DHABHAR - Stress and Supression and Enhacing Effects of IS

Neuroimmunomodulation 2009;16:300–317 Published online: June 29, 2009
DOI: 10.1159/000216188
Enhancing versus Suppressive Effects of

Stress on Immune Function: Implications for
Immunoprotection and Immunopathology
Firdaus S. Dhabhar
Department of Psychiatry & Behavioral Sciences, and Stanford Institute for Immunity, Transplantation, & Infection,
Stanford University, Stanford, Calif., USA
Key Words shown that several critical factors influence the direction
Acute stress-induced enhancement ⴢ Fight-or-flight stress ⴢ (enhancing vs. suppressive) of the effects of stress or stress
Immune cell distribution ⴢ Immune function, effects of hormones on immune function: (1) Duration (acute vs. chron-
stress ⴢ Immune function, enhancing vs. suppressive ic) of stress: Acute or short-term stress experienced at the
effects ⴢ Immunoprotection vs. immunopathology ⴢ time of immune activation can enhance innate and adaptive
Innate/primary immune responses ⴢ Leukocyte trafficking ⴢ immune responses. Chronic or long-term stress can sup-
Adaptive/secondary immune responses press immunity by decreasing immune cell numbers and
function and/or increasing active immunosuppressive
mechanisms (e.g. regulatory T cells). Chronic stress can also
Abstract dysregulate immune function by promoting proinflamma-
Stress is known to suppress immune function and increase tory and type-2 cytokine-driven responses. (2) Effects of
susceptibility to infections and cancer. Paradoxically, stress stress on leukocyte distribution: Compartments that are en-
is also known to exacerbate asthma, and allergic, autoim- riched with immune cells during acute stress show immu-
mune and inflammatory diseases, although such diseases noenhancement, while those that are depleted of leuko-
should be ameliorated by immunosuppression. Moreover, cytes, show immunosuppression. (3) The differential effects of
the short-term fight-or-flight stress response is one of na- physiologic versus pharmacologic concentrations of glucocor-
ture’s fundamental defense mechanisms that enables the ticoids, and the differential effects of endogenous versus syn-
cardiovascular and musculoskeletal systems to promote sur- thetic glucocorticoids: Endogenous hormones in physiologi-
vival, and it is unlikely that this response would suppress im- cal concentrations can have immunoenhancing effects.
mune function at a time when it is most required for surviv- Endogenous hormones at pharmacologic concentrations,
al (e.g. in response to wounding and infection by a predator and synthetic hormones, are immunosuppressive. (4) The
or aggressor). These observations suggest that stress may timing of stressor or stress hormone exposure relative to the
suppress immune function under some conditions while en- time of activation and time course of the immune response: Im-
hancing it under others. The effects of stress are likely to be munoenhancement is observed when acute stress is experi-
beneficial or harmful depending on the type (immunopro- enced at early stages of immune activation, while immuno-
tective, immunoregulatory/inhibitory, or immunopatholog- suppression may be observed at late stages of the immune
ical) of immune response that is affected. Studies have response. We propose that it is important to study and, if
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© 2009 S. Karger AG, Basel Firdaus S. Dhabhar

1021–7401/09/0165–0300$26.00/0 Department of Psychiatry & Behavioral Sciences, and
Fax +41 61 306 12 34 Stanford Institute for Immunity, Transplantation, & Infection, Stanford University
E-Mail karger@karger.ch Accessible online at: 300 Pasteur Drive, MC 5135, Stanford, CA 94305-5135 (USA)
www.karger.com www.karger.com/nim E-Mail dhabhar@gmail.com
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possible, to clinically harness the immunoenhancing effects exacerbate immunopathology if the enhanced immune
of the acute stress response, that evolution has finely sculpt- response is directed against innocuous or self-antigens, or
ed as a survival mechanism, just as we study its maladaptive dysregulated following prolonged activation as seen dur-
ramifications (chronic stress) that evolution has yet to re- ing chronic stress.
solve. In view of the ubiquitous nature of stress and its sig- In contrast to acute stress, chronic stress has been
nificant effects on immunoprotection as well as immunopa- shown to dysregulate immune responses [5, 6] by altering
thology, it is important to further elucidate the mechanisms the cytokine balance from type-1 to type-2 cytokine-
mediating stress-immune interactions and to meaningfully driven responses [7] and accelerating immunosenescence
translate findings from bench to bedside. [8], and to suppress immunity by decreasing numbers [9],
Copyright © 2009 S. Karger AG, Basel trafficking [9], and function of protective immune cells
while increasing regulatory/suppressor T cells [10]. This
paper discusses the effects of stress on immune function
Introduction and implications of these effects for immunoprotection
versus immunopathology.
Numerous studies have demonstrated adverse effects
of stress on health [1, 2]. These studies show that chronic
or long-term stressors can have health-aversive effects, Stress: Definition, Mediators, and Individual
some of which are mediated through immune mecha- Differences
nisms. However, it is also important to appreciate that a
psychophysiological stress response is one of nature’s fun- Although the word ‘stress’ generally has negative con-
damental survival mechanisms. Without a fight-or-flight notations, stress is a familiar and ubiquitous aspect of life,
stress response, a lion has no chance of catching a gazelle, being a stimulant for some, but a burden for many others.
just as the gazelle has no chance of escape. During such Numerous definitions have been proposed for the con-
short-term stress responses observed in nature, physio- cept of stress. Each definition focuses on aspects of an
logical systems act in synchrony to enable survival. There- internal or external challenge, disturbance, or stimulus,
fore, we hypothesized that just as the stress response on perception of a stimulus by an organism, or on a phys-
prepares the cardiovascular, musculoskeletal and neuro- iological response of the organism to the stimulus [11–
endocrine systems for fight or flight, under certain condi- 13]. Physical stressors have been defined as external chal-
tions, stress may also prepare the immune system for challenges to homeostasis and psychological stressors as the
lenges (e.g. wounding or infection) that may be imposed ‘anticipation justified or not, that a challenge to homeo-
by a stressor (e.g. predator or surgical procedure) [3, 4]. stasis looms’ [13]. An integrated definition states that
Studies have shown that short duration stressors induce a stress is a constellation of events, consisting of a stimulus
redistribution of immune cells within the body and that (stressor), that precipitates a reaction in the brain (stress
immune function is significantly enhanced in organs like perception), that activates physiological fight-or-flight
the skin to which leukocytes traffic during acute stress. systems in the body (stress response) [9]. It is important
Studies have also identified mechanisms involving den- to understand that the only way that a stressor can affect
dritic cell, neutrophil, macrophage, and lymphocyte traf- the brain or body is by inducing biological changes in the
ficking, maturation, and function through which acute organism. Therefore, the physiological stress response is
stressors may enhance innate as well as adaptive immu- critical for mediating the effects of stress on health. This
nity. We suggest that the acute stress response may serve response results in the release of neurotransmitters, hor-
as an endogenous psychophysiological adjuvant that en- mones, peptides and other factors into the circulation or
hances immune responses and may have evolved by virtue locally within tissues. Even cytokines, factors that were
of the fact that many stressful situations (aggression, ac- traditionally thought to be the domain of the immune
cident) result in immune activation (wounding, infection) system, have relatively recently been shown to be released
and vice versa. Interestingly, in modern times, many situ- in the systemic circulation during psychological stress
ations involving immune activation (vaccination, surgery, [14]. The major mediators of stress effects are norepi-
injury) also induce a stress response. It is also important nephrine and epinephrine that are released by the sym-
to recognize that while acute stress-induced immunoen- pathetic nervous system, and corticotropin-releasing
hancement may serve to increase immunoprotection dur- hormone, adrenocorticotropin (ACTH), and cortisol,
