In considering new paradigms for the prevention and treatment of disease and disability, we need to incorporate ways to promote social support and develop family and community strengths and abilities into our interventions. There is now a substantial body of evidence that indicates that the extent to which social relationships are strong and supportive is related to the health of individuals who live within such social contexts. A review of population-based research on mortality risk over the last 20 years indicates that people who are isolated are at increased mortality risk from a number of causes. More recent studies indicate that social support is particularly related to survival postmyocardial infarction. The pathways that lead from such socioenvironmental exposures to poor health outcomes are likely to be multiple and include behavioral mechanisms and more direct physiologic pathways related to neuroendocrine or immunologic function. For social support to be health promoting, it must provide both a sense of belonging and intimacy and must help people to be more competent and self-efficacious. Acknowledging that health promotion rests on the shoulders not only of individuals but also of their families and communities means that we must commit resources over the next decade to designing, testing, and implementing interventions in this area.

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The role of social relations in health promotion

This article presents a meta-analysis of the literature on stress and immunity in humans. The primary analyses include all relevant studies irrespective of the measure or manipulation of stress. The results of these analyses show substantial evidence for a relation between stress and decreases in functional immune measures (proliferative response to mitogens and natural killer cell activity). Stress is also related to numbers and percent of circulating white blood cells, immunoglobulin levels, and antibody titers to herpesviruses. Subsequent analyses suggest that objective stressful events are related to larger immune changes than subjective self-reports of stress, that immune response varies with stressor duration, and that interpersonal events are related to different immune outcomes than nonsocial events. We discuss the way neuroendocrine mechanisms and health practices might explain immune alteration following stress, and outline issues that need to be investigated in this area.

Stress and immunity in humans: a meta-analytic review.

The links between the psychological and physiological features of cancer risk and progression have been studied through psychoneuroimmunology. The persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis in the chronic stress response and in depression probably impairs the immune response and contributes to the development and progression of some types of cancer. Here, we overview the evidence that various cellular and molecular immunological factors are compromised in chronic stress and depression and discuss the clinical implications of these factors in the initiation and progression of cancer. The consecutive stages of the multistep immune reactions are either inhibited or enhanced as a result of previous or parallel stress experiences, depending on the type and intensity of the stressor and on the animal species, strain, sex, or age. In general, both stressors and depression are associated with the decreased cytotoxic T-cell and natural-killer-cell activities that affect processes such as immune surveillance of tumours, and with the events that modulate development and accumulation of somatic mutations and genomic instability. A better understanding of the bidirectional communication between the neuroendocrine and immune systems could contribute to new clinical and treatment strategies.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(04)01597-9.pdf

Stress, depression, the immune system, and cancer

Negative emotions can intensify a variety of health threats. We provide a broad framework relating negative emotions to a range of diseases whose onset and course may be influenced by the immune system; inflammation has been linked to a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, Alzheimer's disease, frailty and functional decline, and periodontal disease. Production of proinflammatory cytokines that influence these and other conditions can be directly stimulated by negative emotions and stressful experiences. Additionally, negative emotions also contribute to prolonged infection and delayed wound healing, processes that fuel sustained proinflammatory cytokine production. Accordingly, we argue that distress-related immune dysregulation may be one core mechanism behind a large and diverse set of health risks associated with negative emotions. Resources such as close personal relationships that diminish negative emotions enhance health in part through their positive impact on immune and endocrine regulation.

/pdf/emotions-morbidity-and-mortality-new-perspectives-from-21xqw9h3pz.pdf

Emotions, morbidity, and mortality: new perspectives from psychoneuroimmunology.

