J Neuroimmune Pharm (2006) 1: 421–427
DOI 10.1007/s11481-006-9036-0
INVITED REVIEW
Stress-Induced Immune Dysregulation: Implications
for Wound Healing, Infectious Disease and Cancer
Jonathan P. Godbout & Ronald Glaser
Received: 20 April 2006 / Accepted: 13 July 2006 / Published online: 10 August 2006
# Springer Science + Business Media, Inc. 2006
Abstract The communication between the central nervous
system and the immune system occurs via a complex network
of bidirectional signals linking the nervous, endocrine and
immune systems. The field of psychoneuroimmunology
(PNI) has provided new insights to help understand the
pathophysiological processes that are linked to the immune
system. Work in this field has established that psychological
stress disrupts the functional interaction between the nervous
and immune systems. Stress-induced immune dysregulation
has been shown to be significant enough to result in health
consequences, including reducing the immune response to
vaccines, slowing wound healing, reactivating latent herpes-
viruses, such as Epstein–Barr virus (EBV), and enhancing the
risk for more severe infectious disease. Chronic stress/
depression can increase the peripheral production of proin-
flammatory cytokines, such as interleukin (IL)-6. High serum
levels of IL-6 have been linked to risks for several conditions,
such as cardiovascular disease, type 2 diabetes, mental health
complications, and some cancers. This overview will discuss
J. P. Godbout : R. Glaser
Institute for Behavioral Medicine Research,
Ohio State University, Columbus, OH, USA
J. P. Godbout : R. Glaser
Department of Molecular Virology,
Immunology, and Medical Genetics,
Ohio State University, Columbus, OH, USA
R. Glaser
Comprehensive Cancer Center,
Ohio State University, Columbus, OH, USA
R. Glaser (*)
2175 Graves Hall, 333 W. 10th Avenue,
Ohio State University, Columbus, OH 43210, USA
e-mail: glaser.1@osu.edu
the evidence that psychological stress promotes immune
dysfunction that negatively impacts human health.
Key words stress . immunity . cytokines . behavior
Abbreviations
HPA hypothalamic–pituitary–adrenal
SNS sympathetic nervous system
GC glucocorticoids
EBV Epstein–Barr virus
NPC nasopharyngeal carcinoma
BL Burkitt_s lymphoma
Introduction
Psychological stress can be defined as a perceived stress
that influences an individual_s ability to cope with life
events. It is clear that psychological stress impacts immune
function and health (Fig. 1). Clinical and experimental
evidence indicates that the duration and the course of the
stress are the pivotal factors that determine the nature of the
stress-induced immune change and any health-related
outcome (reviewed by Glaser and Kiecolt-Glaser 2005;
Segerstrom and Miller 2004).
In many circumstances, short-term stressors augment
certain aspects of immune function, which, as a conse-
quence, can be either beneficial or detrimental. A classic
example of a beneficial response is the “fight or flight
response,” where activation of both the hypothalamic–
pituitary–adrenal (HPA) axis and the sympathetic nervous
system (SNS) prepares an organism to deal with a threat by
increasing heart rate, increasing blood flow to skeletal
muscle, and elevating glucose metabolism. In regard to
immunity, this acute activation of HPA- and SNS-mediated
422 J Neuroimmune Pharm (2006) 1: 421–427

Wound healing
Stress Stress
Psychological
Recent evidence indicates that physiological stress impairs
Humans: Rodents:
wound healing by attenuating the initial inflammatory phase
Academic Stress Restraint Stress of the repair process. This first phase of wound healing is
Marital Discord Social Disruption Stress
Primary Caregiver of a Repeated Foot Shock Stress
cell-mediated and depends on the interactions between
Demented Spouse Other Stress Models chemokines, cytokines, and growth factors to recruit
Other Factors
phagocytes and fibroblasts at the wound site and to help
promote remodeling of damaged tissue. This early response
is pivotal because when it is impaired, the entire healing
cascade is disrupted (Hubner et al. 1996). This is clinically
Immune Dysfunction
relevant because stress-induced deficits in wound healing
are related to longer hospitalization and an increase in
Innate
Cell Meditated
Adaptive complications following surgical procedures (Kiecolt-
Wound Repair
Antibody Production Glaser et al. 1998).
