Abstract from: Brain, Behavior, and Immunity (in press, 2008)
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Antagonistic Characteristics are Positively Associated with Inflammatory Markers Independently of Trait Negative Emotionality

Marsland, A. L., Prather, A. A., Petersen, K. L., Cohen, S., & Manuck, S. B.

Recent evidence suggests that individuals with certain personality traits are at elevated risk for chronic systemic inflammation. To date, this literature has focused on the related traits of hostility and negative affect (NA). In this study, we examine the covariation of trait measures of hostility and NA with the inflammatory mediators interleukin-6 and C-reactive protein. We also explore whether observed associations reflect independent contributions of cognitive, affective and behavioral components of hostile dispositions or shared trait variance with global negative affectivity. Subjects were a diverse sample of 855 relatively healthy middle-aged community volunteers (50% male) from the Adult Health and Behavior Project. The Buss and Perry Aggression Questionnaire (BPAQ) and an Abbreviated Cook-Medley Hostility Scale (ACM) were used to measure dimensions of hostility, and the Multidimensional Personality Questionnaire was used to measure trait NA. Regression analyses accounting for demographic characteristics and medical covariates showed a positive relationship of all components of hostility and trait NA with both IL-6 and CRP. After controlling for trait NA, only the behavioral component of hostility was independently associated with the inflammatory markers. The relationships of cognitive and affective components of hostility with inflammatory markers were largely explained by lifestyle factors, particularly body mass index and smoking. In contrast, lifestyle factors did not explain the covariation of hostile behavioral tendencies and inflammation. These findings suggest that unique attributes of aggresive behavioral tendencies account for much of the variability in inflammation associated with hostility and negative emotions, raising the possibility that individuals high in aggression are at increased risk of inflammatory disease.

Eighty-four healthy graduate participants were administered the standard course of 3 hepatitis B vaccinations. Five months after the first dose (shortly after the second injection), each participant completed psychosocial measures, and a blood sample was drawn for determination of hepatitis B surface antibody titer. After completion of the vaccination series, participants performed an acute stress protocol, consisting of a 30-min adaptation period and a 5-min evaluative speech task. Blood was drawn at the end of the resting and task periods for assessment of cellular immune measures. Lower antibody response, as assessed after the second hepatitis B injection, was predicted independently by (a) high trait negative affect and (b) diminished T-cell proliferation in response to PHA. These data provide evidence that trait negative affect and the magnitude of stress-induced suppression of immune function may have clinical significance.

Psychological Stress and Antibody Response to Immunization: A Critical Review of the Human Literature.

Cohen, S., Miller, G.E., and Rabin, B.S.

Objective: To evaluate the evidence for the hypothesis that psychological stress influences antibody response to immunization in humans.

Methods: Critical review of the literature.

Results: The evidence supports an association between psychological stress and suppression of humoral immune (antibody) response to immunization. This association is convincing in the case of secondary immune response but weak for primary response. The lack of consistent evidence for a relation with primary response may be attributable to a failure to consider the critical point(s) when stress needs to be elevated in the course of the production of antibody. Lower secondary antibody responses were found among patients with chronically high levels of stress (severe enduring problems or high levels of trait negative affect). These responses were found most consistently among older adults. Lower secondary responses were also found for those reporting acute stress or negative affect, but only in studies of S-IgA antibody where psychological and antibody measures were linked very closely in time. Health practices did not mediate relations between stress and antibody responses, however, there were indications that elevated cortisol levels among stressed patients could play a role. Evidence also suggests the possible influences of dispositional stress-reactivity and low positive affect in the inhibition of antibody production.

Conclusions: The literature supports a relationship between psychological stress and antibody responses to immunizations. The data are convincing in the case of secondary response but weak for primary response. More attention to the kinetics of stress and antibody response and their interrelations is needed in future research.

Psychological Interventions and the Immune System: A Meta-Analytic Review and Critique.

Miller, G.E., and Cohen, S.

This article reviews evidence for the hypothesis that psychological interventions can modulate the immune response in humans, and presents a series of models depicting the psychobiological pathways through which this might occur. Although more than eighty-five trials have been conducted, meta-analyses reveal only modest evidence that interventions can reliably alter immune parameters. The most consistent evidence emerges from hypnosis and conditioning trials. Disclosure and stress-management show scattered evidence of success. Relaxation demonstrates little capacity to elicit immune change. While these data provide only modest evidence of successful immune modulation, it would be premature to conclude that the immune system is unresponsive to psychological interventions. This literature has important conceptual and methodological issues that need to be resolved before any definitive conclusions can be reached.

