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This week, you were asked to read the article, “Stress-Induced Immune Dysfunction: Implications for Health”. Stress is something we all experience at different times in our lives. While this article summarizes a lot of research that was done a number of years ago, there is still research going on in this area as we learn more about the interplay between our bodies and minds when it comes to stress.

Now that you have read about this research, including what these authors feel we still need to do more research about, what would you research next about the impact of stress? Tell us the following:

Question you want to know that is related to stress and the body.

How would you go about researching this? (This should be about one paragraph.)

What challenges do you see in researching this question?

In your replies to your classmates, address the following:

Do you think their question is a useful one to research?

Why or why not?

Do you think the method they proposed for researching it makes sense?

Be specific about why or why not.

Would you propose a different approach?

Do you see any additional challenges to researching their question?

PERSPECTIVES
SCIENCE AND SOCIETY
Stress-induced immune dysfunction:
implications for health
Ronald Glaser and Janice K. Kiecolt-Glaser
Abstract | Folk wisdom has long suggested
that stressful events take a toll on health.
The field of psychoneuroimmunology (PNI)
is now providing key mechanistic evidence
about the ways in which stressors — and
the negative emotions that they generate
— can be translated into physiological
changes. PNI researchers have used
animal and human models to learn how
the immune system communicates
bidirectionally with the central nervous
and endocrine systems and how these
interactions impact on health.
The central nervous system (CNS), the
endocrine system and the immune system are
complex systems that interact with each other.
Various stressors — from parachute jumping
to academic examinations to bereavement —
can dysregulate the immune response by
affecting the interplay of these systems.
Psychoneuroimmunology (PNI) is the broad
interdisciplinary research field that addresses
the interactions of these three systems1,2.
Studies undertaken during the past two
decades have provided evidence that immune
alterations that are stimulated by stressful
events, ranging from commonplace daily
hassles to chronic calamities, can provoke
health changes. One definition of a stressor is
a stimulus that activates the hypothalamic–
pituitary–adrenal (HPA) axis and/or the sympathetic nervous system (SNS) to help an
organism to adapt physiologically to deal
with a threat3. More broadly, psychological
stress ensues when events or environmental
demands exceed an individual’s perceived
ability to cope4. Researchers often categorize
stressors by their duration and course (discrete
versus continuous)5 (BOX 1). For example,
chronic stressors, such as suffering a traumatic
injury that leads to physical disability, can
force people to restructure key aspects of
their daily lives. Whereas chronic stressors are
deleterious to immune function, some investigators have suggested that very brief stressors, lasting less than 2 hours, might enhance
some aspects of immune function, such as
trafficking of cells from lymphoid organs to
the peripheral blood and the skin (BOX 2).
Stressors can increase susceptibility to infectious agents, influence the severity of infectious
disease, diminish the strength of immune
responses to vaccines, reactivate latent herpesviruses and slow wound healing. Moreover,
stressful events and the distress that they evoke
can also substantially increase the production
of pro-inflammatory cytokines that are associated with a spectrum of age-related diseases.
Accordingly, stress-related immune dysregulation might be one core mechanism behind a
diverse set of health risks1,3.
CNS–immune–endocrine interactions
Modulation of the immune response by the
CNS is mediated by a complex network of
bidirectional signals between the nervous,
endocrine and immune systems (FIG. 1). The
HPA axis and the autonomic nervous system provide two key pathways for immunesystem dysregulation: stressors can activate
the sympathetic–adrenal–medullary (SAM)
axis, as well as the HPA axis, and thereby
provoke the release of pituitary and adrenal
Box 1 | How is stress assessed?
When events or environmental demands exceed an individual’s ability to cope, the ensuing
psychological stress response typically includes negative thoughts and emotions4. Studies of
stress and immunity often use measures of negative mood that assess symptoms of general
distress, anxiety or depression. Researchers might also assess the number and type of recent
significant stressful life changes, or they might ask participants to rate their perceptions of stress
on a scale by answering certain questions, such as how frequently in the past week did you feel
you could not control important things in your life, or how often did you feel that things were
piling up so high that you could not overcome them4.
