Clinics in Dermatology (2013) 31, 18–30

Psychological stress and immunoprotection versus

immunopathology in the skin
Firdaus S. Dhabhar, PhD ⁎
Department of Psychiatry and Behavioral Sciences, Institute for Immunity Transplantation and Infection,
Stanford Cancer Institute, Stanford University School of Medicine, 259 Campus Drive, MC 5135, Stanford, CA 94305-5135

Abstract Stress is thought to suppress immune function and increase susceptibility to infections and
cancer. Paradoxically, stress is also known to exacerbate autoimmune/proinflammatory disorders (eg,
psoriasis, atopic dermatitis) that should be ameliorated by immunosuppression. Here we review studies
showing that although chronic stress (lasting for weeks/months/years) can suppress/dysregulate immune
function, acute stress (lasting for minutes to hours) can have immunoenhancing effects. Short-term
stress experienced at the time of immune activation enhances dendritic cell, neutrophil, macrophage, and
lymphocyte trafficking, maturation, and function, and has been shown to augment innate and adaptive
immunity; therefore, depending on the conditions of immune activation, and the nature of the activating
antigen, short-term stress can enhance the acquisition and expression of immunoprotection or
immunopathology. In contrast, chronic stress suppresses or dysregulates innate and adaptive immune
responses by altering the Type 1-Type 2 cytokine balance, inducing low-grade chronic increases in
proinflammatory factors, and suppressing numbers, trafficking, and function of immunoprotective cells.
Chronic stress also increases susceptibility to skin cancer by suppressing Type 1 cytokines and
protective T cells while increasing regulatory/suppressor T cell number/function. It is important to
recognize that the adaptive function of a physiological stress response is to promote survival. Stress-
related neurotransmitters, hormones, and factors act as biological alarm signals that prepare the immune
and other physiological systems for potential challenges (eg, wounding or infection) perceived by the
brain (eg, detection of an attacker); however, this may exacerbate immunopathology (eg, psoriasis,
atopic dermatitis) if the enhanced immune response is directed against innocuous or self-antigens, or if
the system is chronically activated as seen during long-term stress. In view of the ubiquitous nature of
stress and its significant effects on immunoprotection and immunopathology, it is important to further
elucidate the mechanisms mediating both the salubrious and the harmful effects of stress, and to
meaningfully translate findings from bench to bedside.
© 2013 Elsevier Inc. All rights reserved.

Introduction important to appreciate that a psycho-physiological stress

response is one of nature's fundamental survival mecha-
Numerous studies have demonstrated adverse effects of nisms. Without a fight-or-flight stress response, a lion has no
stress on health.1,2 These studies show that chronic or long- chance of catching a gazelle, just as the gazelle has no chance
term stressors can have harmful effects, some of which are of escape. During such short-term stress responses, multiple
mediated through immune mechanisms; however, it is also physiological systems are activated to enable survival. We
have hypothesized that just as the stress response prepares
⁎ Corresponding author. Tel.: +1 650 736 8565. the cardiovascular, musculoskeletal, and neuroendocrine
E-mail address: dhabhar@gmail.com systems for fight or flight, under certain conditions, stress

0738-081X/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.clindermatol.2011.11.003
Effects of stress on skin immune function 19