NK Activity to Vaccination
Circulating Inflammatory In several human studies, psychological stress caused a
Infectious
Cytokines Episodes substantial delay in wound healing. For example, attenuated
Reactivation of wound healing was evident in older women who where
Latent Virus
primary caregivers of a demented spouse (Kiecolt-Glaser et
al. 1995). In this study, caregivers and age-matched controls
were subjected to a standardized 3.5-mm punch biopsy
Potential Complications
wound on the forearm. Wound healing in caregivers was
Increased clinical symptoms of an infection
Decreased resiliency in recovery from infection prolonged an average of 9 days longer (48 vs. 39 days)
Prolonged recovery from surgical procedures compared with controls. Moreover, peripheral blood leuko-
Behavioral/cognitive deficits
Tumor promotion/progress on cytes (PBLs) isolated from caregivers had lower levels of
interleukin (IL)-1 gene expression after treatment with
Fig. 1 The potential impact of psychological stress on immune
function and health. This figure depicts the multiple ways psycholog-
lipopolysaccharide (LPS) (Kiecolt-Glaser et al. 1995). In
ical stress can influence the immune system and health span. Chronic another study, when oral mucosal wounds were made in the
stress in human or rodent models can cause dysfunction in the innate, hard palate of dental students either before an examination
adaptive, and acquired mediated immune responses. These stress- period or during a vacation period, academic stress slowed
associated impairments in immunity can increase morbidity and
mortality by causing more serious deficits in physical and mental
wound healing by approximately 40% (Marucha et al.
health. 1998). Recent findings also indicate that the stress of a
hostile marital relationship delayed wound healing. Couples
with hostile marital interactions showed a 60% reduction in
wound healing repair, which was associated with a decrease
pathways increases leukocyte trafficking and enhances in proinflammatory cytokine IL-1β, IL-6, and tumor
adaptive (B cell) immune responses (reviewed by Dhabhar necrosis factor (TNF)-α levels at the wound site (Kiecolt-
2003; Sanders and Kohm 2002). Acute stress improved the Glaser et al. 2005). Taken together, these studies indicate
delayed-type hypersensitivity response in mice (Dhabhar that psychological stress significantly prolongs wound-
2003), which was purported to be a protective mechanism healing time, potentially through a mechanism involving
against wound infection following an aggressive encounter the reduction of the cell-mediated inflammatory response at
(Altemus et al. 2001). There is, however, a negative side to the wound site.
acute stress, which is associated with hyperimmune A potential explanation for this healing delay is that
responses in asthma, allergic responses, and latent viral stress stimulates HPA axis-dependent production of gluco-
reactivation. Thus, the influence of acute stress on the corticoid (GC) hormones. Adrenocorticotrophic growth
immune system is undoubtedly a complex interaction that hormone (ACTH) stimulation of the adrenal gland pro-
warrants further investigation. What is well established, motes the release of GCs. In general, GCs influence
however, is that chronic or excessive stress has a immune cells by suppressing differentiation and prolifera-
deleterious affect on immunity. This is illustrated in studies tion, regulating gene transcription, and reducing expression
showing that psychological stress delays the wound healing of cell adhesion molecules that are involved in immune cell
process, increases severity and duration of infectious trafficking (reviewed by Sternberg 2006). Relevant to
disease, promotes reactivation of latent viruses, and may wound healing, the GC cortisol functions as an anti-
even be a cofactor for tumor development and progression. inflammatory agent and modulates Th1-mediated immune
J Neuroimmune Pharm (2006) 1: 421–427
responses that are essential for the initial phase of healing.