ing exposure to infectious agents or wounding, it may also that make up the hypothalamic-pituitary-adrenal (HPA)
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Enhancing vs. Suppressive Effects of Neuroimmunomodulation 2009;16:300–317 301

Stress on Immune Function
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axis. Since virtually every cell in the body expresses re- type-1 and type-2 cytokine-driven immune responses
ceptors for one or more of these factors, they can induce are all defined in terms of their cellular and cytokine
changes in almost all cells and tissues and inform them components. In addition to these categorizations, it is
about the presence of a stressor. also useful to define immune responses in terms of their
Although stress can be harmful when it is chronic or end-effects. Therefore, we suggest that immune respons-
long-lasting [1, 5, 6, 15], it is often overlooked that a stress es can be categorized as being immunoprotective, immu-
response has salubrious adaptive effects in the short run nopathological, and immunoregulatory/inhibitory. It is
[16, 17]. Therefore, major distinguishing characteristics of important to bear in mind that while all these categories
stress are duration and intensity. Acute stress has been de- provide useful constructs with which to organize ideas,
fined as stress that lasts for a period of minutes to hours, concepts and models, an overall in vivo immune response
and chronic stress as stress that persists for several hours is likely to consist of several types of responses with vary-
per day for weeks or months [9]. Dysregulation of the cir- ing amounts of dominance from each category. Each of
cadian cortisol rhythm is one marker that appears to co- the proposed end-effect-based categories is defined be-
incide with the deleterious effects of chronic stress [9, 10, low:
18]. The intensity of stress may be gauged by the peak lev- Immunoprotective responses are defined as responses
els of stress hormones, neurotransmitters, and other that promote efficient wound healing, eliminate viral in-
physiological changes such as increases in heart rate and fections and cancer, and mediate vaccine-induced immu-
blood pressure, and by the amount of time for which these nological memory. Key characteristics of immunoprotec-
changes persist during stress and following the cessation tion involve active immune surveillance, a rapid and
of stress. It is important to note that significant individu- robust response upon immune activation, efficient clear-
al differences in stress perception, processing, and coping ance of the activating agent or pathogen, followed by rap-
have been observed [17, 19]. Individual differences be- id resolution of inflammation. Immunoprotective re-
come particularly relevant while studying human sub- sponses are critical for completion of the proliferative and
jects because stress perception, processing, and coping remodeling phases of wound healing. Wound healing is
mechanisms can have significant effects on the kinetics important not only for frank wounds where the initiating
and peak levels of circulating stress hormones and on the event is tissue damage itself, but also for tissue-intrinsic
duration for which these hormone levels are elevated. An- ‘wounds’ where the initiating event is an immune re-
imal studies showing significant strain differences in sponse precipitated by intracellular infection during
stress reactivity and peak hormone levels [20, 21], adapta- which there can be collateral tissue damage. Innate and/
tion to stress [22], and in distribution and activation of or adaptive type-1 or type-2 immune responses can all
adrenal steroid receptors and corticosteroid-binding confer immunoprotection depending on the type of the
globulin levels [20, 23], suggest that genetic as well as en- pathogen (viral, bacterial, protozoan, fungal, helmin-
vironmental factors play a role in establishing individual thic), on whether it is intra- or extracellular, and on the
differences [20, 22–24]. The ability of humans to generate accompanying wounding conditions (e.g. sterile, infect-
and experience internal psychological stressors in the ab- ed, external or internal).
sence of external stressors can result in long-term activa- Immunopathological responses are defined as those
tion of the physiological stress response that often has del- that are directed against self- (autoimmune disease like
eterious effects. The magnitude and duration of stress-in- multiple sclerosis, arthritis, lupus) or innocuous antigens
duced elevations in catecholamine and glucocorticoid (asthma, allergies) and responses that involve chronic,
hormones can have significant effects on immune cell dis- non-resolving inflammation. Immunopathology is also
tribution and function [4, 25, 26]. involved during low-level, long-term elevations in local
and/or systemic inflammatory mediators that are thought
to contribute to disorders like cardiovascular disease,
Immune Responses Defined in Terms of Their End obesity, and depression [27–29].
Effects: Immunoprotective, Immunopathological, Immunoregulatory/inhibitory responses are defined
and Immunoregulatory/Inhibitory as those that involve immune cells and factors that in-
hibit the function of other immune cells. Although the
While discussing immune responses, it is useful to previous concept of suppressor T cells became mired in
categorize them in terms of their principal cellular and controversy, recent studies suggest that there is an arm
molecular components. For example, innate, adaptive, of the immune system that functions to inhibit immune
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302 Neuroimmunomodulation 2009;16:300–317 Dhabhar

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responses. Regulatory CD4+CD25+FoxP3+ T cells, in- Stress-Induced Changes in Immune Cell Distribution
terleukin (IL)-10, and TGF-␤ have been shown to have
immunoregulatory/inhibitory functions. The physio- Effective immunoprotection requires rapid recruit-
logical function of these factors is to keep proinflamma- ment of leukocytes into sites of surgery, wounding, infec-
tory, allergic, and autoimmune responses in check [30]. tion, or vaccination. Immune cells circulate continuously
However, it has also been suggested that immunoregula- on surveillance pathways that take them from the blood,
tory/inhibitory factors may suppress antitumor immu- through various organs, and back into the blood. This
nity and be indicative of negative prognosis for cancer circulation is essential for the maintenance of an effective
[31]. immune defense network [32]. The numbers and propor-
tions of leukocytes in the blood provide an important
representation of the state of distribution of leukocytes in
Factors That May Determine Whether Stress Will the body and of the state of activation of the immune sys-
Enhance or Suppress Immune Function and the tem. The ability of acute stress to induce changes in leu-
Potential Health Consequences of These Effects of kocyte distribution within different body compartments
Stress is perhaps one of the most underappreciated effects of
stress and stress hormones on the immune system [3].
Several critical factors are likely to influence the di- Numerous studies have shown that stress and stress
rection (enhancing vs. suppressive) of the effects of stress hormones induce significant changes in absolute num-
or stress hormones, and the nature of the immune re- bers and relative proportions of leukocytes in the blood.
sponse (immunoprotective, immunoregulatory/inhibi- In fact, changes in blood leukocyte numbers were used as
tory, or immunopathological) that is affected. These in- a measure of stress before methods were available to di-
clude: (1) the effects of stress on leukocyte distribution rectly assay the hormone [33]. Studies have also shown
in the body; (2) the duration (short-term/acute vs. long- that glucocorticoid [34, 35] and catecholamine hormones
term/chronic) of stress; (3) the differential effects of [26] induce rapid and significant changes in leukocyte
physiologic versus pharmacologic concentrations of glu- distribution and that these hormones are the major me-
cocorticoids, and the differential effects of endogenous diators of the effects of stress. Stress-induced changes in
(e.g. cortisol, corticosterone) versus synthetic (e.g. dexa- blood leukocyte numbers have been reported in numer-
methasone) glucocorticoids, and (4) the timing of stress- ous species including humans [3, 36–40]. This suggests
or or stress hormone exposure relative to the time of ac- that the phenomenon of stress-induced leukocyte redis-
tivation and ensuing time course of the immune re- tribution has a long evolutionary lineage, and that per-
sponse. It is important to recognize that factors such as haps it has important functional significance.