may also prepare the immune system for challenges (eg, stimulus (stressor) that precipitates a reaction in the brain
wounding or infection) that may be imposed by a stressor (stress perception) that activates physiological fight or flight
(eg, predator, or, in modern times, a medical/surgical systems in the body (stress response).13 The only way that a
procedure). 3,4 Studies have shown that short-duration stressor can affect the brain or body is through the
stressors induce a redistribution of immune cells within the physiological stress response. The major mediators of stress
body and that immune function is significantly enhanced in effects are norepinephrine and epinephrine, which are released
organs like the skin to which leukocytes traffic during acute by the sympathetic nervous system and corticotrophin-
stress. Studies have also identified mechanisms involving releasing hormone, adrenocorticotropin, and cortisol,
dendritic cell, neutrophil, macrophage, and lymphocyte which arise following activation of the hypothalamic-
trafficking, maturation, and function through which acute pituitary-adrenal axis. Because virtually every cell in the
stressors may enhance innate as well as adaptive immunity. body expresses receptors for one or more of these factors,
Acute stress response may serve as an endogenous psycho- stress hormones can induce changes in almost all cells and
physiological adjuvant that enhances immune responses and tissues and inform them about the presence of a stressor.
may have evolved by virtue of the fact that stressful Although stress can be harmful when it is chronic or long
situations (aggression or accident) often result in immune lasting,1,8,9,18 it is often overlooked that a stress response has
activation (wounding or infection) and immune activating salubrious adaptive effects in the short run.6,19 Major
events (accidental wounding) can often trigger a stress distinguishing characteristics of stress are duration and
response (resulting from pain and the realization that one has intensity. Acute stress has been defined as stress that lasts
been wounded).5-7 Interestingly, many clinical situations for a period of minutes to hours, and chronic stress as stress
involving immune activation (eg, vaccination, surgery) also that persists for several hours per day for weeks or months.13
induce a stress response. Although acute stress-induced Dysregulation of the circadian cortisol rhythm is one maker
immunoenhancement may serve to increase immunoprotec- that appears to coincide with the deleterious effects of
tion during exposure to infectious agents or wounding, it chronic stress.13,14,20 The intensity of stress may be gauged
may also exacerbate immunopathology if the enhanced by the peak levels of stress hormones, neurotransmitters, and
immune response is directed against innocuous or self- other physiological changes, such as increases in heart rate
antigens, or dysregulated following prolonged activation as and blood pressure, and by the amount of time for which
seen during chronic stress. In contrast to acute stress, chronic these changes persist during stress and following the
stress has been shown to dysregulate immune responses8,9 cessation of stress. There are significant individual differ-
by altering the cytokine balance from Type-1 to Type-2 ences in stress perception, processing, and coping.19,21.
cytokine-driven responses10 and accelerating immunosenes- Individual differences become particularly relevant while
cence11,12 and to suppresses immunity by decreasing studying human subjects because stress perception, proces-
numbers,13 trafficking,13 and function of protective immune sing, and coping mechanisms can have significant effects on
cells while increasing regulatory/suppressor T cells.14 We the kinetics and peak levels of circulating stress hormones
discuss the effects of stress on immune function and and on the duration for which these hormone levels are
implications of these effects for immunoprotection versus elevated. Animal studies showing strain differences in stress
immunopathology. We propose that it is important to study, reactivity and peak hormone levels,22,23 adaptation to
and if possible, to harness clinically, the immunoenhancing stress,24 and in distribution and activation of adrenal steroid
effects of the acute stress response that evolution has finely receptors and corticosteroid binding globulin levels,22,25
sculpted as a survival mechanism, just as we study its suggest that genetic as well as environmental factors play a
maladaptive ramifications (chronic stress) that evolution yet role in establishing individual differences.22,24-26 The ability
has to catch up with. of humans to generate and experience psychological
stressors in the absence of external stressors can result in
long-term activation of the physiological stress response,
which often has deleterious effects. The magnitude and
Stress: definition, mediators, and duration of stress-induced elevations in catecholamine and
individual differences glucocorticoid hormones can have significant effects on
immune cell distribution and function.4,27,28
Although the word “stress” generally has negative con-
notations, stress is a familiar and ubiquitous aspect of life,
being a stimulant for some, but a burden for many others.
Numerous definitions have been proposed for the concept of The immune triad: immunoprotection,
stress. Each definition focuses on aspects of an internal or immunopathology, and immunoregulation
external challenge, disturbance, or stimulus; on perception of
a stimulus by an organism; or on a physiological response When discussing immune responses, it is useful to
of the organism to the stimulus.15-17 An integrated definition categorize them in terms of their principal cellular and
states that stress is a constellation of events, consisting of a molecular components. For example, innate, adaptive, Th1,
20 F. Dhabhar