In addition, researchers often study the psychological and immunological responses of
individuals who are experiencing a distress-generating event (for example, students taking an
examination or spouses going through a divorce) or a more chronic stressor (such as caring for
a husband or wife who has Alzheimer’s disease)5. Other longer-term stressors that are associated
with immune alterations have included ‘burnout’ at work, job strain, unemployment, and
isolation and exposure to the hostile climate of Antarctica81. Adverse immunological changes
have also been documented for weeks or months following such natural disasters as earthquakes
and hurricanes, with more persistent immune dysregulation among those who suffered greater
personal losses82. Stressors that are perceived as unpredictable and/or uncontrollable might
continue to be associated with increased levels of stress hormones, even after repeated
exposures83. The ability to ‘unwind’ after stressful events — that is, to return to one’s
neuroendocrine baseline in a relatively short time — is thought to influence the total burden
that stressors place on an individual84.
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© 2005 Nature Publishing Group
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hormones. For example, the catecholamines
(adrenaline and noradrenaline), adrenocorticotropic hormone (ACTH), cortisol,
growth hormone and prolactin are all influenced by negative events and negative emotions (BOX 1), and each of these hormones
can induce quantitative and qualitative
changes in immune function. Furthermore,
depression can substantially boost cortisol levels, and increases in cortisol levels can provoke
multiple adverse immunological changes.
Almost all immune cells have receptors for
one or more of the hormones that are associated with the HPA and SAM axes; these are
called ‘stress’ hormones (TABLE 1). Immune
modulation by these hormones might proceed through two pathways: directly, through
binding of the hormone to its cognate receptor at the surface of a cell; or indirectly — for
example, by inducing dysregulation of the
production of cytokines, such as interferon-γ
(IFN-γ), interleukin-1 (IL-1), IL-2, IL-6 and
tumour-necrosis factor (TNF). Cytokines
such as IFN-γ have many functions and affect
different target cells. Therefore, there are secondary effects of many stress hormones on
the immune response6,7.
Moreover, communication between the
CNS and the immune system is bidirectional.
For example, IL-1 influences the production
of corticotropin-releasing hormone (CRH)
by the hypothalamus. In turn, CRH can affect
the HPA axis and thereby trigger increases in
stress hormone levels, which results in dysregulation of immune function (FIG. 1). In addition,
lymphocytes can synthesize hormones such
as ACTH, prolactin and growth hormone8.
The role of lymphocyte-derived hormones in
immune responses is not well understood,
although they might have a role in modulating cell function within the microenvironment of lymphoid organs. Furthermore,
studies that show nerve fibres in the spleen
and thymus provide evidence of direct connections or ‘hard-wiring’ between the SNS
and lymphoid organs9. Therefore, there are
many pathways through which stressors might
influence immune function1,6. Moreover,
many individuals working in the field of PNI
are now focusing their efforts on immunesystem-to-brain communication and how the
activation of inflammatory-cytokine networks might shape mood, cognition and
behaviour10,11.
In addition to the direct influences of psychological states on endocrine and immune
function, stressed individuals are more likely
to have health habits that put them at greater
risk, including poorer sleep patterns, poorer
nutrition, less exercising and a greater propensity for abuse of alcohol, cigarettes and other
Box 2 | Can stress be beneficial?
The best evidence that stress might be good for the immune system comes from studies of mice
that are exposed to very brief stressors. Delayed-type-hypersensitivity skin responses following
either primary or secondary cutaneous antigen exposure were augmented following stressors
lasting 2 hours, compared with the response of non-stressed control animals. These effects seem
to be mediated by glucocorticoid- and adrenaline-induced stress responses85. It has been argued
that such immunoenhancement would be beneficial to survival, because skin wounding and
infection can result from brief aggressive encounters in nature85. In humans, short-term
stressors, such as public speaking, briefly increase natural-killer-cell activity5,86 and increase the
numbers of some types of leukocyte5. The latter change probably reflects transient alterations
in lymphocyte migration from lymphoid organs and peripheral blood, which is mediated by
receptors at the cell surface of lymphocytes (TABLE 1) or through sympathetic-nervous-system
innervation of lymphoid organs such as the spleen9. However, the same short-term stressors also
produce transitory changes in humans that would generally be seen as maladaptive: they reduce
lymphocyte proliferation5, increase pro-inflammatory cytokine production86 and impair the
