychoneuroimmunology (PNI) is a field of research that deals with the complex interactions between the central nervous system, endocrine and immune systems, and how behavior/stress can modify these interactions. In this review, I have selected some of our papers that represent our efforts to study the effects of stress on the immune response and also include selected papers that describe how our PNI program at The Ohio State University Medical Center has evolved; virtually all of this research has been performed in collaboration with Janice Kiecolt-Glaser and others in our research group.

In this study, we searched for evidence for reactivation of three latent herpesviruses, Epstein-Barr virus (EBV), herpes simplex virus type-1 (HSV-1), and human herpesvirus 6 (HHV-6), in West Point cadets experiencing two different stressors. Blood samples were obtained from cadets before and after a 6-week training period known as "Cadet Basic Training" (CBT), at a baseline prior to final examinations, and then once again during the week of final examinations. Antibody titers to latent HSV-1, EBV, and HHV-6 were determined as a measure of the steady-state expression of latent virus. EBV virus capsid antigen (VCA) IgG antibody titers were unchanged in blood samples obtained prior to and immediately after CBT. However, EBV antibody titers were significantly higher in the blood sample obtained during examination week than in the baseline period before examination; they were also higher than antibody titers before/after CBT. None of the serum samples were positive for EBV VCA IgM antibodies, indicating that the changes in antibody titers to EBV were not associated with recent EBV infections in the class. No significant changes in antibody titers to HSV-1 or HSV-6 were found over the identical time periods, including examination week. Academic stress but not CBT modulated the steady-state expression of latent EBV, resulting in the reactivation of latent virus. The same stressors, however, did not affect the steady-state expression of latent HSV-1 or HSV-6, at least as measured by changes in antibody titers. The data provide additional evidence of the impact of different psychological stressors on the steady-state expression of latent herpesviruses., (Copyright 1999 Academic Press.)

The stress of physical restraint has been shown to modulate the cellular immune response during a viral infection. We have studied the effects of stress on the humoral immune response during infection by influenza virus. Restraint stress altered the kinetics of the antibody response; seroconversion in the IgG and IgA isotypes was delayed in virus-infected C57BL/6 mice subjected to repeated cycles of physical restraint. However, the magnitude and isotype of the mature antibody response were unaffected during the plateau phase; no significant differences were observed between restrained/infected and nonrestrained/infected mice. Thus, the time during infection at which the antibody response was measured was a significant variable in the study of stress-induced alterations of the host's response to a replicating viral antigen. While restraint stress did not significantly affect the magnitude or class of the humoral response, it did alter the kinetics of response.

Using a murine model, we have previously shown that restraint stress is able to suppress the development of herpes simplex virus (HSV)-specific cytotoxic T lymphocytes (CTL) and natural killer (NK) cell activity in the popliteal lymph nodes following local footpad infection. These studies of the primary cell-mediated immune response to HSV infection have been extended to examine the effects of a similar stressor on the development of HSV-specific memory CTL (CTLm) following local and systemic HSV infection. In addition, the effect of stress on HSV-specific CTLm localization and proliferation in the popliteal lymph node following reexposure to HSV was investigated. Lastly, the ability to stimulate HSV-specific CTLm to the lytic phenotype under conditions of restraint stress was examined. Restraint stress did not inhibit the generation of HSV-specific CTLm. However, restraint stress inhibited the ability to activate CTLm to the lytic phenotype. In HSV seropositive mice (primed prior to stress), restraint stress prevented the in vivo activation and/or migration of HSV-specific CTLm in the popliteal lymph nodes. These findings demonstrate that activation of HSV-specific immunological memory can be inhibited by physiological changes associated with stress. Such immune inhibition may provide a possible mechanism for the development of recrudescent herpetic disease.

Stressful events suppress a broad spectrum of both humoral and cellular immunological responses. However, studies of the effects of stress on the development of specific antiviral immune responses have not been reported. We have utilized an established murine model of an acute, local footpad Herpes simplex virus type 1 (HSV-1) infection to study the effect of restraint stress on the generation of HSV-specific cytotoxic T lymphocytes (CTL) and natural killer (NK) cell activity. Lymphoproliferative responses in the popliteal lymph nodes following footpad infection as well as the generation of HSV-specific CTL and NK cell activity were depressed in restrained mice compared to infected, unrestrained controls. Frequency analyses of HSV-specific pre-CTL indicated that suppression of the CTL response occurred early in the sequence of events that precedes the generation of functionally lytic CTL and was not mediated by a diminished IL-2 response. Although restrained mice exhibited fewer lymphocytes in the popliteal lymph nodes, the subset distribution was the same as that in the unrestrained controls. Furthermore, stress-induced immunosuppression resulted in a higher titer of infectious HSV at the site of infection. Overall, these findings provide evidence that physiological changes associated with restraint stress can influence the immune response to a specific viral infection and alter the course of viral pathogenesis.

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.