Th2, Th17, and so on, immune responses are all defined in Whether a stressor enhances or suppresses immune
terms of their cellular and cytokine components. Although function, the end-effect of the immune response determines
such categories provide useful constructs with which to whether the stress-immune interactions have beneficial or
organize ideas, concepts, and models, an overall in vivo harmful effects on health (Figure 1). Given the definitions in
immune response is likely to consist of several types of the preceding section, stress-induced enhancement of
responses with varying amounts of dominance from each immunoprotection is likely to have beneficial effects,
category. Therefore, in addition to these categories, it is also whereas stress-induced suppression of immunoprotection is
useful to define immune responses in terms of their end- likely to be harmful. Similarly, stress-induced enhancement
effects. We suggest that immune responses can be of immunopathology or long-term proinflammation is also
categorized as being immunoprotective, immunopathologi- likely to be harmful. Finally, stress-induced enhancement of
cal, and immunoregulatory/suppressive (for review see7,29). active immunoregulation/inhibition is likely to be beneficial
Immunoprotective responses are defined as responses that in cases of autoimmune and proinflammatory disorders and
promote efficient wound healing, eliminate viral infections harmful in cases of infections and cancer.
and cancer, and mediate vaccine-induced immunological
memory. Immunopathological responses are defined as those
that are directed against self- (autoimmune diseases like
psoriasis, multiple sclerosis, arthritis, lupus) or other antigens Stress-induced changes in immune
(skin hypersensitivities, allergies, asthma), as well as cell distribution
responses that involve chronic, nonresolving inflammation.
Immunopathology is also involved in low-grade, chronic Effective immunoprotection requires rapid recruitment of
elevations in local and/or systemic inflammatory mediators leukocytes into sites of wounding, infection, surgery, or
that are thought to contribute to disorders like cardiovas- vaccination. Immune cells circulate continuously on surveil-
cular disease, obesity, and depression. Immunoregulatory/ lance pathways that take them from the blood, through
suppressive responses are defined as those that involve various organs, lymphatic vessels, and nodes, and back into
immune cells and factors that regulate/inhibit the function of the blood. This circulation is essential for the maintenance of
other immune cells. Although the previous concept of an effective immune defense network.30 The numbers and
suppressor T cells became mired in controversy, recent proportions of leukocytes in the blood provide an important
studies suggest that a critical arm of the immune system representation of the state of distribution of leukocytes in the
functions to inhibit immune responses. body and of the state of activation of the immune system.
The ability of acute stress to induce changes in leukocyte
distribution within different body compartments is perhaps
one of the most underappreciated effects of stress and stress
Factors that determine whether stress will hormones on the immune system.3,13
Numerous studies have shown that acute or short-term
enhance or suppress immune function and the stress induces significant changes in absolute numbers and
potential health consequences of these effects relative proportions of leukocytes in the blood. Stress-
of stress induced changes in blood leukocyte numbers have been
reported in fish,31 hamsters,32 mice,33,34 rats,3,35-37 rabbits,38
Critical factors that are likely to influence the direction horses,39 nonhuman primates,40 and humans.41-46 This
(enhancing versus suppressive) of the effects of stress or suggests that the phenomenon of stress-induced leukocyte
stress hormones and the nature of the immune response redistribution has a long evolutionary lineage, and that
(immunoprotective, immunopathological, or immunoregu- perhaps it has important functional significance. Interesting-
latory/suppressive) that is affected include (1) the effects of ly, changes in blood leukocyte numbers were used as a
stress on leukocyte distribution in the body, (2) the measure of stress before methods were available to directly
duration (short-term/acute versus long-term/chronic) of assay stress hormones.47 Studies have also shown that
stress, (3) the differential effects of physiologic versus glucocorticoid36,48,49 and catecholamine28,43,50-53 hormones
pharmacologic concentrations of glucocorticoids and the induce rapid and significant changes in leukocyte distribu-
differential effects of endogenous (eg, cortisol, corticoste- tion and that these hormones are the major mediators of the
rone) versus synthetic (eg, dexamethasone) glucocorticoids, effects of stress.
and (4) the timing of stressor or stress hormone exposure Acute stress induces an initial increase followed by a
relative to the time of activation and ensuing time course decrease in blood lymphocyte and monocyte numbers, and
of the immune response. Factors, such as gender, genetics, an increase in blood neutrophil numbers.46 Stress conditions
age, the route of administration and nature of the that result in activation of the sympathetic nervous system,
immunizing antigen, and time during the circadian cycle, especially conditions that induce high levels of norepineph-
may additionally affect the relationship between stress and rine, generally induce an increase in circulating leukocyte
immune function. numbers. These conditions may occur during the beginning
Effects of stress on skin immune function 21
STRESSOR IMMUNE RESPONSE END EFFECT POTENTIAL HEALTH OUTCOME

BENEFICIAL:
IMMUNO-PROTECTION
If acute stress is experienced during EFFICACY OF
ACUTE or vaccination, wounding, or infection VACCINATION & WOUND HEALING,
SHORT-TERM RESISTANCE TO
STRESS INFECTION & CANCER

IMMUNO-PATHOLOGY
If acute stress is experienced during self /
innocuous antigen / allergen exposure HARMFUL:
PRO-INFLAMMATORY &
IMMUNO-PATHOLOGY AUTOIMMUNE DISEASE
If chronic stress induces an increase in
dysregulated, pro-inflammatory or
Type-2 cytokine driven responses

CHRONIC or HARMFUL:
LONG-TERM EFFICACY OF
STRESS IMMUNO-SUPPRESSION VACCINATION & WOUND HEALING,
If chronic stress decreases baseline RESISTANCE TO
leukocyte numbers, suppresses leukocyte
function, or mobilizes immuno-suppressive INFECTION & CANCER
mechanisms (e.g. regulatory T cells)
BENEFICIAL:
PRO-INFLAMMATORY &
AUTOIMMUNE DISEASE

Fig. 1 Effects of acute/short-term and chronic/long-term stress on immunoprotection, immunopathology, and immunoregulation/suppression,
and their implications for wound healing, vaccination, resistance to infections/cancer, and proinflammatory and autoimmune diseases. (Reprinted
with permission of S. Karger AG, Basel from Dhabhar FS.7)

of a stress response, very short duration stress (order of battle stations within the body. 7,13 Such a leukocyte
minutes), mild psychological stress, or during exercise. In redistribution may enhance immune function in compart-
contrast, stress conditions that result in the activation of the ments to which immune cells traffic during stress, and
hypothalamic-pituitary-adrenal (HPA) axis generally induce subsequently demonstrate that a stress-induced redistribution
a decrease in circulating leukocyte numbers. These condi- of leukocytes from the blood to the skin and subcutaneous
tions often occur during the later stages of a stress response, tissues is accompanied by a significant enhancement of
long duration acute stressors (order of hours), or during skin immunity.54-56
severe psychological, physical or physiological stress. Thus, Because the blood is the most accessible and commonly
an acute stress response induces bidirectional changes in used compartment for human studies, it is important to
blood lymphocyte and monocyte numbers. Soon after the evaluate carefully how changes in blood immune parameters
beginning of stress (order of minutes) or during mild acute might affect in vivo immune function in the context of the
stress, or exercise, catecholamine hormones and neurotrans- specific experiment or study at hand. Because most blood-
mitters induce the body's “soldiers” (leukocytes), to exit their collection procedures involve a certain amount of stress,
“barracks” (spleen, lung, marginated pool and other organs) because all patients or subjects will have experienced acute
and enter the “boulevards” (blood vessels and lymphatics). and chronic stress, and because many studies of psycho-
This results in an increase in blood leukocyte numbers, the physiological effects on immune function focus on stress, the
effect being most prominent for NK cells and granulocytes. effect of stress on blood leukocyte distribution becomes a
As the stress response continues, activation of the HPA axis factor of considerable clinical importance.
results in the release of glucocorticoid hormones that induce
leukocytes to exit the blood and take position at potential
“battle stations” (skin, mucosal lining of gastrointestinal and
urinary-genital tracts, lung, liver, and lymph nodes) in Effects of acute stress on leukocyte trafficking
preparation for immune challenges which may be imposed to a site of surgery or immune activation
by the actions of the stressor.3,4,54 Such a redistribution of
leukocytes results in a decrease in blood leukocyte numbers. Subcutaneously implanted surgical sponges have been
Thus, acute stress may result in a redistribution of leukocytes used as clinically relevant in vivo arenas to elucidate the
from the barracks, through the boulevards, and to potential effects of stress on the kinetics, magnitude, subpopulation,
22 F. Dhabhar