ability of the skin to repair abrasions86. Further studies need to be carried out to help to clarify
health outcomes that are associated with short-term acute stressors.
drugs. Although these health behaviours have
immune and endocrine consequences, these
indirect effects of stress are not addressed
here; we focus on immune dysregulation by
stressors and the health consequences of
these changes.
Stress and infectious-disease risks
Stressors can enhance the risk of developing
infectious disease, and they can also prolong
infectious illness episodes. For the mouse
models used to explore this relationship,
restraint is a commonly used stressor. Mice are
placed in tubes such that they can move forwards or backwards but cannot turn around;
holes in the tubes ensure that the mice do not
overheat. Restraint is often applied overnight,
because this is the most active time for mice.
One example of data obtained using a mouse
model of influenza-virus infection shows that
restraint stress altered the immune response
to the virus, including the kinetics of the
antibody response and suppression of both
pro-inflammatory and anti-inflammatory
cytokine responses12,13. Mononuclear-cell
trafficking to virus-infected lungs was significantly reduced in stressed animals, as
was the size of the draining lymph nodes.
Virus-specific cytokine responses of T cells
in restraint-stressed mice were restored in
the draining lymph nodes by pharmacological blockade of the glucocorticoid receptor
with the glucocorticoid receptor antagonist
RU486. These and related studies have
shown that the HPA axis and the SNS are
the main immunoregulatory pathways that
can influence the pathophysiology of a viral
infection12,13.
Consistent with the mouse data on stress
and influenza-virus infections, influenza-virus
vaccine studies with human participants show
that stress can influence infectious-disease
2 4 4 | MARCH 2005 | VOLUME 5
risks. For example, men and women who were
chronically stressed by caring for a spouse with
dementia showed clear deficits in both their
cellular and humoral immune responses to an
influenza-virus vaccine compared with wellmatched control individuals who were not
carers14,15. The protective capacity of antiviral
vaccines depends on their ability to induce
both humoral and cell-mediated immune
responses16, both of which were poorer in
the stressed carers compared with control
individuals. Stress-associated impairments
in antibody responses after vaccination with
influenza virus have also been shown in
younger adults17.
Further studies have confirmed the finding
that stressful events and the negative emotions, such as anxiety and depression, that
accompany them can modulate the antibody
and T-cell responses to other antiviral vaccines, including the vaccines against infection
with hepatitis B virus and rubella virus18,19.
Moreover, antibody responses to antibacterial
vaccines are also influenced by stress: for
example, following vaccination, antibody
titres to a pneumococcal vaccine decreased
during a 6-month period in the carers of
spouses with dementia, whereas antibody
titres were stable in non-carers20. Similarly,
undergraduates who had received a meningitis C conjugate vaccine and who reported
greater stress had a poorer antibody response
1–12 months after vaccination21.
Responses to vaccines show clinically relevant alterations in immunological responses
to challenge under well-controlled conditions; accordingly, they function as a proxy for
a response to an infectious agent. Individuals
who were more distressed and more anxious
had immune responses to vaccines that were
delayed, substantially weaker and/or shorterlived. As a consequence, it is reasonable to
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Stressor
Hypothalamus
Corticotropinreleasing hormone
Pituitary gland
Brain
‘Hard-wiring’
sympathetic
innervation
Adrenocorticotropic
hormone
Adrenal
gland
Cortex
Prolactin
and growth
hormone
Lymph node
Medulla
Peripheral blood
Glucocorticoid
hormones
Noradrenaline
and adrenaline
NK cell
B cell
T cell
Cytokines,
such as IL-1
Monocyte
APC
Figure 1 | Stress-associated modulation of the hormone response by the central nervous
system. Experiencing a stressful situation, as perceived by the brain, results in the stimulation of
the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic–adrenal–medullary (SAM) axis.
The production of adrenocorticotropic hormone by the pituitary gland results in the production of
glucocorticoid hormones. The SAM axis can be activated by stimulation of the adrenal medulla to
produce the catecholamines adrenaline and noradrenaline, as well as by ‘hard-wiring’, through
sympathetic-nervous-system innervation of lymphoid organs. Leukocytes have receptors for stress
hormones that are produced by the pituitary and adrenal glands and can be modulated by the binding
of these hormones to their respective receptors. In addition, noradrenaline produced at nerve endings
can also modulate immune-cell function by binding its receptor at the surface of cells within lymphoid