gender, genetics, age, the route of administration and na- Studies have shown that stress-induced changes in
ture of the immunizing antigen, and time of day, may blood leukocyte numbers are characterized by a signifi-
additionally affect the relationship between stress and cant decrease in numbers and percentages of lympho-
immune function. cytes and monocytes, and by an increase in numbers and
It is also important to bear in mind that whether a percentages of neutrophils [3, 37]. Flow cytometric analy-
stressor enhances or suppresses immune function, it is ses revealed that absolute numbers of peripheral blood T
the end-effect of the affected immune response that af- cells, B cells, NK cells, and monocytes all show a rapid
fects the health of the organism or individual (fig. 1). Giv- and significant decrease (40–70% lower than baseline)
en the definitions in the preceding section, stress-in- during stress [3]. Moreover, it has been shown that stress-
duced enhancement of immunoprotection is likely to induced changes in leukocyte numbers are rapidly re-
have beneficial effects while stress-induced suppression versed upon the cessation of stress [3]. In apparent con-
of immunoprotection is likely to be harmful. Similarly, trast to animal studies, human studies have shown that
stress-induced enhancement of immunopathology or stress increases rather than decreases blood leukocyte
long-term proinflammation is also likely to be harmful. numbers [39, 41, 42]. This apparent contradiction may be
Finally, stress-induced enhancement of active immuno- resolved by taking the following factors into consider-
regulation/inhibition is likely to be beneficial in case of ation: First, stress-induced increases in blood leukocyte
autoimmune and proinflammatory disorders and harm- numbers in humans have been studied using stress con-
ful in case of infections and cancer. ditions which result in the activation of primarily the
sympathetic nervous system. These stressors are often of
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Color version available online
Stressor Immune response end-effect Potential health outcome
Beneficial:
Immunoprotection
Efficacy of
If acute stress is experienced during
Acute or vaccination, wounding, or infection vaccination and wound healing
short-term Resistance to
stress infection and cancer
Immunopathology
If acute stress is experienced during self/
innocuous antigen/allergen exposure Harmful:
Proinflammatory and
Immunopathology autoimmune disease
If chronic stress induces an increase in
dysregulated, proinflammatory or
type-2 cytokine-driven responses
Chronic or Harmful:
long-term Efficacy of
stress Immunosuppression vaccination and wound healing
If chronic stress decreases baseline Resistance to
leukocyte numbers, suppresses leukocyte
infection and cancer
function, or mobilizes immunosuppressive
mechanisms (e.g. regulatory T cells)
Beneficial:
Proinflammatory and
autoimmune disease
Fig. 1. The relationship among stress, immune function, and duced increases in proinflammatory or type-2 cytokine-mediat-
health outcomes. Acute stress experienced during vaccination, ed immune responses may also exacerbate inflammatory and
wounding, or infection may enhance immunoprotective respons- autoimmune disease. Chronic stress-induced suppression of im-
es. Acute stress experienced during immune activation in re- mune responses may decrease the efficacy of vaccination and
sponse to self/innocuous antigens or allergens may exacerbate wound healing and decrease resistance to infection and cancer.
proinflammatory and autoimmune disorders. Chronic stress-in-
a short duration (few minutes) or relatively mild (e.g. pub- increase in circulating leukocyte numbers. These condi-
lic speaking) [39, 41, 42]. Second, the increase in total tions may occur during the beginning of a stress response,
leukocyte numbers may be accounted for mainly by very-short-duration stress (order of minutes), mild psy-
stress- or catecholamine-induced increases in granulo- chological stress, or during exercise. In contrast, stress
cytes and NK cells [26, 39, 41, 42]. Third, stress or phar- conditions that result in the activation of the HPA axis
macologically-induced increases in glucocorticoid hor- induce a decrease in circulating leukocyte numbers.
mones induce a significant decrease in blood lymphocyte These conditions often occur during the later stages of a
and monocyte numbers [33, 35, 39]. Thus, stress condi- stress response, long-duration acute stressors (order of
tions that result in a significant and sustained activation hours), or during severe psychological, physical or physi-
of the HPA axis result in a decrease in blood leukocyte ological stress. An elegant and interesting example in
numbers. support of this hypothesis comes from Schedlowski et al.
It has been proposed that acute stress induces an ini- [39] who measured changes in blood T-cell and NK cell
tial increase followed by a decrease in blood leukocyte numbers as well as plasma catecholamine and cortisol
numbers [4]. Stress conditions that result in activation of levels in parachutists. Measurements were made 2 h be-
the sympathetic nervous system, especially conditions fore, immediately after, and 1 h after the jump. Results
that induce high levels of norepinephrine, may induce an showed a significant increase in T-cell and NK cell num-
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bers immediately (minutes) after the jump that was fol- function focus on stress, the effects of stress on blood leu-
lowed by a significant decrease 1 h after the jump. An kocyte distribution become a factor of considerable im-
early increase in plasma catecholamines preceded early portance.
increases in lymphocyte numbers, whereas the more de- Dhabhar et al. [37, 46] were the first to propose that
layed rise in plasma cortisol preceded the late decrease in stress-induced changes in blood leukocyte distribution
lymphocyte numbers [39]. Importantly, changes in NK may represent an adaptive response. They suggested that
cell activity and antibody-dependent cell-mediated cyto- acute stress-induced changes in blood leukocyte num-
toxicity closely paralleled changes in blood NK cell numbers represent a redistribution of leukocytes from the
bers, thus suggesting that changes in leukocyte numbers blood to organs such as the skin, draining sentinel lymph
may be an important mediator of apparent changes in nodes, and other compartments [4, 45]. They hypothe-
leukocyte ‘activity’. Similarly, Rinner et al. [43] have sized that such a leukocyte redistribution may enhance
shown that a short stressor (1 min handling) induced an immune function in compartments to which immune
increase in mitogen-induced proliferation of T and B cells cells traffic during stress. In agreement with this hypoth-
obtained from peripheral blood, while a longer stressor esis, it was demonstrated that a stress-induced redistribu-
(2 h immobilization) induced a decrease in the same pro- tion of leukocytes from the blood to the skin is accompa-
liferative responses. In another example, Manuck et al. nied by a significant enhancement of skin immunity [45–
[44] showed that acute psychological stress induced a sig- 47].
nificant increase in blood CTL numbers only in those
subjects who showed heightened catecholamine and car-
diovascular reactions to stress. Functional Consequences of Stress-Induced
Thus, an acute stress response may induce biphasic Changes in Immune Cell Distribution
changes in blood leukocyte numbers. Soon after the be-
ginning of stress (order of minutes) or during mild acute When interpreting data showing stress-induced
stress, or exercise, catecholamine hormones and neu- changes in functional assays such as lymphocyte prolif-
rotransmitters induce the body’s ‘soldiers’ (leukocytes), eration or NK activity, it may be important to bear in
to exit their ‘barracks’ (spleen, lung, marginated pool and mind the effects of stress on the leukocyte composition
other organs) and enter the ‘boulevards’ (blood vessels of the compartment in which an immune parameter is
and lymphatics). This results in an increase in blood leu- being measured. For example, it has been shown that
kocyte numbers, the effect being most prominent for NK acute stress induces a redistribution of leukocytes from
cells and granulocytes. As the stress response continues, the blood to the skin and that this redistribution is ac-
activation of the HPA axis results in the release of gluco- companied by a significant enhancement of skin cell-me-
corticoid hormones which induce leukocytes to exit the diated immunity (CMI) [16, 45]. In what might at first
blood and take position at potential ‘battle stations’ (such glance appear to be contradicting results, acute stress has
as the skin, lung, gastrointestinal and urinary-genital been shown to suppress splenic and peripheral blood re-
tracts, mucosal surfaces, and lymph nodes) in prepara- sponses to T-cell mitogens [48] and splenic IgM produc-
tion for immune challenges which may be imposed by the tion [49]. However, it is important to note that in contrast
actions of the stressor [3, 4, 45]. Such a redistribution of to the skin that is enriched in leukocytes during acute
leukocytes results in a decrease in blood leukocyte num- stress, peripheral blood and spleen are relatively depleted
bers. Thus, acute stress may result in a redistribution of of leukocytes during acute stress [50]. This stress-induced
leukocytes from the barracks, through the boulevards, decrease in blood and spleen leukocyte numbers may
and to potential battle stations within the body. contribute to the acute stress-induced suppression of im-
Since the blood is the most accessible and commonly mune function in these compartments.