For instance, adult women with higher perceived stress
scores had elevated levels of salivary cortisol and decreased
concentrations of the inflammatory cytokines, IL-1α and
IL-8, at wound sites. These two cytokines are chemo-
attractants that are necessary for the initial inflammatory
phase of wound healing (Glaser et al. 1999b). Other
inflammatory cytokines, such as TNFα and IL-6, were also
decreased at the wound site of stressed individuals (Kiecolt-
Glaser et al. 2005). Moreover, the stress of caregiving was
associated with a shift away from a Th1 cytokine profile
toward a Th2 profile, with an increase in IL-10 synthesizing
T cells (Glaser et al. 2001). Finally, in medical students
experiencing examination stress, microarray analysis of
neutrophils at the wound site revealed a transcriptional
profile consistent with suppression of neutrophil activity
(Roy et al. 2005). Collectively, these findings indicate that
psychological stress impairs normal cell-mediated immuni-
ty at the wound site, causing a significant delay in the
healing process.
Psychological stress can also be studied in mouse
models by using, for example, physical restraint or
disruption of the social hierarchy (Sheridan et al. 2000).
Mouse models have provided significant insight into the
mechanism underlying how stress attenuates wound heal-
ing. Similar to human studies, inflammatory cytokines were
found to be down-regulated in the early phase of wound
healing in stressed mice (Mercado et al. 2002a, b) and the
glucocorticoid hormone, corticosterone, played a major role
in the delayed healing response (Padgett et al. 1998a; Rojas
et al. 2002). For example, restraint stress caused wounds to
heal approximately 27% slower than wounds in control
mice, which was associated with decreased leukocyte
infiltration to the wound site at 1 to 3 days postwounding
(Padgett et al. 1998a). Moreover, corticosterone levels were
elevated 4-fold in restraint stressed mice. When corticoste-
rone signaling was blocked with the glucocorticoid inhib-
itor RU4055, wound healing rates of restraint stressed mice
returned to baseline values (Padgett et al. 1998a).
Glucocorticoid hormones can suppress inflammatory
cytokine production by modulating the activity of the
transcription factor, nuclear factor kappa B (NFκB)
(reviewed by Padgett and Glaser 2003). NFκB is a potent
activator of proinflammatory gene transcription and its
activity is modulated by GCs via several mechanisms
including increased transcription of the inhibitor of NFκB
(IκB), competition for inflammatory gene promoter sites,
and reduction of active NFκB translocation into the nucleus
(De Bosscher et al. 2000; Hofmann et al. 1998; Hofmann
and Schmitz 2002). Thus, it is plausible that high cortisol
levels associated with stress limit NFκB transcriptional
activity and subsequently, reduce proinflammatory gene
expression at the wound site (Padgett and Glaser 2003).
423
Infectious disease
Psychological stress and the accompanying negative emo-
tions such as anxiety and depression can impair B- and T-
cell-meditated immune responses. This is significant because
stress-induced immune dysfunction is associated with
increases both in severity and duration of an infectious
disease. For instance, psychological stress increased the risk
of developing clinical symptoms to a rhinovirus infection
(Stone et al. 1992). Moreover, higher perceived stress scores
were associated with the severity of clinical symptoms
associated with respiratory virus infections (Cohen et al.
1991) and stress caused a delay in the recovery from these
infections (Cohen et al. 1998). Stress may also influence the
pathogenesis of human immunodeficiency virus (HIV). The
psychological stress related to the concealment of sexuality
(Cole et al. 1996) in HIV-positive males, was associated
with a more rapid progression into AIDS (Leserman et al.
1999). Furthermore, in studies with monkeys, the stress of
an unstable living environment was associated with higher
simian immunodeficiency virus (SIV)-RNA levels in
plasma after virus inoculation, indicating stress-enhanced
viral replication (Capitanio et al. 1998).
Psychological stress impairs the immune response to
several antiviral/bacterial vaccines, including hepatitis B
virus (Glaser et al. 1992; Jabaaij et al. 1996), pneumococcal
bacteria (Glaser et al. 2000), rubella virus (Morag et al.