organs. These interactions are bidirectional in that cytokines produced by immune cells can modulate
the activity of the hypothalamus. APC, antigen-presenting cell; IL-1, interleukin-1; NK, natural killer.
assume that these same individuals would
also be slower to develop immune responses
to pathogens; therefore, they could be at
greater risk of developing more severe illness. Consistent with this argument, adults
who show poorer responses to vaccines also
experience higher rates of clinical illness22.
In agreement with these vaccine studies,
researchers have also shown that distress can
alter an individual’s susceptibility to infection
with respiratory viruses4,23, 24. In a group of 394
healthy volunteers who were inoculated with
one of five strains of respiratory virus, severity of both respiratory infection and clinical
cold symptoms increased in a dose–response
relationship as scores increased on a psychological stress index. The stress index was a
compilation of three common measures: the
number of stressful life events, the degree
that a participant felt that current demands
exceeded his or her ability to cope, and
scores from a negative-emotion word list
(including words such as sad, angry and nervous). Importantly, the risk did not differ
across the five strains of respiratory virus
studied. In further related work from the
same laboratory, stressors that lasted for
1 month or more were the best predictors of
developing colds; volunteers who reported
more enduring interpersonal difficulties
with family or friends were substantially
more likely to develop a cold after inoculation with a rhinovirus23. Similarly, other
researchers reported that individuals who
NATURE REVIEWS | IMMUNOLOGY
developed cold symptoms following inoculation with rhinovirus had higher numbers
of recent stressful life events than those who
did not24.
Studies carried out with human participants in which individuals have been exposed
to a pathogen or a vaccine give researchers a
means of controlling exposure and dosage;
moreover, because immune function can
be assessed before the infectious challenge,
these studies provide excellent data on causality, thereby complementing evidence from
research that addresses the course of naturally
occurring infections25–35. The similarity of the
data from human and rodent studies provides
strong evidence that stress can dysregulate the
humoral and cellular immune responses to
pathogens and increase the risk of developing
infectious disease.
HIV and the herpesviruses are different
from many other viruses, such as rhinoviruses and influenza virus, in that they
remain in a latent state in the body after primary infection. To investigate the possibility
that social stress was a contributor to the
rate of progression in HIV-associated disease, rhesus macaques were inoculated with
simian immunodeficiency virus (SIV)36.
Animals that were assigned to the stable
social condition (the same three animals
met every day) had lower concentrations of
SIV RNA in plasma early after inoculation
and survived longer than those in the unstable social condition (different two-, threeand four-member groups were formed
every day).
Studies of HIV-infected men have also indicated that stress increases the rate of disease
progression. For example, in a longitudinal
study of HIV-positive men who were asymptomatic at entry to the study, faster progression
to AIDS was associated with more stressful
life events and less social or interpersonal support25; indeed, at 5.5 years after entry into the
study, the probability of developing AIDS was
two- to threefold higher in men who were
above the median level for stress or below the
median level for support compared with those
who were below the median level for stress or
above the median level for support. Other
researchers reported that the course of HIV
infection was accelerated in gay men who concealed their homosexual identity compared
with men who did not26.
Considerable anecdotal evidence has supported the relationship between psychological
stress and the development, duration and
recurrence of herpesvirus infections. The cellular immune response has an important role
in controlling the pathophysiology of both
lytic herpesvirus infections and the expression
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Table 1 | Interactions of hormones and immune cells
Hormone
Expression of receptors
by immune cells
Examples of effects on cell function
References
Glucocorticoids
T and B cells, neutrophils,
monocytes and macrophages
Inhibit inflammation; inhibit the
production of IL-12 by antigenpresenting cells; induce a shift
from production of TH1 to TH2 cytokines
87,88
Substance P
T and B cells, eosinophils,
mast cells, monocytes and
macrophages
Stimulates mitogen-induced
blastogenesis; increases trafficking
of cells from lymph nodes to
peripheral blood; stimulates
monocytes to produce several
cytokines, such as IL-1, IL-6
and TNF
89
Neuropeptide Y
T and B cells, dendritic cells,
monocytes and macrophages
Can downregulate antibody
production to T-cell-dependent
antigens by its effect on dendritic
cells, and T and B cells
90
Corticotropinreleasing hormone
T cells, monocytes