used compartment for human studies, it is important to Moreover, in contrast to acute stress, chronic stress
carefully evaluate how changes in blood immune param- has been shown to suppress skin CMI and a chronic
eters might reflect in vivo immune function in the con- stress-induced suppression of blood leukocyte redistri-
text of the specific experiments or study at hand. More- bution is thought to be one of the factors mediating the
over, since most blood collection procedures involve a immunosuppressive effect of chronic stress [9]. Again, in
certain amount of stress, since all patients or subjects will what might appear to be contradicting results, chronic
have experienced acute and chronic stress, and since stress has been shown to enhance mitogen-induced pro-
many studies of psychophysiological effects on immune liferation of splenocytes [51] and splenic IgM production
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[49]. However, the spleen is relatively enriched in T cells phages, in response to saline, LTN or TNF- ␣; neutro-
during chronic glucocorticoid administration, suggest- phils, only in response to TNF-␣, and NK and T cells
ing that it may also be relatively enriched in T cells during only in response to LTN. These results showed that acute
chronic stress [52], and this increase in spleen leukocyte stress significantly enhances the kinetics and magnitude
numbers may contribute to the chronic stress-induced of leukocyte infiltration into a site of immune activation
enhancement of immune parameters measured in the or surgery in a subpopulation and chemoattractant-spe-
spleen. cific manner, with tissue damage, antigen-, or pathogen-
It is also important to bear in mind that the heteroge- driven chemoattractants synergizing with acute stress to
neity of the stress-induced changes in leukocyte distribu- further determine the specific subpopulations that are
tion [3] suggests that using equal numbers of leukocytes recruited [53]. Thus, depending on the primary che-
in a functional assay may not account for stress-induced moattractants driving an immune response, acute stress
changes in relative percentages of different leukocyte may selectively mobilize specific leukocyte subpopula-
subpopulations in the cell suspension being assayed. For tions into sites of surgery, wounding, or inflammation.
example, samples that have been equalized for absolute Such a stress-induced increase in leukocyte trafficking
numbers of total blood leukocytes from control versus may be an important mechanism by which acute stress-
stressed animals may still contain different numbers of ors alter the course of different (innate vs. adaptive, ear-
specific leukocyte subpopulations (e.g. T cells, B cells or ly vs. late, acute vs. chronic) protective or pathological
NK cells). Such changes in leukocyte composition may immune responses.
contribute to the effects of stress even in functional assays
using equalized numbers of leukocytes from different
treatment groups. Therefore, stress may affect immune Acute Stress-Induced Enhancement of Innate/
function at a cellular level (e.g. phagocytosis, antigen pre- Primary Immune Responses
sentation, killing, antibody production) and/or through
leukocyte redistribution that could increase or decrease In view of the skin being one of the target organs to
the number of cells with a specific functional capacity in which leukocytes traffic during stress, studies were con-
the compartment being studied. ducted to examine whether skin immunity is enhanced
when immune activation/antigen exposure occurs fol-
lowing a stressful experience. Studies showed that acute
Effects of Acute Stress on Leukocyte Trafficking to a stress experienced at the time of novel or primary antigen
Site of Surgery or Immune Activation exposure results in a significant enhancement of the en-
suing skin immune response [16]. Compared to controls,
Viswanathan and Dhabhar [53] used a subcutaneous- mice restrained for 2.5 h before primary immunization
ly implanted surgical sponge model to elucidate the ef- with keyhole limpet hemocyanin (KLH) showed a sig-
fects of stress on the kinetics, magnitude, subpopulation, nificantly enhanced immune response when re-exposed
and chemoattractant specificity of leukocyte trafficking to KLH 9 months later. This immunoenhancement was
to a site of immune activation or surgery. Mice that were mediated by an increase in numbers of memory and ef-
acutely stressed before subcutaneous implantation or the fector helper T cells in sentinel lymph nodes at the time
surgical sponge showed a two- to threefold higher neu- of primary immunization. Further analyses showed that
trophil, macrophage, NK cell and T-cell infiltration than the early stress-induced increase in T-cell memory may
non-stressed animals. Leukocyte infiltration was evi- have stimulated the robust increase in infiltrating lym-
dent as early as 6 h and peaked between 24 and 48 h. Im- phocyte and macrophage numbers observed months lat-
portantly, at 72 h, sponges from non-stressed and acute- er at a novel site of antigen re-exposure. Enhanced leuko-
ly stressed mice had comparable and significantly lower cyte infiltration was driven by increased levels of the
leukocyte numbers indicating effective resolution of in- type-1 cytokines, IL-2 and ␥-interferon (IFN-␥), and
flammation in both groups. These authors also exam- TNF-␣, observed at the site of antigen re-exposure in an-
ined the effects of stress on early (6 h) leukocyte infiltra- imals that had been stressed at the time of primary im-
tion in response to a predominantly proinflammatory munization. Given the importance of inducing long-last-
cytokine, tumor necrosis factor- ␣ (TNF-␣), and lym- ing increases in immunological memory during vaccina-
phocyte-specific chemokine, lymphotactin (LTN). Acute tion, it has been suggested that the neuroendocrine stress
stress significantly increased infiltration of macro- response is nature’s adjuvant that could be psychologi-
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cally and/or pharmacologically manipulated to safely in- Acute Stress-Induced Enhancement of Adaptive/
crease vaccine efficacy. Secondary Immune Responses
In a series of elegant experiments, Saint-Mezard et al.
[54] similarly showed that acute stress experienced at the Studies have shown that in addition to enhancing pri-
time of sensitization resulted in a significant increase in mary cutaneous immune responses, acute stress experi-
the contact hypersensitivity (CHS) response. These in- enced at the time of antigen re-exposure can also enhance
vestigators showed that acute stress experienced during secondary or recall responses in skin [45]. Compared to
sensitization enhanced dendritic cell migration from non-stressed controls, mice that were acutely stressed at
skin to sentinel lymph nodes and also enhanced priming the time of antigen re-exposure showed a significantly
of lymph node CD8+ T cells. These CD8+ T cells re- larger number of infiltrating leukocytes at the site of the
sponded in greater numbers at the site of antigen re-ex- immune reaction. These results demonstrated that a rela-
posure during the recall phase of the CHS response. tively mild behavioral manipulation can enhance an im-
These studies also suggested that the effects of acute portant class of immune responses that mediate harmful
stress in this case were mediated primarily by norepi- (allergic dermatitis) as well as beneficial (resistance to
nephrine [54]. Other investigators have similarly report- certain viruses, bacteria, and tumors) aspects of immune
ed stress-induced enhancement of type-1 cytokine-driv- function.
en CMI [55–57] and type-2 cytokine-driven humoral im- Blecha et al. [55] reported a similar stress-induced en-
munity [57, 58]. hancement of CHS reactions in mice, and Flint et al. [60]
Viswanathan et al. [59] further elucidated the molecu- showed that acute stress enhanced CHS responses in both
lar and cellular mediators of the immunoenhancing ef- male and female mice and that immunoenhancement
fects of acute stress. They showed that compared to non- was partially dependent on glucocorticoid hormones,
stressed mice, acutely stressed animals showed signifi- and a stress-induced enhancement of the elicitation phase
cantly greater pinna swelling, leukocyte infiltration, and of skin CMI has also been reported in hamsters [36]. Tak-
upregulated macrophage chemoattractant protein-1 en together, studies show that acute stress can signifi-
(MCP-1), macrophage inflammatory protein-3␣ (MIP- cantly enhance the immunization/sensitization/induc-
3␣), IL-1␣, IL-1␤, IL-6, TNF-␣, and IFN-␥ gene expres- tion as well as the re-exposure/elicitation/recall phases of
sion at the site of primary antigen exposure. Stressed an- skin CMI.
imals also showed enhanced maturation and trafficking
of dendritic cells from skin to lymph nodes, higher num-
bers of activated macrophages in skin and lymph nodes, Hormone and Cytokine Mediators of Stress-Induced
increased T-cell activation in lymph nodes, and enhanced Enhancement of Immune Function
recruitment of surveillance T cells to skin. These findings
showed that important interactive components of innate Although much work remains to be done, to identify
(dendritic cells and macrophages) and adaptive (surveil- molecular, cellular, and physiological mechanisms medi-
lance T cells) immunity are mediators of the stress-in- ating the adjuvant-like, immunoenhancing effects of
duced enhancement of a primary immune response. Such acute stress, several studies have begun to identify endo-
immunoenhancement during primary immunization crine and immune mediators of these effects. Studies have
may induce a long-term increase immunologic memory shown that corticosterone and epinephrine are important
resulting in subsequent augmentation of the immune re- mediators of an acute stress-induced immunoenhance-
sponse during secondary antigen exposure. ment [46]. Adrenalectomy, which eliminates the gluco-
In addition to elucidating mechanisms that could be corticoid and epinephrine stress response, eliminated the
targeted to reduce stress-induced exacerbation of aller- stress-induced enhancement of skin CMI. Low-dose cor-
gic, autoimmune, and proinflammatory reactions, the ticosterone or epinephrine administration significantly
above-mentioned studies provide further support for the enhanced skin CMI [46]. In contrast, high-dose cortico-
idea that a psychophysiological stress response is nature’s sterone, chronic corticosterone, or low-dose dexametha-
fundamental survival mechanism that could be thera- sone administration significantly suppressed skin CMI.