1999), meningitis virus (Burns et al. 2002), and influenza
virus (Kiecolt-Glaser et al. 1996; Miller et al. 2004;
Vedhara et al. 1999). This is biologically significant
because immune responses to vaccinations are good
indicators of how a person would respond to a pathogen.
In support of this relationship, individuals who had
attenuated immune responses against influenza virus vac-
cination also experienced higher rates of clinical illness and
longer clinical episodes (Patriarca 1994).
These impaired immune responses to influenza virus
vaccination are paralleled in stress studies. For instance,
caregivers of a demented spouse showed dramatic deficits
in both cellular and humoral immune responses to an
influenza virus vaccine compared with noncaregivers.
Antibody production at 1 month after vaccination was
markedly reduced in caregivers and antigen-specific pro-
duction of IL-2 by peripheral blood mononuclear cells
(PBMCs) was also attenuated in caregivers (Kiecolt-Glaser
et al. 1996). Moreover, caregivers with poorer antibody
responses to influenza virus vaccination had elevated
concentrations of salivary cortisol that were correlated with
higher perceived stress scores (Vedhara et al. 1999).
Therefore, similar to wound healing studies, these reports
point toward a role of prolonged HPA axis-dependent
production of glucocorticoids. This relationship is further
substantiated in mouse studies using restraint stress, where
424
glucocorticoids were markedly elevated by stress (Padgett
et al. 1998a). In this restraint model, stress impaired
antibody production to influenza virus 2 weeks following
vaccination and caused deficits in cell-mediated immunity
with decreased IL-2 production (Sheridan et al. 1991).
Latent virus reactivation
There is mounting evidence that supports the relationship
between psychological stress and the development, dura-
tion, and recurrence of viral infections including the
herpesviruses, herpes simplex virus type 1 (HSV-1), and
Epstein–Barr virus (EBV). The cellular immune response
plays a critical role in controlling the pathophysiology of
both lytic herpesvirus infections and/or the expression/
replication of latent herpesviruses. When cellular immunity
is impaired, one or more herpesviruses can be reactivated,
which frequently results in a severe infection and even
death. For instance, psychological stressors are associated
with an increased frequency of lesions in women infected
with HSV-1 or HSV-2 (Cohen et al. 1999). Moreover, stress
was associated with longer recurrences of genital herpes in
women (Cohen et al. 1999) and increased incidence of
herpes zoster virus (VZV) (i.e., shingles) in older individ-
uals (Schmader et al. 1990). Furthermore, HSV-1 reactiva-
tion and impaired immunity to HSV-1 infection have been
demonstrated in mouse models of stress. For example, in a
mouse ocular model of HSV-1 infection, reactivation of
latent HSV-1 was induced by social disruption stress but
not restraint stress (Padgett et al. 1998b). In a mouse
footpad model of HSV infection, restraint stress reduced
cytotoxic T lymphocyte (CTL)-mediated killing of HSV-1
infected cells (Bonneau et al. 1991). Abrogation of a
functional HPA or SAM axis reversed the stress-dependent
suppression of the CTLs (Bonneau et al. 1993), indicating a
role of stress hormones in this immune dysfunction.
EBV is a gamma herpesvirus and the etiological agent
for infectious mononucleosis, and is a human tumor virus
implicated in several malignant diseases including naso-
pharyngeal carcinoma (NPC), African Burkitt_s lymphoma
(BL), B cell lymphoma, and posttransplant lymphomas
(Ansell et al. 1999; Brousset 2002; Petrella et al. 1997;
Touitou et al. 2003). Several studies have demonstrated that
stress promotes latent EBV reactivation, which is reflected
in the higher antibody titers to EBV antigens such as the
virus capsid antigen (VCA). For example, in medical
students, examination stress increased the steady-state
expression of latent EBV. Higher antibody titers to EBV
VCA IgG were observed at the time of examination,
compared to 1 month prior to the exam (Glaser et al.