and macrophages
Increases production of IL-1
by monocytes; evidence for
autocrine and/or paracrine
modulation of inflammation
91
Prolactin
T and B cells, granulocytes,
NK cells, monocytes and
macrophages
Can stimulate lymphoid-cell clonal
expansion; might function as an
in vitro co-mitogen for NK cells
and macrophages
92,93
Growth hormone
T and B cells, NK cells,
monocytes and macrophages
Helps to maintain competence of
T and B cells, and macrophages;
stimulates antibody production
and NK-cell activity
94
Catecholamines
(adrenaline and
noradrenaline)
T and B cells, NK cells,
monocytes and macrophages
Induce a shift to a TH2 response,
involving antigen-presenting cells
and TH1 cells
95
Serotonin
T and B cells, NK cells,
monocytes and macrophages
Modulates the synthesis of IFN-γ
by NK cells; stimulates the
production of IL-16 (a chemotactic
factor) by T cells
96
IFN-γ, interferon-γ; IL, interleukin; NK, natural killer; TH, T helper; TNF, tumour-necrosis factor.
and/or replication of latent herpesviruses.
When the cellular immune response is
impaired, one or more herpesviruses can be
reactivated, and herpesvirus infections are
often more severe.
Herpes simplex virus (HSV) is a natural
human pathogen that is characterized by its
ability to cause an acute infection at a peripheral site and to establish a latent infection in the
local sensory ganglia, and stress can exacerbate
HSV lytic infection. Mouse models have been
developed to study the effect of stress on the
pathophysiology of HSV latent and lytic infections. Indeed, several studies carried out during
the past 15 years have provided compelling
experimental evidence that stress not only
increases the development and severity of
HSV infection, in both the peripheral nervous system13,37–39 and the CNS, but also suppresses components of primary13,37,39–41 and
memory13,38,41 cytotoxic T lymphocyte (CTL)
responses to HSV infection.
Surgical and pharmacological approaches
have shown the ability of both the HPA13 and
the SAM41 axes to mediate stress-induced
modulation of immunity and HSV-associated
pathology. For example, mice treated with
6-hydroxydopamine (6-OHDA) to induce
peripheral sympathetic denervation were
inhibited in their ability to generate primary
HSV-1-specific CTLs when infected with
the virus41. The suppression of CTL production could result from a large release of
noradrenaline induced by 6-OHDA and
increased levels of corticosterone. In another
study, surgical removal of the adrenal gland
blocked the suppression of HSV-1-specific
CTLs that was induced by restraint stress
and also blocked the production of IL-6
and IFN-γ13.
Relationships between neuroendocrine
activity, immune function and latent HSV
reactivation have also been documented42,43;
infected mice that were exposed to a stressor
showed reactivation of the latent virus,
whereas non-stressed controls showed no
reactivation43. It is important to keep in mind
that these experiments were carried out using
mice in a laboratory setting; however, the data
still provide some insight into how stress
2 4 6 | MARCH 2005 | VOLUME 5
could modulate the immune response to
HSV in humans.
Indeed, psychological stressors have been
linked to more frequent recurrences of lesions
in individuals who are latently infected with
HSV-1 or HSV-2. For example, women who
reported greater persistent stress from events
that lasted longer than 1 week also had more
recurrences of genital herpes28. Similarly,
more chronically distressed individuals had
more frequent recurrences of re-activation of
HSV-1 (REF. 29) and HSV-2 (REF. 30).
The incidence of Herpes zoster (also known
as shingles), which is caused by the reactivation
of latent varicella-zoster virus (VZV), increases
with age, presumably owing to a decline in cellmediated immunity to VZV44. A case–control
study indicated that psychological stress in
healthy community-dwelling older adults
was associated with the occurrence of herpes
zoster31. Other researchers evaluated the possibility that VZV-specific immunity could be
altered by means of a behavioural intervention, such as T’ai chi (also known as ‘meditation through movement’)44. Older adults who
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Epithelial cell
Cutaneous wound
a
Skin
Other chemoattractants
PDGF
Platelet
Neutrophil
T cell
Recruitment of
inflammatory cells
c
Production of CXCL8,
IL-1α, IL-1β, CCL2,
VEGF, TGF-β and TNF
b
Endothelial cell
Macrophage
Blood
Figure 2 | Influence of stress on pro-inflammatory cytokine responses in wound healing. Stress
can influence key pro-inflammatory cytokine responses in the early phase (the first 24 hours) of the healing
of skin wounds, through dysregulation of cytokine secretion at the wound site and recruitment and
activation of circulating peripheral-blood leukocytes that traffic to the wound site48,52,54. Using a skin
wound as an example, blood platelets at the wound site produce platelet-derived growth factors (PDGFs) (a).
Other chemoattractants are also produced by activated parenchymal cells. A concentration gradient
is established, with higher levels of chemoattractants at the wound site attracting immune cells, such as