peutically harnessed to augment immune function dur- These results suggested a novel role for adrenal stress hor-
ing vaccination, wound healing or infection. mones as endogenous immunoenhancing agents. They
also showed that stress hormones released during a cir-
cumscribed or acute stress response may help prepare the
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immune system for potential challenges (e.g. wounding or vaccination, wound healing or infection [16]. In keeping
infection) for which stress perception by the brain may with this hypothesis, studies conducted by our group
serve as an early warning signal. Studies by Flint et al. [60] have shown that patients undergoing knee surgery, who
have also suggested that corticosterone is a mediator of show a robust and adaptive immune cell redistribution
the stress-induced enhancement of skin CHS, while Saint- profile during the acute stress of surgery, also show sig-
Mezard et al. [54] have suggested that the adjuvant-like nificantly enhanced recovery. Similarly, studies conduct-
effects of stress on dendritic cell and CD8+ T-cell migra- ed by Edwards et al. [61, 62] have shown that acute stress-
tion and function are mediated by norepinephrine. ors can enhance vaccine-induced humoral and CMI in
Studies have also examined the immunological me- human subjects. Further research is required to test the
diators of an acute stress-induced enhancement of skin hypothesis that behavioral and/or pharmacological in-
immunity. Since IFN-␥ is a critical cytokine mediator of duction of the acute psychophysiological stress response
CMI and delayed as well as CHS, studies were conducted can be used therapeutically to enhance protective immu-
to examine its role as a local mediator of the stress-in- nity during wound healing, infection, and cancer and to
duced enhancement of skin CMI [47]. The effect of acute enhance vaccine efficacy. Such intervention is likely to
stress on skin CMI was examined in wild-type and allow for safe and effective enhancement of protective
IFN-␥ receptor gene knockout mice (IFN-␥R–/–) that immunity because it would tap into the body’s natural,
had been sensitized with 2,4-dinitro-1-fluorobenzene endogenous adjuvant mechanisms to enhance immune
(DNFB). Acutely stressed wild-type mice showed a sig- function.
nificantly larger CMI response than non-stressed mice.
In contrast, IFN-␥R–/– mice failed to show a stress-in-
duced enhancement of skin CMI. Immunoneutralization Chronic Stress Can Suppress Immunoprotection,
of IFN-␥ in wild-type mice significantly reduced the While Enhancing Immunopathological and
stress-induced enhancement of skin CMI. In addition, an Immunoregulatory/Suppressive Responses
inflammatory response to direct IFN-␥ administration
was significantly enhanced by acute stress. These results In contrast to acute stressors, chronic stress has been
showed that IFN-␥ is an important local mediator of a shown to suppress type-1 cytokine-driven protective im-
stress-induced enhancement of skin CMI [47]. In addi- mune responses while enhancing proinflammatory and
tion to IFN-␥, TNF-␣, MCP-1, MIP-3␣, IL-1, and IL-6 type-2 cytokine-driven immune responses [5]. Chronic
have also been associated with a stress-induced enhance- stress also appears to mobilize immunoregulatory/inhib-
ment of the immunization/sensitization phase of skin itory mechanisms [10]. Therefore, chronic stress is likely
CMI [16, 59]. It is clear that further investigation is neces- to exacerbate proinflammatory diseases and increase
sary in order to identify the most important molecular, susceptibility to infections and cancer. Dhabhar and
cellular and physiological mediators of a stress-induced McEwen [9] conducted studies designed to examine the
enhancement of skin immunity. effects of increasing the intensity and duration of acute
stress as well as the transition from acute to chronic stress
on skin immune function. These studies showed that
Acute Stress Psychophysiology as an Endogenous acute stress administered for 2 h prior to antigenic chal-
Adjuvant lenge significantly enhanced skin CMI [9]. Increasing the
duration of stress from 2 to 5 h produced the same mag-
We initially suggested that just as the acute stress re- nitude immunoenhancement. Interestingly, increasing
sponse prepares the cardiovascular, musculoskeletal, and the intensity of acute stress produced a significantly larg-
neuroendocrine systems for flight or flight, it may also er enhancement of the CMI response that was accompa-
prepare the immune system for challenges such as wound- nied by increasing magnitudes of leukocyte redeploy-
ing and infection that are likely to result due to the ac- ment. In contrast, these studies found suppression of the
tions of the stressor (predator, or process of undergoing skin immune response when chronic stress exposure was
surgery) [45, 50]. Upon seeing the evidence in support of begun 3 weeks before sensitization and either discontin-
the above hypothesis, we put forth the novel hypothesis ued upon sensitization, or continued an additional week
that a psychophysiological stress response is nature’s fun- until challenge, or extended for 1 week after challenge [9].
damental survival mechanism that could be therapeuti- Interestingly, acute stress-induced redistribution of pe-
cally harnessed to augment immune function during ripheral blood lymphocytes was attenuated with increas-
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ing duration of stressor exposure and correlated with at- pharmacological concentrations of glucocorticoids exert
tenuated glucocorticoid responsivity. These results sug- immunosuppressive effects, whereas under different con-
gested that stress-induced alterations in lymphocyte ditions, physiologic concentrations may exert immuno-
redeployment may play an important role in mediating modulatory, immunoenhancing, or immunosuppressive
the bidirectional effects of stress on cutaneous CMI [9]. effects. It is important to recognize that the source (natu-
An association between chronic stress and reduced skin ral vs. synthetic) and concentration (physiologic vs. phar-
CMI has also been reported in human subjects [63]. macologic) of glucocorticoid hormones, the effects of
Given the importance of cutaneous CMI in elimina- other physiologic factors (hormones, cytokines, and neu-
tion of immunoresponsive tumors like squamous cell rotransmitters), and the state of activation of an immune
carcinoma (SCC) [64, 65], Saul et al. [10] examined the parameter (naive vs. activated leukocyte, early vs. late ac-
effects of chronic stress on susceptibility to ultraviolet tivation, etc.) are all important factors which ultimately
(UV) radiation-induced SCC. Mice were exposed to a determine the nature of the effects of glucocorticoids on
minimal erythemal dose of UVB three times a week for a given immune response. Immunoenhancing effects of
10 weeks. Half of the UVB-exposed mice were left non- glucocorticoids are discussed below, whereas immuno-
stressed (i.e., they remained in their home cages) and the suppressive effects are discussed in the following sec-
other half were chronically stressed (i.e., restrained dur- tion.
ing weeks 4–6). UV-induced tumors were measured Acute stress-induced enhancement of skin CMI is me-
weekly from week 11 through week 34, blood was col- diated by adrenal stress hormones [46]. Adrenalectomy,
lected at week 34, and tissues were collected at week 35. which eliminates the glucocorticoid and epinephrine
mRNA expression of IL-12p40, IFN-␥, IL-4, IL-10, CD3␧, stress response, eliminated the stress-induced enhance-
and CCL27/CTACK, the skin T-cell-homing chemokine, ment of skin CMI. Low-dose corticosterone or epineph-
in dorsal skin was quantified using real-time polymerase rine administration significantly enhanced skin CMI
chain reaction. CD4+, CD8+, and CD25+ leukocytes and produced a significant increase in T-cell numbers in
were counted using immunohistochemistry and flow cy- lymph nodes draining the site of the CMI reaction [46].