and chemoattractant specificity of leukocyte trafficking to a leukocyte infiltration was driven by increased levels of the
site of immune activation or surgery.34 Mice that were Type-1 cytokines, interleukin (IL)-2 and interferon (IFN)- γ,
acutely stressed before sponge implantation showed a two to and TNF-α, observed at the site of antigen reexposure in
threefold higher neutrophil, macrophage, NK cell, and T-cell animals that had been stressed at the time of primary
infiltration than nonstressed animals. Enhanced leukocyte immunization. Given the importance of inducing long-
infiltration was evident as early as 6 hours and peaked lasting increases in immunological memory during vaccina-
between 24 and 48 hours. Importantly, sponges from tion, we have suggested that the neuroendocrine stress
nonstressed and acutely stressed mice had comparable and response is nature's adjuvant that could be psychologically
significantly lower leukocyte numbers at 72 hours, indicating and/or pharmacologically manipulated to safely increase
effective resolution of inflammation in both groups. These vaccine efficacy.6,7,19
authors also examined the effects of stress on early (6 hours) A similar enhancement of the sensitization/immunizatio-
leukocyte infiltration in response to a predominantly n/induction phase of cell-mediated immunity by different
proinflammatory cytokine, tumor necrosis factor (TNF)-α, types of stressors administered at the time of antigen
and lymphocyte-specific chemokine, lymphotactin (LTN). exposure has been observed in mice, rats, and nonhuman
Acute stress significantly increased infiltration of macro- primates.57-59 A series of elegant experiments also showed
phages, in response to saline, LTN or TNF-α; neutrophils, that acute stress experienced at the time of sensitization
only in response to TNF-α; and NK and T cells only in resulted in a significant increase in the contact hypersensi-
response to LTN. These results showed that acute stress tivity (CHS) response.60 Other studies further elucidated the
significantly enhances the kinetics and magnitude of molecular and cellular mediators of the immunoenhancing
leukocyte infiltration into a site of immune activation or effects of acute stress.61 They showed that compared with
surgery in a subpopulation and chemoattractant specific nonstressed mice, acutely stressed animals showed signifi-
manner with tissue damage, antigen-, or pathogen- driven cantly greater pinna swelling, leukocyte infiltration, and
chemoattractants synergizing with acute stress to further upregulated macrophage chemoattractant protein-1 (MCP-1),
determine the specific subpopulations that are recruited.34 macrophage inflammatory protein-3α (MIP-3α), IL-1α, IL-
Depending on the primary chemoattractants driving an 1β, IL-6, TNF-α, and IFN-γ gene expression at the site of
immune response, acute stress may selectively mobilize primary antigen exposure. Stressed animals also showed
specific leukocyte subpopulations into sites of surgery, enhanced maturation and trafficking of dendritic cells from
wounding, or inflammation. Such a stress-induced increase skin to lymph nodes, higher numbers of activated macro-
in leukocyte trafficking may be an important mechanism by phages in skin and lymph nodes, increased T-cell activation
which acute stressors alter the course of different (innate in lymph nodes, and enhanced recruitment of surveillance T
versus adaptive, early versus late, acute versus chronic) cells to skin. These findings showed that important
protective or pathological immune responses. interactive components of innate (dendritic cells and
macrophages) and adaptive (surveillance T cells) immunity
are mediators of the stress-induced enhancement of a
primary immune response. Such immunoenhancement
Acute stress-induced enhancement of innate/ during primary immunization may induce a long-term
primary immune responses in skin increase immunologic memory resulting in subsequent
augmentation of the immune response during secondary
In view of the skin's being one of the target organs to antigen exposure.
which leukocytes traffic during stress, studies were con-
ducted to examine whether skin immunity is enhanced when
immune activation/antigen exposure takes place following a
stressful experience. Studies showed that acute stress Acute stress-induced enhancement of
experienced at the time of novel or primary antigen exposure adaptive/secondary immune responses in skin
results in a significant enhancement of the ensuing skin
immune response.6 Compared with controls, mice restrained In addition to enhancing primary cutaneous immune
for 2.5 hours before primary immunization with keyhole responses, acute stress experienced at the time of antigen
limpet hemocyanin (KLH) showed a significantly enhanced reexposure can also enhance secondary or recall responses in
immune response when reexposed to KLH 9 months later. skin.54 Compared with nonstressed controls, mice that were
This immunoenhancement was mediated by an increase in acutely stressed at the time of antigen reexposure showed a
numbers of memory and effector helper T cells in sentinel significantly larger number of infiltrating leukocytes at the
lymph nodes at the time of primary immunization. Further site of the immune reaction. These results demonstrated that a
analyses showed that the early stress-induced increase in relatively mild behavioral manipulation can enhance an
T-cell memory may have stimulated the robust increase in important class of immune responses that mediate harmful
infiltrating lymphocyte and macrophage numbers observed (allergic dermatitis) as well as beneficial (resistance to certain
months later at a novel site of antigen reexposure. Enhanced viruses, bacteria, and tumors) aspects of immune function.
Effects of stress on skin immune function 23