1994; Glaser et al. 1991). Moreover, academic stress caused
a reduction in EBV-specific CTL-mediated killing of B
J Neuroimmune Pharm (2006) 1: 421–427
cells latently infected with EBV (Glaser et al. 1994). PBLs
isolated from stressed EBV-positive individuals also
showed reduced proliferation to purified EBV polypeptides
(Glaser et al. 1993), indicating a reduction of the memory T
cell response to the virus (reviewed by Glaser et al. 2005).
EBV and several other latent herpesviruses including
VZV and cytomegalovirus (CMV) are reactivated by the
psychological stress associated with spaceflight (Mehta et
al. 2004; Mehta et al. 2000; Payne et al. 1999). The highest
levels of salivary EBV DNA, resulting from the shedding
of virus particles synthesized in cells of the nasopharynx,
were found during spaceflight, and the levels of cortisol and
catecholamines were also elevated on the day of landing
(Pierson et al. 2005). Furthermore, in West Point cadets the
stress of final exams promoted EBV reactivation, whereas
the more physical stressor of survival training did not
(Glaser et al. 1999a). These data suggest that there may be
differences in the physiological effects induced by diverse
manifestations of stressors resulting in different health
outcomes. Collectively, these findings support the notion
that stress-induced changes in the cellular immune response
are associated with the reactivation of latent hepresviruses.
The mechanism of how latent viruses are reactivated in
vivo is not well understood. The stress-induced shift in the
cytokine profile away from a Th1 toward a Th2 profile
favors virus induced pathogenesis and survival because it
down-regulates the production of cytokines important for
the T cell response to the virus (Glaser et al. 2006).
Although EBV reactivation and replication is enhanced by
glucocorticoids in vitro (Glaser et al. 1995), in vivo
circulating cortisol levels, in a study from our laboratory,
did not correlate with EBV reactivation, i.e., antibody titers
to this virus (Glaser et al. 1994). We believe that this
mechanism is more complicated than a direct relationship
between absolute glucocorticoid serum levels and latent
EBV reactivation. One critical factor may be how an
individual responds to a stressor. For instance, a recent
study demonstrated that viral reactivation was influenced
by whether a person was a high or low responder to stress.
Although levels of circulating cortisol were similar in
subjects with high and low cardiac reactivity, high stress
responders had the highest levels of EBV antibody titers
(Cacioppo et al. 2002).
Work from our laboratory suggest that stress-induced
latent virus reactivation may not result in complete viral
replication, but rather incomplete replication with increased
production of one or more of the early antigen (EA) viral
proteins (Glaser et al. 2006; Glaser et al. 2005). Recent
work from another laboratory also supports this observation
(Laichalk and Thorley-Lawson 2005). This hypothesis has
implications for the pathophysiology of EBV-associated
disease (Glaser et al. 2006; Glaser et al. 2005). In a series of
studies, we showed that purified EBV-encoded deoxyuri-
J Neuroimmune Pharm (2006) 1: 421–427
dine triphosphate nucleotidohydrolase (dUTPase) induced
immune dysregulation in mice. Mice treated with the EBV
encoded dUTPase also exhibited sickness behavior (Padgett
et al. 2004). Moreover, the EBV-encoded dUTPase treat-
ment induced immune dysregulation in vitro by interfering
with the replication of human PBMCs and inducing
monocytes/macrophages to produce proinflammatory cyto-
kines (Glaser et al. 2006). These studies show that even
partial or abortive reactivation of latent EBV by stress
would be sufficient to cause impairments in immunity and
induce clinical symptoms such as fatigue.