tometry. Stressed mice had a shorter median time to first Moreover, simultaneous administration of these two
tumor (15 vs. 16.5 weeks) and reached 50% incidence ear- stress hormones produced an additive increase in the
lier than controls (15 vs. 21 weeks). Stressed mice also had skin CMI response. These results showed that hormones
lower IFN-␥, CCL27/CTACK, and CD3␧ gene expression released during an acute stress response may help prepare
and lower CD4+ and CD8+ T cells infiltrating within and the immune system for potential challenges (e.g. wound-
around tumors than non-stressed mice. In addition, ing or infection) for which stress perception by the brain
stressed mice had higher numbers of tumor infiltrating may serve as an early warning signal [46].
and circulating CD4+CD25+ suppressor cells than non- A permissive role for glucocorticoids in antibody pro-
stressed mice. These studies showed that chronic stress duction was described over 30 years ago. Several investi-
increased susceptibility to UV-induced SCC by suppress- gators reported that low levels of cortisol were a necessary
ing skin immunity, type-1 cytokines, and protective T factor in cell culture media in order to obtain in vitro an-
cells, and increasing active immunosuppression through tibody production [70]. Moreover, glucocorticoids were
regulatory/suppressor T cells [10]. In addition, chronic determined to be the critical permissive component pres-
stress has also been shown to suppress several other indi- ent in serum supplements of culture media, and it was
ces of immunoprotection [15, 66] and to enhance proin- suggested that variability in antibody production assays
flammatory and type-2 cytokine-driven conditions and may be the result of variability of glucocorticoid content
disorders [7, 67]. in different batches of serum [70]. Under some condi-
tions, glucocorticoids have been shown to shift the bal-
ance of an immune response towards humoral immunity
Bidirectional Effects of Glucocorticoid Hormones on [71–73]. Physiological doses of glucocorticoids have been
Immune Function shown to enhance immunoglobulin production by mito-
gen-stimulated human lymphocytes in culture [74], and
In contrast to the well-known immunosuppressive ef- glucocorticoids have been shown to stimulate B-cell
fects of glucocorticoids, several studies have revealed that number and antibody production in vitro and in vivo
glucocorticoid hormones also exert immunomodulating [75].
[68] and immunoenhancing effects [17, 69]. In general,
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Studies examining the effects of corticosterone on T- induced increases in endogenous glucocorticoids also ap-
lymphocyte proliferation in vitro demonstrate an impor- pear to facilitate the expression of low-affinity Fc␥ recep-
tant mechanism by which corticosterone may mediate tors on peritoneal macrophages [88]. While some studies
the enhancement of immune function [76]. These studies have reported that glucocorticoids inhibit IL-2 receptor
have shown that during the early stages of T-cell activa- (IL-2R) expression in leukocytes [89], a recent study in-
tion, low levels of corticosterone potently enhance anti-T- dicates that the reduced IL-2R expression is secondary to
cell receptor (TCR)-induced lymphocyte proliferation. glucocorticoid suppression of IL-2 [90]. In contrast, stud-
Furthermore, they showed that corticosterone had to be ies have found a stimulating effect of glucocorticoids on
present during the process of TCR activation in order to IL-2 induction of IL-2R mRNA levels in several T-cell
enhance the proliferative response. Other studies have lines [91].
suggested that low concentration corticosterone-induced Several books and articles have extensively reviewed
enhancement of concanavalin A-stimulated mitogenesis the anti-inflammatory or immunosuppressive effects of
of splenocytes from ADX animals may be mediated by glucocorticoid hormones [92–94]. It is apparent from
the type-1 or mineralocorticoid receptor [77]. Finally, it these reviews that under specific conditions, glucocorti-
was shown that corticosterone increases T-cell respon- coids have been shown to suppress immunoglobulin,
siveness to IL-2 and proliferation under conditions of prostaglandin, leukotriene, histamine, and cytokine pro-
high cell densities in vitro, that mimic conditions that are duction, neutrophil superoxide production, macrophage
likely to be found in lymph nodes in vivo [78]. Thus, these function, mitogen- and antigen-induced lymphocyte
in vitro studies indicate a possible mechanism by which proliferation, lymphocyte differentiation, NK cell activ-
stress and stress hormones may enhance immune func- ity and leukocyte migration and activation. Due to their
tion in vivo. potently immunosuppressive actions, glucorticoids are
Several lines of evidence indicate that glucocorticoid widely used in the clinic as anti-inflammatory agents
stress hormones may act synergistically with cytokines to [93].
enhance specific immune reactions. Thus, while gluco- It has been hypothesized that an important physiolog-
corticoids inhibit the synthesis of cytokines under some ic role of endogenous glucocorticoids might be to sup-
conditions, they have also been shown to induce the re- press an ongoing immune response so as to prevent it
lease and potentiate the actions of cytokines under other from reaching levels of reactivity which might cause
conditions. For example, acute psychological stress has damage to self [21, 92, 95, 96]. Strong support for this hy-
been shown to increase circulating TNF-␣, IL-1␤ and IL- pothesis comes from studies that show that adrenalecto-
10 levels in human subjects [14] and acute stress increas- mized rats die within 24–48 h after being immunized
es circulating IL-1␤ and IL-6 in rodents [79, 80]. Gluco- with horse serum or Freund’s complete adjuvant, but they
corticoids have been shown to induce the production of can be rescued by corticosterone replacement therapy
migration inhibitory factor [81]. Moreover, glucocor- [97]. A number of studies involving animal models of in-
ticoids synergistically enhance the induction of acute- flammatory disorders and autoimmune disease also lend
phase proteins by IL-1 and IL-6 [82]. Glucocorticoids support for this hypothesis [73]. These studies have dem-
similarly enhance the biological responses of other cyto- onstrated the existence of a negative feedback loop be-
kines such as IL-2, IFN-␥, granulocyte colony-stimulat- tween the immune system and the HPA axis, such that
ing factor, granulocyte macrophage colony-stimulating proinflammatory mediators arising from an ongoing im-
factor, and oncostatin M [for review, see 83]. mune reaction stimulate the HPA axis [92, 98, 99], which
Synergistic interactions between glucocorticoids and in turn results in the secretion of corticosterone which
cytokines may be mediated by glucocorticoid-induced suppresses the immune response and prevents it from po-
upregulation of cytokine receptors on target cells as de- tentially damaging the host. The protective effects of im-
termined by increased cytokine binding or cytokine re- munosuppression by endogenous glucocorticoids are
ceptor mRNA expression. For example, glucocorticoid- discussed below.
induced TNF receptor has been shown to promote sur-
vival and serve as a costimulatory receptor for T cells [84,
85], and glucocorticoids increase IL-1 binding to human
peripheral blood B cells [86]. Glucocorticoids also act
synergistically with IFN-␥ to induce high-affinity Fc␥
receptors on human monocytic cell lines [87] and stress-
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Immunomodulatory Effects of Timing of Stress or rone reduces the production of IL-2 under these condi-
Stress Hormone Administration Relative to the tions, this decrease is not rate-limiting at this stage since
Timing of Immune Activation and the Time Course exogenously added IL-2 fails to increase proliferation.
of the Ensuing Immune Response However, if corticosterone is administered at later stages,
the enhancement in IL-2R expression is absent, while the
Under certain conditions, physiological levels of en- suppression of IL-2 production is still present. Under
dogenous glucocorticoids have immunoenhancing ef- these conditions, the availability of IL-2 does become
fects while under other conditions similar hormone lev- rate-limiting and hence corticosterone suppresses the
els suppress autoimmune and inflammatory reactions. lymphoproliferative response. Thus, these studies indi-
We hypothesize that these differential effects are achieved cate an important mechanism mediating an endogenous
by differences in overall glucocorticoid sensitivity or re- glucocorticoid-induced immunoenhancement during
ceptivity of the immune response being affected. At the the early stages, and an endogenous glucocorticoid-in-
very beginning of an immune response, certain compo- duced immunosuppression during the later stages of an
nents such as leukocyte trafficking, antigen presentation, immune response.