Other studies have similarly shown enhancement of the induced enhancement of skin immunity. These results
elicitation/recall phase of cell-mediated immunity by differ- showed that IFN-γ is an important local mediator of a
ent stressors administered at the time of antigen reexposure, stress-induced enhancement of skin cell–mediated immuni-
in mice, rats, hamsters, and nonhuman primates.32,57-59 It has ty.56 In addition to IFN-γ, TNF-α, MCP-1, MIP-3α, IL-1,
also been shown that acute stress-enhanced CHS responses in and IL-6 have also been associated with a stress-induced
both male and female mice62; however, they failed to observe enhancement of the immunization/sensitization phase of
the stress-induced enhancement of the sensitization phase of skin cell–mediated immunity.6,61 Given the importance of
CHS63 that has been reported by several independent groups stress effects on skin immune function, further investigation
as described previously.6,57-61,64 is necessary to identify the molecular, cellular, and phy-
siological mediators of a stress-induced enhancement of
skin immunity.

Hormone and cytokine mediators of

stress-induced enhancement of immune function
Fight-or-flight physiology as an adjuvant for
Although much work remains to be done to identify protective and pathological immune
molecular, cellular, and physiological mechanisms mediat- responses—clinical implications
ing the adjuvantlike, immunoenhancing effects of acute
stress, studies have shown that corticosterone and epine- It has been proposed that a psycho-physiological stress
phrine are important mediators of an acute stress-induced response is nature's fundamental survival mechanism that
immunoenhancement.55 Adrenalectomy, which eliminates could be therapeutically harnessed to augment immune
the glucocorticoid and epinephrine stress response, elimi- function during vaccination, wound healing, or infec-
nated the stress-induced enhancement of skin cell mediated tion.6,7,29 These adjuvantlike immunoenhancing effects of
immunity. Low-dose corticosterone or epinephrine admi- acute stress may have evolved because many stressful
nistration significantly enhanced skin cell–mediated immu- situations (aggression, accident) result in immune activation
nity. 55 In contrast, high-dose corticosterone, chronic (wounding, infection) and vice versa. Interestingly, in
corticosterone, or low-dose dexamethasone administration modern times, many medical procedures involving immune
significantly suppressed skin cell–mediated immunity.55 activation (vaccination, surgery) also induce a stress
These results suggested a novel role for adrenal stress response. In keeping with this hypothesis, studies have
hormones as endogenous immunoenhancing agents. Stress shown that patients undergoing knee surgery, who show a
hormones released during a circumscribed or acute robust and adaptive immune cell redistribution profile during
stress response may help prepare the immune system for the acute stress of surgery, also show significantly enhanced
potential challenges (eg, wounding or infection) for recovery.46 Similarly, an elegant series of studies has shown
which stress perception by the brain may serve as an that adjuvant effects of acute mental or exercise stress can
early warning signal. Other studies have also suggested enhance vaccine-induced humoral and cell-mediated immu-
that corticosterone is a mediator of the stress-induced nity in human subjects.65,66
enhancement of skin CHS62 and that the adjuvantlike While short-term stress-induced enhancement of immu-
effects of stress on dendritic cell and CD8+ T-cell noprotective responses have been appreciated relatively
migration and function are mediated by norepinephrine.60 recently, stress-induced exacerbations of proinflammatory
Taken together, these studies suggest that endogenous (eg, dermatitis,67,68 cardiovascular disease,69,70 periodontal
stress hormones in physiological concentrations can have disease,71 and asthma67,72,73) and autoimmune (eg, psoria-
immunoenhancing effects, whereas endogenous hormones sis,74,75 arthritis,76 multiple sclerosis77) diseases are well
at pharmacologic concentrations, and synthetic hormones, known and frequently observed in the clinic. It will be
are immunosuppressive. important for future studies to (1) determine the extent to
Because IFN-γ is a critical cytokine mediator of cell- which stress-induced exacerbation of such disorders is
mediated immunity and delayed as well as contact mediated by immunoenhancing mechanisms activated dur-
hypersensitivity, studies were conducted to examine its ing acute stressors versus immunodysregulatory mechanisms
role as a local mediator of the stress-induced enhancement of activated during chronic stressors, (2) determine the extent
skin cell–mediated immunity.56 The effect of acute stress on to which stress induces the onset of disease versus exacer-
skin cell–mediated immunity was examined in wild-type and bating preexisting conditions, And (3) to use more stan-
IFN-γ receptor gene knockout mice (IFN-γR–/–). Acutely dardized and homogeneous psychological and physiological
stressed wild-type mice showed a significantly larger cell- measures of stress and, where possible, also of the affected
mediated immunity response than nonstressed mice. In immune mediators.
contrast, IFN-γR–/– mice failed to show a stress-induced In terms of mechanistic parallels between basic and
enhancement of skin immunity. Immunoneutralization of human subjects studies, it has been shown that a short-term
IFN-γ in wild-type mice significantly reduced the stress- stress-induced enhancement of skin immunity in mice is
24 F. Dhabhar