Cancer
The literature on stress and cancer is not as extensive as the
wound healing or infectious disease literature, but there are
studies suggesting that physiological changes produced by
stress may play a role in both initiation events and
progression of tumors (Glaser et al. 2005). One possible
connection between stress and cancer development is the
reactivation of latent tumor promoting viruses. As already
discussed, EBV is associated with NPC, BL, non-
Hodgkin_s lymphoma, and posttransplant lymphomas
(Ansell et al. 1999; Brousset 2002; Petrella et al. 1997;
Touitou et al. 2003). Because stress can promote latent
virus reactivation, it is plausible that there is a relationship
between stress and EBV-associated tumors. Moreover,
stress is associated with a reduction in the activity of
natural killer (NK) cells and cytotoxic T cells (Glaser et al.
1994; Levy et al. 1987; Sieber et al. 1992), both cell types
that can target abnormally growing cells for destruction. As
discussed, a stressed-induced shift in the balance from a
Th1 toward a Th2 cytokine profile (Glaser et al. 2001) may
be permissive to virus replication, and thereby increases the
frequency of tumor promotion (Glaser et al. 2005).
Collectively, these studies support the possibility that
stress-induced immune dysregulation could be a cofactor
for increasing the risk for tumor promotion, particularly for
immunogenic tumors induced by oncogenic viruses.
Long-lasting behavioral impairments
As already discussed, chronic stress of caregiving for a
relative with dementia is also associated with immune
dysregulation that has health consequences. Caregiving
stress increased morbidity and mortality (Schulz et al.
2004). Even after the cessation of caregiving, this chronic
stressor still has a long-term impact on the immune
response (Esterling et al. 1996; Kiecolt-Glaser et al. 1996;
Kiecolt-Glaser et al. 2003). It is important to note that, on
one hand, stress can dampen inflammatory-mediated
425
immune responses, and then on the other hand stress can
increase circulating levels of proinflammatory cytokines.
Although these findings are paradoxical, they illustrate that
the influence of stress on the immune system is a complex
interaction. For example, a recent study from our laboratory
showed a reduction of inflammatory cytokines in the
wound site, but revealed an increase in these same
inflammatory cytokines in circulation (Kiecolt-Glaser et
al. 2005). Moreover, data from a 6-year longitudinal study
showed that serum levels of IL-6 in spousal caregivers were
4-fold higher when compared to control subjects (Kiecolt-
Glaser et al. 2003). This is significant because elevated IL-6
serum levels are a risk factor for variety of age-related
diseases such as type 2 diabetes, cardiovascular disease,
and cancer (Harris et al. 1999), and are associated with
mental health complications such as depression and
cognitive impairment (Dentino et al. 1999; Penninx et al.
2003; Weaver et al. 2002). It is noteworthy that the role of
IL-6 in the etiology of depression is unclear; however, there
is an apparent age-dependent association between inflam-
matory conditions and depressive-like symptoms (Kiecolt-
Glaser and Glaser 2002). For instance, older individuals
who experienced a prolonged IL-6 response to an influenza
virus vaccination had a greater incidence of mild depressive
symptoms (Glaser et al. 2003). Collectively, these findings
suggest that chronic psychological stress could play a role
in morbidity and mortality, particularly in older individuals.
Conclusions and future directions
There have been significant strides in understanding how
psychological stress influences immune function. Clinical
and experimental evidence indicates that psychological
stress attenuates the wound healing process and plays a
role in infectious diseases including the reactivation of
latent herpesviruses. Stress may also be a cofactor for both
tumor development and progression. Delineating how stress
influences immune function is important for the develop-
ment of potential behavioral/pharmacological interventions
to lower the incidence of stress-induced immune dysfunc-
tion. Interventions, including nutrition, exercise, and stress-
reducing protocols such as muscle relaxations and yoga,
may provide an approach against stress-mediated impair-
ments in immunity and health. For example, a recent study
showed moderate exercise enhanced wound healing in
older adults (Emery et al. 2005), and a study on hostile
marital relationships demonstrated that marital support
reduced stress-related immune impairments (Kiecolt-Glaser
et al. 2005). Such interventions to reduce stress may be
clinically important in restoring immune function and
improving health outcomes as an adjunct to acceptable
medical management.
426
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