helper T-cell function, leukocyte proliferation, cytokine In a series of seminal studies, Sternberg et al. [21, 100,
and chemokine function, and effector cell function may 101] showed that decreased HPA axis reactivity to in-
all be receptive to glucocorticoid-mediated immunoen- flammatory stimuli results in increased susceptibility to
hancement. In contrast, at a later, more advanced stage of experimental arthritis. A similar role for HPA axis-medi-
an immune response these components may be more re- ated endogenous immunoregulation has been shown for
ceptive to glucocorticoid-mediated immunosuppression. development of autoimmune thyroiditis, lupus erythe-
While this hypothesis needs to be tested through further matosus, and avian scleroderma in obese-strain (OS)
experiments, examples from studies showing temporal chickens [102]. Sternberg et al. [21, 95, 96, 100] investi-
differences in the sensitivity of immune reactions to the gated the influence of the HPA axis on the development
effects of physiologic concentrations of glucocorticoid of streptococcal cell wall (SCW)-induced arthritis in fe-
hormones are presented below. male rats belonging to the genetically related Lewis/N
Studies examining the effects of corticosterone on T- (LEW/N) and Fischer 344/N (F344/N) strains. The F344/
lymphocyte proliferation in vitro support the hypothesis N strain is resistant to the development of SCW-induced
that there may be temporal differences in the receptivity arthritis, whereas the LEW/N strain is susceptible. Inter-
of an immune response to the enhancing versus suppres- estingly, the F344/N strain mounts a significantly greater
sive effects of endogenous glucocorticoid hormones [76]. corticosterone and ACTH response than the LEW/N
These studies have shown that during the early stages of strain when challenged with a variety of stressors or with
T-cell activation, low levels of corticosterone potently en- inflammatory mediators like SCW peptidoglycan poly-
hance anti-TCR-induced lymphocyte proliferation. How- saccharide, or IL-1␣ [20, 21, 23, 100], and compared to the
ever, during later stages of culture, the same levels of cor- F344 strain, the LEW strain shows a significantly greater
ticosterone suppress T-lymphocyte proliferation. Fur- habituation or adaptation to an acute or chronic stressor
thermore, Wiegers et al. [76] showed that corticosterone [22]. F344/N rats treated with the glucocorticoid receptor
had to be present during the process of TCR activation in antagonist, RU-486, are rendered susceptible to SCW-in-
order to enhance the proliferative response. If corticoste- duced arthritis indicating that they do carry the immune
rone was added to the culture system more than 2 h after response genes with potential for triggering autoimmu-
the initiation of TCR activation, the enhancement of lym- nity [21, 100]. Conversely, LEW rats treated with pharma-
phoproliferation was not observed. cologic doses of dexamethasone become completely re-
Interestingly, Wiegers and Reul [for review, see 83] sistant to the development of SCW-induced arthritis [21,
have shown that these bidirectional effects of corticoste- 100]. Furthermore, compared to F344 rats, adrenal ste-
rone on different stages of T-lymphocyte proliferation are roid receptors in neural and immune tissues of LEW rats
mediated by opposing effects of corticosterone on IL-2R show a significantly lower magnitude of activation in re-
versus the cytokine itself. Thus, during the early stages of sponse to stress-induced increases in plasma corticoste-
lymphocyte proliferation, corticosterone induces an in- rone [20, 23]. Thus, strain differences in plasma cortico-
crease in IL-2R␣ expression. This increases the IL-2 re- sterone levels are also manifest as significant differences
ceptivity of lymphocytes and is reflected by an increase in the extent of activation of corticosterone receptors in
in lymphocyte proliferation [76]. Although corticoste- target tissues.
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Experimental allergic encephalomyelitis (EAE) is an- tory effects of stress, we proposed that a stress response
other animal model of an autoimmune disease in which and its effects on immune function be viewed in the con-
a similar immunosuppressive role for the HPA axis has text of a stress spectrum [4, 9] (fig. 2). One region of this
been proposed [for review, see 73]. The LEW strain shows spectrum is characterized by acute stress or eustress, i.e.,
a greater susceptibility to EAE [73]. MacKenzie et al. [103] conditions of short-duration stress that may result in im-
have suggested that during the preclinical phase of EAE, munopreparatory or immunoenhancing physiological
elevations in plasma corticosterone may regulate the conditions. An important characteristic of acute stress is
lymphoproliferative stage of the disease, and that during a rapid physiological stress response mounted in the pres-
the clinical phase of the disease, elevations in plasma cor- ence of the stressor, followed by a rapid shutdown of the
ticosterone as well as splenic norepinephrine may regu- response upon cessation of the stressor. The other region
late other recovery-oriented immune mechanisms. Simi- of the stress spectrum is characterized by chronic stress or
lar correlations between HPA axis hyporeactivity and distress, i.e., repeated or prolonged stress which may re-
susceptibility to autoimmune disease have been observed sult in dysregulation or suppression of immune function.
for autoimmune conditions in chickens [102]. In an ele- An important characteristic of chronic stress is that the
gant series of studies using an EAE model, del Rey et al. physiological response either persists long after the stress-
[104] demonstrated that a proinflammatory/autoimmune or has ceased, or is activated repeatedly to result in an
response itself stimulates the HPA axis primarily through overall integrated increase in exposure of the organism
cytokines like IL-1, and that HPA axis activation is inde- to stress hormones. The concept of ‘allostatic load’ has
pendent of the stress and discomfort associated with been proposed to define the ‘psychophysiological wear
EAE-induced paralysis. and tear’ that takes place while different biological sys-
Complementing these preclinical studies, a series of tems work to stay within a range of equilibrium (allosta-
elegantly conducted clinical studies [105, 106] have shown sis) in response to demands placed by internal or external
that patients with atopic dermatitis [107] and asthma chronic stressors [for review, see 1, 12]. We suggest that
[108] show decreased reactivity of their HPA axis [109]. A conditions of high allostatic load would result in dysreg-
more complex role for sympathetic nervous system in- ulation or suppression of immune function. Importantly,
volvement in autoimmune disease has also been pro- a disruption of the circadian corticosterone/cortisol
posed [110]. rhythm may be an indicator and/or mediator of distress
Glucocorticoid hormones may exert their protective or high allostatic load [9]. The stress spectrum also pro-
immunosuppressive effects by inhibiting the production poses that acute or chronic stress is generally superim-
or actions of proinflammatory molecules as discussed posed on a psychophysiological health maintenance equi-
previously. In addition, it has been hypothesized that glu- librium (fig. 2). The extent and efficiency with which an
cocorticoids may suppress certain autoimmune reactions organism returns to its health maintenance equilibrium
by inducing a shift towards a Th2 or humoral immune after stress depends on resilience, which we define as re-
response [67, 73, 111]. For example, stimulation of the serve capacity of psychophysiological systems to recover
HPA axis by inflammatory mediators released during the from challenging conditions (fig. 2). Factors such as cop-
initiation of an autoimmune response results in increased ing mechanisms, sense of control, optimism, social sup-
plasma corticosterone. Increased corticosterone levels port, early life experiences, learning, genetics, and sleep
may shift the balance of the ongoing immune reaction may be important mediators of psychological resilience
from a Th1-directed (cell-mediated) response towards a (fig. 2). Factors such as neuroendocrine reactivity, genet-
Th2-directed (antibody-mediated) response, by promot- ics, environment, nutrition, and sleep may be important
ing the production of IL-4 and suppressing the produc- mediators of physiological resilience (fig. 2). The psycho-
tion of IL-2 [71]. physiological basis of resilience and reserve capacity are
underinvestigated and provide an important opportuni-
ty for future research.