mediated by enhanced maturation and trafficking of dendritic glucocorticoid responsivity. These results suggested that
cells from skin to draining lymph nodes, larger numbers of stress-induced alterations in lymphocyte redeployment
activated macrophages in skin and lymph nodes, and may play an important role in mediating the bidirectional
increased T-cell activation in lymph nodes.61 These findings effects of stress on cutaneous cell-mediated immunity.13
are in agreement with studies that showed that acute An association between chronic stress and reduced skin
psychological stress in human participants induces a cell–mediated immunity has also been reported in
significant decrease in epidermal Langerhans cells that the human subjects.88,89
authors suggest represents a trafficking of these cells from
the skin to draining lymph nodes,78 a phenomenon that has
elegantly been shown to have striking similarities in “mice
and men.”79 Effects of acute versus chronic stress on
Taken together, results from numerous studies show squamous cell carcinoma
that stress can significantly enhance innate as well as
adaptive immunity and can potentiate the immunization/ Given the importance of cutaneous cell-mediated immu-
sensitization/induction as well as the elicitation/recall nity in elimination of immunoresponsive tumors like
phases of an immune response. These mechanisms may squamous cell carcinoma (SCC),90,91 and given the skin-
contribute to stress-induced enhancement of immunoprotec- immunoenhancing effects of acute or short-term stress,
tion, but could also mediate clinically well-known examples studies have examined the effects of acute stress adminis-
of stress-induced exacerbation of proinflammatory and tered at the time of ultraviolet light (UV) exposure (minimum
autoimmune disorders and may also be of relevance to erythemal dose, 3 times per week) on gene expression of
psychodermatology.80 Further investigation of mechanisms chemokines and cytokines, infiltration of helper and
mediating stress-induced enhancement of immune function cytolytic T cells that are critical for controlling and/or
is critical for identifying specific biological factors/targets eliminating SCC and on tumor incidence, number, and
that may be therapeutically manipulated to enhance size.92 Compared with controls, the short-term stress group
protective immune responses, or ameliorate/eliminate showed greater cutaneous T-cell–attracting chemokine
stress-induced exacerbation of proinflammatory or autoim- (CTACK)/CCL27, RANTES, IL-12, and IFN-γ gene
mune diseases. expression (at weeks 7, 20, and 32 after the beginning
of UV exposure), higher skin-infiltrating T-cell numbers
(weeks 7 and 20), lower tumor incidence (weeks 11-20),
and fewer tumors (weeks 11-26). These results suggest
Chronic stress-induced suppression/ that activation of short-term stress physiology increased
dysregulation of skin immunity chemokine expression and T-cell trafficking and/or function
during/following UV exposure, and enhanced Type 1
In contrast to acute stressors, chronic stress has been cytokine-driven cell-mediated immunity that is crucial for
shown to suppress or dysregulate immune function resistance to SCC.92 Therefore, the physiological fight-or-
including skin immunity (for review see8,81-87). Studies flight stress response and its adjuvantlike immunoenhancing
have investigated the effects of increasing the intensity effects may provide a novel and important mechanism for
and duration of acute stress as well as the transition from enhancing immune system–mediated tumor-detection/elimi-
acute to chronic stress on skin immune function. 13 nation that merits further investigation.
These studies showed that acute stress administered for In light of the immunosuppressive effects of chronic
2 hours before antigenic challenge significantly enhanced stress, studies were conducted to investigate the effects of
skin cell–mediated immunity.13 Increasing the duration chronic stress on the emergence and progression of SCC.14
of stress from 2 to 5 hours produced the same magni- Compared with nonstressed controls, chronically stressed
tude immunoenhancement. Interestingly, increasing the mice had lower IFN-γ, CCL27/CTACK, and CD3ɛ gene
intensity of acute stress produced a significantly larger expression and lower CD4+ and CD8+ T cells infiltrating
enhancement of the cell-mediated immune response that within and around tumors. Chronically stressed mice also
was accompanied by increasing magnitudes of leukocyte showed a shorter median time to first tumor (15.0 versus
redeployment. In contrast, suppression of the skin immune 16.5 weeks) and reached 50% incidence earlier than con-
response was observed when chronic stress exposure was trols (15 weeks versus 21 weeks). Interestingly, stressed
begun 3 weeks before primary immunization and either mice had higher numbers of tumor-infiltrating and circulat-
discontinued following immunization, or continued an ing regulatory/suppressor T cells than nonstressed mice.
additional week until reexposure to the antigen, or These studies showed that chronic stress increased suscep-
extended for 1 week after reexposure.13 Interestingly, tibility to UV-induced SCC by suppressing skin immunity,
acute stress-induced redistribution of peripheral blood Type 1 cytokines, and protective T cells, and increasing
lymphocytes was attenuated with increasing duration active immunosuppressive mechanisms mediated by reg-
of stressor exposure and correlated with attenuated ulatory/suppressor T cells.14
Effects of stress on skin immune function 25