The Stability of and Intercorrelations Among Cardiovascular, Immune, Endocrine, and Psychological Reactivity.

Cohen, S., Hamrick, N., Rodriguez, M.S., Feldman, P.J., Rabin, B.S., and Manuck, S.B.

One hundred fifteen college students were exposed to an evaluative speech task twice, separated by two weeks. At both sessions, we assessed cardiovascular, endocrine, immune, and psychological response at baseline and during the task. We found stability across sessions for stress-induced increases in anxiety and task engagement, heart rate, blood pressure, norepinephrine (but not epinephrine), cortisol, natural killer cell cytotoxicity, and numbers of circulating CD3+, CD8+, and CD56+ (but not CD4+ or CD19+) lymphocytes. The stable cardiovascular, immune, and endocrine reactivities were intercollated, providing evidence of a unified physiological stress response across these outcomes. Although stable stress-induced increases in task engagement were associated with the physiological stress responses, stress-induced anxiety was not.

The Impact of Personality on the Reporting of Unfounded Symptoms and Illness.

Feldman, P.J., Cohen, S., Doyle, W.J., Skoner, D.P., and Gwaltney, J.M.

We examined the role of personality in the reporting of symptoms and illness not supported by underlying pathology. After assessment of the "Big Five" personality factors, 276 healthy volunteers were inoculated with a common cold virus. On each of the following five days, we assessed objective indicators of pathology, self-reported symptoms, and self-reported illness onset. Neuroticism was directly associated with reports of unfounded (without a physiological basis) symptoms in individuals at baseline and post-inoculation in those with and without colds. Neuroticism was also indirectly associated with reports of unfounded illness through greater symptom reporting. Openness was associated with reporting unfounded symptoms in those with verifiable colds, while conscientiousness was associated with reporting unfounded illness in those who were not ill.

Negative Emotions and Acute Physiological Responses to Stress.

Feldman, P.J., Cohen, S., Lepore, S.J., Matthews, K.A., Kamarck, T.W., and Marsland, A.L.

One pathway through which stressors are thought to influence physiology is through their effects on emotion. We used meta-analytic statistical techniques with data from nine studies to test the effects of acute laboratory stressors (speech, star mirror-image tracing, handgrip) on emotional (undifferentiated negative emotion, anger, anxiety) and cardiovascular (CV) response. In all of the studies, participants responded to stressors with both increased CV response and increased negative emotion. Increases in negative emotion were associated with increases in CV response across tasks, however, these associations were small. The range of variance accounted for was between 2% and 12%. Thus, the contribution of negative emotion, as assessed in these studies, to physiological responses to acute laboratory stressors was limited. Although these results raise questions about the role of emotion in mediating stress-elicited physiological responses, the nature of the acute laboratory stress paradigm may contribute to the lack of a strong association.

Social Status and Susceptibility to Respiratory Infections.

Cohen, S.

Adults and children of lower socioeconomic status (SES) are at higher risk for a wide range of communicable infectious diseases, especially respiratory infections. Greater risk for infectious illness among people with lower SES is thought to be attributable to increased exposure to infectious agents and decreased host resistance to infection. We summarize three studies that examine the prospective association of several markers of social status (unemployment, perceived and observed social status) with host resistance to upper respiratory infections. Unemployment was associated with increased susceptibility to infection in adult humans. Lower social status in male monkeys was also associated with increased susceptibility, as was lower perceived social status in humans. The association of social status and susceptibility was accounted for primarily by increased risk in the lowest social status groups. However, further increases in social status were associated with further decreases in susceptibility in both monkeys and humans.

Psychological Stress, Cytokine Production and Severity of Upper Respiratory Illness.

Cohen, S., Doyle, W. J., and Skoner, D. P.

Objective: To assess the role of psychological stress in the expression of illness among infected subjects and test the plausibility of local pro-inflammatory cytokine production as a pathway linking stress to illness.

Methods: After completing a measure of psychological stress, 55 subjects were experimentally infected with an influenza A virus. Subjects were monitored in quarantine daily for upper respiratory symptoms, mucus production, and nasal lavage levels of interleukin (IL) 6.