The Stress-Immune Spectrum The stress spectrum, taken together with the preceding
discussion, shows that the duration, intensity/concentra-
It is often overlooked that a stress response has salubri- tion, and timing of exposure to stressor-induced physi-
ous adaptive effects in the short run [3, 16, 17, 45, 46, 53, ological activation (neurotransmitters, hormones, and
69], although stress can be harmful when it is long-lasting their molecular, cellular, organ-level and systemic effects)
[1, 5, 9]. In order to reconcile these seemingly contradic- are critical for determining whether stress will enhance
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Color version available online
Stress spectrum
Acute Chronic
(minutes to hours) (months to years)
Stressor
Maintenance
equilibrium
Stress
perception
and processing
Psychological resilience
Coping, control, optimism, support, early
experiences, learning, sleep, genetics
Physiological
stress
response
Physiological resilience
Physiological health, genetics,
habituation, environment, nutrition, sleep
Psycho- Active Health Health-

physiological protective maintenance aversive
state
Immune Immune Immune

enhancement equilibrium dysregulation
Leukocyte mobilization Normal/resting Leukocyte mobilization
Innate response surveillance, Innate response
Adaptive response and leukocyte Adaptive response
Th1 or Th2 response turnover Th2 response
Immunoprotection Immunoprotection
Fig. 2. The stress spectrum model. We have proposed a definition genetics, environment, nutrition, and sleep are important media-
of stress as a constellation of events, consisting of a stimulus (stress- tors of physiological resilience. Psychological resilience mechanisms
or), that precipitates a reaction in the brain (stress perception & pro- are especially important in humans because they can limit the dura-
cessing), that activates physiologic fight-or-flight systems in the tion and magnitude of chronic stress responses. By the same token,
body (physiological stress response) [9]. The duration of a physiolog- psychogenic stressors can be particularly detrimental in human
ical stress response is the critical determinant of its effects on im- subjects because they may generate stress responses long after
mune function and health. The stressor itself may be acute (e.g. nar- stressor exposure or even in the absence of physical stressors or sa-
rowly missing being hit by a car) or chronic (e.g. caring for a chron- lient threats. The physiological stress response is the ultimate effector
ically ill child, spouse or parent). Stress perception and processing by arm of the stress spectrum. It may consist of acute or chronic phys-
the brain are critical for determining the duration and magnitude iological activation (neurotransmitters, hormones, and their mo-
of the physiological stress response stimulated by any given stressor. lecular, cellular, organ-level and systemic effects) that results in psy-
Acute or chronic stress is generally superimposed on a psychophys- chophysiological states that have different effects on health. Acute
iological health maintenance steady state. The extent and efficiency stress generally results in activation of mechanisms that include en-
with which an organism returns to its health maintenance steady hancement of immune function, while chronic stress results in
state after stress depends on resilience, which we define as the capac- health-aversive conditions that result in dysregulation or suppres-
ity of psychological and interacting physiological systems to recov- sion of immune function. The molecular mechanisms mediating
er from challenging conditions. Factors such as coping mecha- conversion from positive to negative effects of stress on immune
nisms, sense of control, optimism, social support, early life experi- function and health are slowly beginning to emerge, and merit fur-
ences, learning, genetics, and sleep are important mediators of ther investigation. Reprinted from Dhabhar and McEwen [17], with
psychological resilience. Factors such as neuroendocrine reactivity, permission.
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or suppress/dysregulate immune function. The model immune response. Stress and glucocorticoid hormones
shows that the stressor itself can be acute or chronic can either enhance or suppress immune function de-
(fig. 2). Stress perception and processing by the brain and pending on the following factors: (1) The duration (acute
mechanisms mediating psychological and physiological vs. chronic) of stress. (2) Changes in leukocyte distribu-
resilience are critical for determining the duration and tion within the body, and the compartments in which the
magnitude of the physiological stress response (fig. 2). immune response occurs. (3) The concentration (physi-
Psychological resilience mechanisms are especially im- ologic vs. pharmacologic), duration (acute vs. chronic)
portant in humans because they can limit the duration and nature (endogenous vs. synthetic) of glucocorticoid
and magnitude of chronic stress responses. Psychogenic hormone exposure. (4) The timing of stress or stress hor-
stressors are also very important in human subjects be- mone exposure relative to the stage (early vs. late) of an
cause they can generate stress responses long after stress- immune response. Further elucidation of the interactions
or exposure (e.g. posttraumatic stress disorder following among the above-mentioned factors and other nervous,
a severe traumatic experience, or in a milder form, linger- endocrine, and genetic factors in mediating the effects of
ing anger/mood disturbance following a social alterca- stress on immune function is necessary. Importantly,
tion) or even in the absence of a physical stressor or sa- whether a stressor enhances or suppresses immune func-
lient threat (e.g. worrying about whether one’s romantic tion, it is the end-effect of the affected immune response
feelings will be reciprocated). Therefore, following stress- that affects the health of the organism or individual. For
or exposure and its processing by the brain, there ensues example, stress-induced enhancement of immunopro-
a physiological stress response. This response may consist tective responses is likely to be beneficial while stress-in-
of acute or chronic physiological activation (neurotrans- duced enhancement of immunopathology is harmful.
mitters, hormones, and their molecular, cellular, organ- These findings need to be explored and investigated fur-
level and systemic effects) which results in psychophysi- ther and translated from bench to bedside.
ological states that have different effects on overall health It is important to recognize that humans as well as
and immune function as shown in figure 2. While there animals experience stress as an intrinsic part of life, and
is significant evidence from animal studies to support in conjunction with many standard diagnostic, clinical,
this model, it needs to be further examined in studies in- and experimental manipulations. Unintended stressors
volving human subjects. may significantly affect these measures and overall health
outcomes. Thus, when conducting clinical, diagnostic, or
experimental procedures, it may be important to account
Conclusion for the effects of stress on the specific physiologic param-
eter or health outcome being measured. For example, it is
Stress has long been suspected to play a role in the eti- critical to elucidate and account for the effects of stress
ology of many diseases, and numerous studies have and/or stress hormones on changes in leukocyte distribu-
shown that stress can be immunosuppressive and hence tion within different body compartments. Where possi-
may be detrimental to health. Moreover, glucocorticoid ble, redistribution needs to be monitored in terms of
stress hormones are widely regarded as being immuno- changes in absolute numbers of specific subpopulations
suppressive, and are used clinically as anti-inflammatory of leukocytes. Stress-induced changes in immune cell
agents. However, studies have shown that the acute stress numbers and/or function could significantly affect re-
response may play a critical adaptive and protective role, sults (in case of experiments), diagnosis (in case of medi-
with stress hormones and neurotransmitters preparing cal tests), or outcome (in case of treatment procedures
the immune system for potential challenges (e.g. wound- and surgery).
ing or infection) that are perceived by the brain (e.g. the Due to a host of psycho-sociopolitical factors, stress
detection of predator or attacker) [9, 16, 37, 45, 53]. It may has unfortunately become an increasing and inevitable
be useful to further study, and clinically harness, the part of people’s lives. Stress is also a major factor during
acute stress response that evolution has finely sculpted to the diagnosis, treatment, and follow-up for most diseases.
be one of nature’s crucial survival mechanisms, at least as Chronic stress has been shown to dysregulate immune
much as we study its maladaptive ramifications (chronic function and is thought to play a role in the etiology of
stress) that evolution yet has to catch up with. many diseases. In contrast, it has been shown that activa-
This paper illustrates the complex role that stress and tion of acute stress physiology may enhance protective
stress hormones play as modulators and regulators of an immune responses [3, 16, 45, 59]. We propose that it is
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important to further study, and clinically harness the im- ing, infections, or cancer) or suppress (during auto-
munological effects of the acute stress response, that evo- immune or inflammatory disorders) the immune re-
lution has finely sculpted as a survival mechanism, just sponse depending on the outcome most beneficial for
as we study its maladaptive ramifications (chronic stress) the patient.
that evolution has yet to resolve. A determination of the
physiologic mechanisms through which stress and stress
hormones enhance or suppress immune responses is crit- Acknowledgments
ically important for elucidating risk, developing preven-
I wish to thank current and previous members of my labora-
tative and therapeutic interventions, and optimizing a
tory, particularly, Jean Tillie, Dr. Kavitha Viswanathan, Dr. Ali-
patient’s response to treatment. The elucidation of such son Saul, Kanika Ghai, and Christine Daugherty, whose work and
mechanisms would facilitate development of biomedical publications are among those discussed in this chapter. The work
treatments designed to harness an individual’s physiol- described here was supported by grants from the NIH (AI48995
ogy to selectively enhance (during vaccination, wound- and CA107498) and The Dana Foundation.
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Neuroimmunomodulation 2009;16:300–317 Published online: June 29, 2009

Enhancing versus Suppressive Effects of

© 2009 S. Karger AG, Basel Firdaus S. Dhabhar

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