Immunomodulatory effects of timing of stress corticotrophin-releasing hormone, 101,102 mast cell fac-
or stress hormone administration relative to tors,101,103 and mediators that also induce neurogenic
inflammation.104 Therefore, it is clear that much research
the timing of immune activation and the time remains to be done to identify the various psychophysiolog-
course of the ensuing immune response ical factors that may mediate the effects of stress and other
emotional states on skin immune reactivity.
Under certain conditions, endogenous glucocorticoids
have immunoenhancing effects, whereas under other condi-
tions these hormones suppress autoimmune and inflamma-
tory reactions. It is possible that these differential effects are The stress-immune spectrum
achieved by differences in overall glucocorticoid sensitivity
or receptivity of the affected immune response. At the It is often overlooked that a stress response has salubrious
beginning of an immune response, certain components, such adaptive effects in the short run,3,6,7,19,34,54,55,105 although
as leukocyte trafficking, antigen presentation, helper T-cell stress can be harmful when it is long-lasting.1,8,13 To
function, leukocyte proliferation, cytokine and chemokine reconcile these seemingly contradictory effects of stress, we
function, and effector cell function, may be receptive to proposed that a stress response and its effects on immune
glucocorticoid-mediated immunoenhancement. In contrast, function be viewed in the context of a STRESS SPEC-
at a later, more advanced stage of an immune response, these TRUM4,7,13 (Figure 2). One region of this spectrum is
components may be more receptive to glucocorticoid- characterized by ACUTE STRESS or EUSTRESS, ie,
mediated immunosuppression. Although this hypothesis conditions of short-duration stress that may result in
needs to be tested through further experiments, studies immunopreparatory, or immunoenhancing physiological
examining the effects of corticosterone on T-lymphocyte conditions. An important characteristic of acute stress is a
proliferation in vitro support the hypothesis that there may be rapid physiological stress response mounted in the presence
temporal differences in the receptivity of an immune of the stressor, followed by a rapid shut-down of the response
response to the enhancing versus suppressive effects of upon cessation of the stressor. The opposite region of the
endogenous glucocorticoid hormones.93 These studies have stress spectrum is characterized by CHRONIC STRESS or
shown that during the early stages of T-cell activation, low DISTRESS, ie, repeated or prolonged stress that may result
levels of corticosterone potently enhance anti-TCR-induced in dysregulation or suppression of immune function. An
lymphocyte proliferation; however, during later stages of important characteristic of chronic stress is that the
culture, the same levels of corticosterone suppress T- physiological response either persists long after the stressor
lymphocyte proliferation.93 It has been shown that cortico- has ceased, or is activated repeatedly to result in an overall
sterone had to be present during the process of TCR T-cell integrated increase in exposure of the organism to stress
receptor activation to enhance the proliferative response. If hormones. The concept of “allostatic load” has been
corticosterone were added to the culture system more than 2 proposed to define the “psychophysiological wear and
hours after the initiation of TCR activation, the enhancement tear” that takes place while different biological systems
of lympho-proliferation was not observed. work to stay within a range of equilibrium (allostasis) in
response to demands placed by internal or external chronic
stressors (for review see1,16). Conditions of high allostatic
load are likely to result in dysregulation or suppression of
Other potential mediators of the effects of immune function. Importantly, a disruption of the circadian
stress on skin immune function corticosterone/cortisol rhythm may be an indicator and/or
mediator of distress or high allostatic load.13 The STRESS
Although the preceding discussion has focused on the role SPECTRUM also proposes that acute or chronic stress
of psychological stress and stress hormones in mediating is generally superimposed on a psycho-physiological
changes in skin cell–mediated immunity, numerous other HEALTH MAINTENANCE EQUILIBRIUM (Figure 2).
studies have examined other mediators of the effects of The extent and efficiency with which an organism returns
changes in central nervous system activity on skin immunity to its health maintenance equilibrium after stress depends
as well as cutaneous wound healing, and changes in skin on RESILIENCE, which we define as the capacity of
barrier function.94-96 Although the principal stress hormones psychophysiological systems to recover from challenging
appear to play a major role, additional factors that could conditions (Figure 2). Factors such as coping mechanisms,
mediate the effects of stress and other emotional states on sense of control, optimism, social support, early life
skin immunity include the actions of cutaneous nerves experiences, learning, genetics, and sleep may be important
and the release of peptides like calcitonin gene–related mediators of PSYCHOLOGICAL RESILIENCE (Figure 2).
peptide, substance P, vasoactive intestinal peptide,97,98 and Factors such as neuro-endocrine reactivity, genetics, envi-
proopiomelanocortin peptides99,100 such as alpha-melano- ronment, nutrition, and sleep may be important mediators
cyte stimulating hormone, local and systemic release of of PHYSIOLOGICAL RESILIENCE (Figure 2). The
26 F. Dhabhar