Results: Higher psychological stress assessed prior to the viral challenge was associated with greater symptom scores, greater mucus weights, and higher IL-6 lavage concentrations in response to infection. The IL-6 response was temporally related to the two markers of illness severity, and mediation analyses indicated that these data were consistent with IL-6 acting as a major pathway through which stress was associated with increased symptoms of illness. However, this pattern of data is also consistent with rises in IL-6 occurring in response to tissue damage associated with illness symptoms.

Conclusions: Psychological stress predicts a greater expression of illness and an increased production of IL-6 in response to an upper respiratory infection.

Pathways Linking Major Depression and Immunity in Ambulatory Female Patients.

Miller, G. E., Cohen, S., and Herbert, Tracy B.

Objective: The goals of this study were to investigate whether depression is associated with cellular immunity in ambulatory patients and to identify neuroendocrine and behavioral pathways that might account for this relationship. Method: We studied 32 women who met DSM-IV criteria for Major Depressive Disorder and 32 healthy female control subjects. The groups were matched on age and ethnicity. All were unmedicated and free of disease involving the immune system. Results: Depressed subjects had reduced proliferative responses to the mitogens ConA and PHA compared to controls. Natural killer cell activity was reduced among older depressed subjects but enhanced among younger depressed subjects. Although depression was associated with elevated circulating levels of norepinephrine and estradiol, these hormones could not account for the immunologic differences between depressed and control subjects. Depression was also associated with greater tobacco and caffeine consumption, less physical activity, and poorer sleep quality. Mediational analyses were consistent with physical activity acting as a pathway through which depression was associated with reduced lymphocyte proliferation. Conclusions: Ambulatory patients with mild to moderately severe depression exhibit reduced mitogen-stimulated lymphocyte proliferative responses and altered natural killer cell cytotoxicity. The relationship between depression and proliferative responses may be mediated by physical activity.

Cohen, S., Doyle, W. J., Skoner, D. P., Rabin, B. S., and Gwaltney, J. M.
 
Objective: To examine the hypothesis that diverse ties to friends, family, work, and community are associated with increased host resistance to infection.

Design:  After reporting the extent of  participation in 12 types of social ties (e.g., spouse, parent, friend, workmate, member of social group), subjects were given nasal drops containing one of two rhinoviruses, and monitored for the development of  a common cold.

Setting:  Quarantine.

Participants:  276 healthy volunteers, ages 18-55, neither HIV positive nor pregnant.

Outcome Measures: Colds (illness in the presence of a verified infection), mucus production, mucociliary clearance function, and amount of viral replication.

Results:  In response to both viruses, those with more types of social ties were less susceptible to common colds, shed less virus, produced less mucus, and were more effective in ciliary clearance of their nasal passages.  These relations were unaltered by statistical controls for pre-challenge virus-specific antibody, virus-type, age, gender, season, body mass, education, and race.   Susceptibility to colds decreased in a dose-response manner with increased diversity of the social network.  There was an adjusted relative risk of 4.2 comparing persons with fewest (1-3) to those with most (6 or more) types of social ties.  Although smoking, poor sleep quality, alcohol abstinence, low dietary intake of vitamin C, elevated catecholamine levels, and being introverted were all associated with greater susceptibility to colds, they could only partially account for the relation between social network diversity and incidence of colds.

Conclusions: More diverse social networks were associated with greater resistance to upper respiratory illness.
 

Types of Stressors That Increase Susceptibility to the Common Cold in Healthy Adults.

Cohen, S., Frank, E., Doyle, W. J., Skoner, D. P., Rabin, B. S., and Gwaltney, J.

Two-hundred seventy-six volunteers completed a life stressor interview and psychological questionnaires and provided blood and urine samples.  They were then inoculated with common cold viruses and monitored for the onset of disease.  Although severe acute stressful life events (less than 1 month long) were not associated with developing colds, severe severe chronic stressors (1 month or longer) were associated with a substantial increase in risk of disease.  This relation was attributable primarily to under- or unemployment and to enduring interpersonal difficulties with family or friends.  The association between chronic stressors and susceptibility to colds could not be fully explained by differences among stressed and nonstressed persons in social network characteristics, personality, health practices, or prechallenge endocrine or immune measures.
 
 Updated April 8, 2008