This is a broad meta-analysis of the relations of both depression and stressors to immunological assays. The number of study samples (greater than 180) and measures (greater than 40) is much more extensive than any so far. Analyses are done by both fixed and random effects. By a fixed-effects analysis, both major depression and naturally occurring acute stressors are associated with (1) an overall leukocytosis, (2) mild reductions in absolute NK-cell counts and relative T-cell proportions, (3) marginal increases in CD4/CD8 ratios, and (4) moderate decreases in T- and NK-cell function. However, the degree of heterogeneity of the studies' results raises questions about their robustness. Therefore, we also did the first random effects analysis to estimate what is likely to appear in future studies. For depression, the analysis showed the immunological correlates included (1) an overall leukocytosis, manifesting as a relative neutrophilia and lymphoenia; (2) increased CD4/CD8 ratios; (3) increased circulating haptoglobin, PGE(2), and IL-6 levels; (4) reduced NK-cell cytotoxicity; and (5) reduced lymphocyte proliferative response to mitogen. For stressors, the random effects analysis showed that future studies are likely to find the following effects: (1) an overall leukocytosis, manifesting as an absolute lymphocytosis; (2) alterations in cytotoxic lymphocyte levels, CD4/CD8 ratios, and natural killer cell cytotoxicity with the direction of change depending on the chronicity of the stressor; (3) a relative reduction of T-cell levels; (3) increased EBV antibody titers; (4) reduced lymphocyte proliferative response and proportion of IL-2r bearing cells following mitogenic stimulation; and (5) increased leukocyte adhesiveness. The random-effects analysis revealed that for both major depression and naturally occurring stressors the following effects are shared: leukocytosis, increased CD4/CD8 ratios, reduced proliferative response to mitogen, and reduced NK cell cytotoxicity. The implications for these findings for disease susceptibility and the pathophysiology of these conditions is discussed.

The relationship of depression and stressors to immunological assays: a meta-analytic review.

In a prospective study of 15 spouses of women with advanced breast carcinoma, lymphocyte stimulation responses to phytohemagglutinin, concanavalin A, and pokeweed mitogen were significantly suppressed during the first two months following the death of a spouse compared with prebereavement levels. A highly significant suppression was seen as early as one month after bereavement. No differences were found in total lymphocyte or B- or T-cell numbers. An intermediate level of mitogen responsivity was found during the four- to 14-month period after bereavement. Suppressed immunity following the death of a spouse may be related to the increased morbidity and mortality associated with bereavement. (JAMA1983;250:374-377)

Suppression of Lymphocyte Stimulation Following Bereavement

It has been shown experimentally that psychosocial processes influence the susceptibility to some infections, to some neoplastic processes, and to some aspects of humoral and cell-mediated immune responses. These psychosocial effects may be related to hypothalamic activity. Reviewing the mechanisms that may be involved in the role of the hypothalamus in immune responses indicates that there is no single mediating factor. Various processes may participate, including the autonomic nervous system and neuroendocrine activity. The research reviewed has been limited primarily to a consideration of the effect of hypothalamic lesions on humoral immune responses. There is some evidence (45, 80) indicating that hypothalamic lesions also modify cell-mediated immune responses. Further research is required to evaluate the effect of the hypothalamus on cell-mediated immunity.

https://science.sciencemag.org/content/sci/191/4226/435.full.pdf

Influence of brain and behavior on the immune system

Suppression of lymphocyte stimulation by anterior hypothalamic lesions in the guinea pig

Premature separation of rat pups from their mothers, on postnatal Day 15, produced a decreased response of peripheral blood lymphocytes to phytohemagglutnin (PHA) at 40 days of age. A significant lymphopenia was also found in the early weaned animals at 40 days of age although this was accounted for statistically by their lower body weight. These consequences of early maternal separation may have been mediated through the effects of early separation on nutritional state, hypothalamic function, or maturation of the immune system.

Premature maternal separation and lymphocyte function.

Whole blood and isolated lymphocyte stimulation in healthy men were compared utilizing PHA, ConA, and PWM. Dose response curves with each of the 3 mitogens were found to differ with the two techniques of lymphocyte stimulation. When incubation time was lengthened PWM responses increased markedly in both the whole blood and isolated lymphocyte assays. Increased incubation time had no effect on PHA cultures and increased the responses with ConA in the whole blood method. In each study, responses with 3H-thymidine were comparable to responses utilizing 125IUdR.

Maria Camerino

Papers

Suppression of Lymphocyte Stimulation Following Bereavement

Influence of brain and behavior on the immune system

Suppression of lymphocyte stimulation by anterior hypothalamic lesions in the guinea pig

Premature maternal separation and lymphocyte function.

Comparison of a simplified whole blood and isolated lymphocyte stimulation technique.