STRESS SPECTRUM
ACUTE CHRONIC
(minutes to hours) (months to years)

STRESSOR
MAINTENANCE
EQUILIBRIUM
STRESS
PERCEPTION
& 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 & leukocyte adaptive response
Th1 or Th2 response turnover Th2 response
immunoprotection immunoprotection

Fig. 2 The Stress Spectrum Model describes the relationships among the duration (acute or chronic) of stress, psychological and
physiological resilience mechanisms, and immune and health outcomes. (Reprinted with permission from Dhabhar and McEwen.19)

psychophysiological basis of resilience are underinvestigated riences chronic stress, the higher the chances of there
and provide an important opportunity for future research. being detrimental effects on health; however, biological
This model suggests that an effective strategy for health organisms, including humans, are resilient. It takes long
maintenance would be to stay within the ʽʽgood stress" and exposures to chronic stress to critically break down physio-
psycho-physiological equilibrium regions of the stress- logical systems. Getting sufficient sleep, engaging in
spectrum while minimizing the time spent on the chronic moderate exercise, and establishing a moderate but
stress side. Personal strategies for returning to equilibrium healthy diet may increase stress resilience.
following stressor exposure are likely to involve different The Stress Spectrum, taken together with the preceding
strokes for different folks, ie, different individuals may discussion, shows that the duration, intensity/concentra-
need/use different means (eg, walking, running, dancing, tion, and timing of exposure to stressor-induced physio-
yoga, meditation, reading, music, painting, sleeping, or other logical activation (neurotransmitters, hormones, and
de-stressors) to return to their psycho-physiological equi- their molecular, cellular, organ-level and systemic
librium after a stressful experience. The longer one expe- effects) are critical for determining whether stress will
Effects of stress on skin immune function 27

enhance or suppress/dysregulate immune function. The cally, the important connection between stress and the
model shows that the stressor itself can be acute or chronic exacerbation of skin disorders has been known for a long
(Figure 2). Stress perception and processing by the brain and time96,109,110 and is an important aspect of psychodermatol-
mechanisms mediating psychological and physiological ogy.80 The studies described here shed light on potential
resilience are critical for determining the duration and mechanisms that may mediate the bidirectional effects of
magnitude of the physiological stress response (Figure 2). stress on skin immune function, and provide targets for
Psychological resilience mechanisms are especially important clinical interventions that may be designed to dampen or
in humans because they can limit the duration and magnitude eliminate stress-induced exacerbation of skin immunopa-
of chronic stress responses. Psychogenic stressors are also thology. Although decades of research have examined the
very important in human subjects because they can generate pathological effects of stress on immune function and on
stress responses long after stressor exposure (eg, posttraumatic health, the study of salubrious or health-promoting effects of
stress disorder following a severe traumatic experience, or in a stress is relatively new.6,7,19,29 Therefore, the studies
milder form, lingering anger/mood disturbance following a presented here also provide a framework for developing
social altercation) or even in the absence of a physical stressor therapeutic interventions that harness the mind and body's
or salient threat (eg, worrying about whether one's romantic endogenous health-promoting mechanisms to enhance
feelings will be reciprocated). Following stressor exposure protective immunity during vaccination, infection, wound
and its processing by the brain, there ensues a PHYSIOLOG- healing, or cancer. Much work remains to be done to
ICAL STRESS RESPONSE. This response may consist of elucidate the mechanisms mediating the salubrious versus
acute or chronic physiological activation (neurotransmitters, health-aversive effects of stress and to translate findings from
hormones, and their molecular, cellular, organ-level, and bench to bedside. This work is extremely important because
systemic effects), which results in PSYCHO-PHYSIOLOG- stress is a ubiquitous aspect of life and although chronic
ICAL STATES that have different effects on overall health stress is thought to play a role in the etiology of numerous
and immune function, as shown in Figure 2. Although there is diseases, acute or short-term stress is one of nature's
significant evidence from animal studies to support this fundamental survival mechanisms that could be clinically
model, it needs to be further examined in studies involving harnessed to enhance immunoprotection.
human subjects.

Acknowledgment
Conclusions
The author acknowledges Dr Kavitha Viswanathan, Dr
An important function of physiological mediators re- Alison Saul, Christine Daugherty, and Jean Tillie, whose
leased under conditions of acute or short-term psychological work and publications are among those discussed in this
stress may be to ensure that appropriate leukocytes are chapter. Supported by the National Institutes of Health
present in the right place, at the right time, and activated in (AI48995, AR46299, & CA107498), The Dana Foundation,
the right manner to respond to an immune challenge that and startup funds from the Carl & Elizabeth Naumann Fund.
could be initiated by the stress-inducing agent (eg, attack by
a predator, invasion by a pathogen). The modulation of
immune cell distribution by acute stress may be an adaptive References
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