* Laboratory of Clinical and Experimental Endocrinology and Immunology, Wadsworth Center, Albany, New York 12201; and
Department of Psychology, Williams College, Williamstown, Massachusetts 01267
Received September 17, 2001; accepted November 29, 2001
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ABSTRACT |
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INTRODUCTION |
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Psychological stress, like chemical and physical stressors, can exert an effect on immune reactivity and on disease, although it is important to make a distinction between transient stress and stress that exists over longer periods (as in the case of low SES-associated factors, for example). Moreover, although popular conception has it that stress impairs the immune system, some studies have suggested that acute stress actually might facilitate some aspects of immune function. For example, rats subjected to restraint exhibit more robust antigen-specific delayed-type hypersensitivity (DTH) responses than do control animals, when the stress is applied either on initial antigen exposure or on reexposure (Dhabhar, 1998). Human subjects exposed to a laboratory stressor (videotaped speech) (Larson et al., 2001
) or engaging in tandem parachute jumping (Schedlowski et al., 1993
) exhibit transient increases in natural killer-cell (NK) numbers and function. More intense and/or long-lived stressors, on the other hand, typically impair the same measures of immune function. Rats exposed to several weeks of daily restraint, for example, displayed marked declines in delayed-type hypersensitivity (DTH) responses (Dhabhar, 2000
), and human subjects with histories of prolonged life stress exhibited reduced NK activity during and after a laboratory speech stress paradigm (Pike et al., 1997
). A recent study showed that expression of the nuclear transcription factors AP-1 and NF
B in peripheral blood lymphocytes is markedly decreased in women experiencing distress associated with breast biopsy (Nagabhushan et al., 2001
), suggesting a potential molecular mechanism for the immunosuppressive effects of profound stress.
Importantly, the impact of stress on immune function has been linked to increased vulnerability to illness. The stress associated with medical school exams (Glaser et al., 1987) or with caring for an individual with Alzheimer's disease (Glaser and Kiecolt-Glaser, 1997
; Cacioppo et al., 1998
) impairs antiviral immunity and results in reactivation of latent viral infection and impaired responses to vaccination (Glaser et al., 1991
, 1998
, 2000
; Kiecolt-Glaser et al., 1996
). Psychological stress has also been shown to slow the process of wound healing (Kiecolt-Glaser et al., 1998
; Marucha et al., 1998
). Nonhuman primates undergoing maternal separation stress have shown marked and lasting changes in immune functions (Lubach et al., 1995
; Coe, 1993
) as well as increased vulnerability to parasitic infection (Bailey and Coe, 1999
). In patients already diagnosed with disease, psychological stress is associated with poorer disease outcome. A recent prospective study in HIV-infected men found that severe stress, especially in combination with depression, predicated significant declines in CD4+ and CD8+ T lymphocyte numbers over the course of two years (Leserman et al., 1997
). Analogous studies of simian immunodeficiency virus infection in nonhuman primates have shown that psychological stress is associated with shortened survival time (Capitanio and Lerche, 1998
). In rats, emotional stressors that suppress NK function can render animals more susceptible to tumor colonization (Ben-Eliyahu et al., 1991
). Importantly, cognitive behavioral interventions designed to alleviate the distress associated with HIV infection were effective in improving the immunological indices of disease course (Antoni et al., 1991
, 2000
; Cruess et al., 2000
; Lutgendorf et al., 1997
). There is similar evidence from studies of breast cancer patients that alleviation of psychological distress extends life expectancy (Spiegel et al., 1989
), an effect thought to be mediated by having good quality social support (Turner-Cobb et al., 2000
).
Underlying much of the literature on the immunomodulatory effects of stress is the assumption that stress affects each individual similarly. While there is ample evidence to support this assumption, there is nevertheless growing interest in the psychological and genetic variables that render some individuals particularly vulnerable. Changes in immune function during laboratory stressors, for example, are most profound in individuals with the greatest physiological reactivity to the stressor (Herbert et al., 1994), and there is reason to believe, from research on human subjects and nonhuman primates, that these differences in reactivity may be present very early in life (Kagan and Saudino, 2001
; Suomi, 1999
). The stress of beginning a new academic program impaired NK activity, particularly in students less optimistic about their likelihood of academic success (Segerstrom et al., 1998
). Less sociable SIV-infected monkeys showed greater indications of early disease progression than did more sociable animals (Capitanio et al., 1999
). In short, psychological vulnerability to stress increases the immunological impact of the stressor.
Research into the mechanisms by which psychological stresses are translated into impaired immune function and vulnerability to disease has focused primarily on two pathways: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic branch of the autonomic nervous system (Fig. 1). Early work showed that adrenal glucocorticoids, the end products of HPA activation, influence multiple indices of immune reactivity (Ader et al., 1991
), and it has been argued that glucocorticoid production is an important means by which the immune response can be contained (Munck et al., 1984
). The discoveries that increases in glucocorticoids also occur during an immune response (Besedovsky et al., 1985
), and that HPA activation can be induced by proinflammatory cytokines at the hypothalamic level (Sapolsky et al., 1985
) suggest that the immune system makes use of the neuroendocrine system to rein itself in. Recent work, however, has suggested a more complex picture. Whereas acute exposure to high levels of glucocorticoids or prolonged exposure to moderate levels impair various aspects of immune function in vivo (Fleshner et al., 1996
; Dhabhar and McEwen, 1999
; Sheridan et al., 1998
), there is now evidence that endogenous release of adrenal hormones may play a critical role in optimizing immune function. For example, adrenalectomized rats fail to mount a robust antibody response to keyhole limpet hemacyanin (KLH) (Fleshner et al., 2001
, Friedman and Irwin, 2001
). Moreover, the antibody response to KLH is restored more effectively with properly timed corticosterone injections than with simple corticosterone replacement in the drinking water (Fleshner et al., 2001
), suggesting a complex and finely tuned relationship between the immune and neuroendocrine systems. The suppression of mouse host resistance to L. monocytogenes by cold-restraint stress has been shown to be mediated mainly by norepinephrine and lessened by corticosterone (Cao and Lawrence, work in progress). The involvement of glucocorticoids in stress-induced enhancement of DTH responses, mediated largely through influence on the trafficking of cells to the skin compartment (Dhabhar and McEwen, 1999
) further undermines the view that HPA activation suppresses immune function. Nonetheless, the existence of glucocorticoid receptors on the surfaces of multiple populations of immunocompetent cells (Cupps and Fauci, 1982
), as well as evidence for the production of glucocorticoids in primary lymphoid tissue (Ashwell et al., 2000
), provides the means by which aberrant levels of adrenal hormones associated with chronic stress or vulnerability to stress might exert a negative influence on immune function. Even neuropeptides usually thought to be confined to the brain, such as hypothalamic corticotropin-releasing hormone, have been shown to peripherally influence immune reactivity (Baigent, 2001
; McEvoy et al., 2001
).
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Although the literature on immunomodulation by endocrine, neuroendocrine, and autonomic systems is large, far less is known about how the brain regulates immune function. What is known implicates the same areas of the brain that are sensitive to psychological stress. For example, we recently showed that administration of 6-OHDA, an agent that selectively depletes catecholaminergic neurons, into the striatum of the mouse, compromised host resistance to L. monocytogenes as well as the primary antibody response and the DTH response to KLH (Filipov et al., 2001a, b
). Of potential importance, partial (40%) sparing of striatal dopamine by coadministration of an uptake inhibitor along with the 6-OHDA, restored host resistance to L. monocytogenes but did not restore the antibody or DTH response. This result suggests that striatal dopamine systems differentially regulate innate and acquired immune responses. Other studies of brain regulation of immune function have implicated other specific regions, such as the locus coeruleus (Rassnick et al., 1994
) and the limbic system (Jurkowski et al., 2001
), as well as specific neurochemical systems such as dopamine, serotonin, and GABA (Devoino et al., 1994
), all of which are known to be involved in the brain's response to psychological stressors. Interestingly, it has been suggested that psychological stress alone can induce the expression of cytokines in the brain (Nguyen et al., 1998
), and stress-induced activation of the HPA axis may be mediated by cytokine release in the brain (Saperstein et al., 1992
).
As a final intriguing note, there is compelling evidence that regulation of immune function by the brain is asymmetrical. For example, greater electroencephalographic activation of the right frontal region of the brain, relative to the left, was associated with reduced NK activity in twenty healthy women (Kang et al., 1991). In animals, brain laterality effects on peripheral immune reactivities have previously been demonstrated based on paw preference (Neveu, 1993
), and after lesioning right versus left cortical ((Neveu, 1988
, Neveu et al., 1991
) or subcortical areas (Neveu et al., 1992
). The complexities associated with psychoneuroimmunological interactions are further exemplified by evidence demonstrating that genetically identical (inbred) BALB/c mice are behaviorally different (preferential left versus right turning), and their behavioral asymmetry influences their immune responsiveness. Right-turning (left-brain dominant) mice had greater primary antibody responses and DTH to KLH and better host resistance to L. monocytogenes than left-turning (right-brain dominant) mice (Kim et al., 1999
). It is important to note that brain laterality differences have also been correlated with differential sensitivity to stress (Westergaard et al., 2001
). Stress can induce a lateralized generation of neurotransmitter metabolites (Carlson et al., 1991
), which is dependent on the type and duration of the stress (Carlson et al., 1991
; Neveu and Moya, 1997
; Sullivan and Gratton, 1998
). Although cortical dopamine and plasma corticosterone levels (HPA axis) of rats were positively associated after mild physical (2-min tail pinch) and psychological (15-min exposure to cat odors) stress, this relationship was asymmetrical only for the psychological stress (Sullivan and Gratton, 1998
). Even prenatal stress has been reported to affect later behavior in an asymmetrical fashion (Alonso et al., 1997
), and there is evidence that prenatal stress can modify immune reactivity in neonates (Coe et al., 1999
).
Aymmetric brain regulation of immune function may provide a scientific meeting point for psychoneuroimmunology and neurotoxicology. The environmental toxicant lead has been shown to differentially affect immunity of mice based on their brain laterality (Kim et al., 2000), and lead exacerbates CNS control of sickness behavior (Dyatlov et al., in press) including elevated levels of IL-1 and IL-6. Neveu et al.(1998) have reported that right-pawed mice were more sensitive to IL-1-induced sickness than were left-pawed animals. The combination of chemical, physical, and psychological stresses (Fig. 2
) during early development may be especially critical, in that prenatal stress can mediate behavioral and immune changes later in life. These early stresses may influence the brain laterality itself since it is known that hemisphere dominance is not genetic. Mice can be bred for high or low preference, but not for right versus left dominance (Collins, 1991
). The immunomodulatory effects of lead as well as other environmental agents, via central and peripheral means, emphasize the need to consider neuroendocrine immune interactions for evaluation of environmental stressors. Since some environmental pollutants such as lead are already classified as neurotoxicants and immunotoxicants, it is especially important to consider their modulation of neuroimmunological circuitry in conjunction with psychological stress. These combined stresses on early developmental patterns may substantially alter the threshold tolerance for later stresses and exacerbate the detrimental outcomes of such occurrences.
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