neutrophils and macrophages. These cells have important roles in the early phases of wound healing.
For example, neutrophils clean the area of bacteria and, together with activated macrophages, they
phagocytose the bacteria and produce cytokines that stimulate the growth of fibroblasts. The leukocytes
transmigrate through the endothelium of the blood-vessel wall to the wound site in the skin (b) and are
activated to proliferate and produce cytokines and chemokines, such as CXC-chemokine ligand 8
(CXCL8; also known as IL-8), IL-1α, IL-1β, transforming growth factor-β (TGF-β), vascular endothelial
growth factor (VEGF), CC-chemokine ligand 2 (CCL2; also known as MCP1) and tumour-necrosis factor
(TNF), at the wound site (c). These cytokines continue to function as chemoattractants for the continued
migration of cells to the site. The proliferative phase of wound healing involves the recruitment and
replication of cells that are required for tissue regeneration and capillary growth. Therefore, the
downregulation of the early inflammatory response by an increase in serum cortisol levels can help
to explain how stress affects wound healing49.
were randomly assigned to T’ai chi showed
a 50% increase in VZV-specific cellular
immunity between the start and the end of
the 15-week intervention compared with no
change in the ‘waiting-list’ control group.
Epstein–Barr virus (EBV) — the aetiological agent of infectious mononucleosis —
is another herpesvirus that establishes latent
infection and can be modulated by psychological stressors. In one early study, West
Point Military Academy (New York, United
States) cadets who were seronegative for EBV
on entry into the academy were followed for
4 years27. Men with particular psychosocial
risk factors (high motivation for a military
career in the face of poorer academic performance) were more likely to develop infectious
mononucleosis and were likely to be hospitalized for longer periods. In addition, these risk
factors were also associated with increased
EBV-specific antibody titres in cadets who
had been infected with EBV but had not
developed obvious clinical symptoms.
A series of studies provided mechanistic
data that revealed the effect of stress on EBV
latency. Medical students had substantially
higher titres of IgG specific for EBV capsid
antigen, and these were associated with more
stressful examination periods compared
with lower-stress periods45. In a further study
of medical students, examination stress produced a significant decrease in the ability of
EBV-specific CTLs to kill EBV-infected autologous B cells45. The results of several studies
have shown that various psychological stressors — including examination stress, caring
for a spouse with dementia and spaceflights
by astronauts — can reactivate latent EBV
and cytomegalovirus (CMV)32–35,45. Together,
these human and animal studies show that
stress can modulate the steady-state expression of latent HSV, EBV and CMV, downregulating the specific T-cell response to the
virus to an extent that is sufficient to result in
viral reactivation. Although the mechanisms
that underlie stress-associated reactivation of
latent herpesviruses are not fully understood, in vitro studies of cells that are latently
infected with EBV have shown that glucocorticoid hormones can reactivate the virus.
NATURE REVIEWS | IMMUNOLOGY
For example, a glucocorticoid hormone,
dexamethasone, can reactivate latent EBV
and enhance the lytic replication of the virus
in EBV-superinfected cells in vitro, but the
catecholamine hormones do not induce
such a response. Other stress hormones —
CRH and ACTH — cannot induce reactivation of latent EBV, but they can enhance lytic
replication in EBV-superinfected cells46.
Different types of stressor can have different effects on reactivation of latent HSV-1
and EBV43,47. For example, although restraintstressed mice did not show evidence of reactivation of latent HSV-1, infectious HSV-1
was isolated from approximately 50% of the
mice that were subjected to social reorganizational stress, despite both stressors resulting
in similar increases in serum corticosterone
levels43. Data from studies of students at
West Point Military Academy also showed
that different types of stress could have an
impact on the reactivation of latent HSV-1
and EBV47. The mechanisms underlying
these differences are not understood, but
clearly, a factor as obvious as disparities in
glucocorticoid hormone levels is not sufficient to explain variations in viral reactivation. Together, these studies highlight the
complex interactions that underlie the relationships between stress, neuroendocrine
activity, immune function and herpesvirus
pathogenesis, and they indicate the many
ways in which these relationships are central
to a lifelong defence against herpesvirus
infections.
Stress and wound healing
Wound repair progresses through several
overlapping stages48. In the initial inflammatory stage, vasoconstriction and blood coagulation are followed by platelet activation and
the release of platelet-derived growth factors
(PDGFs), as well as the release of chemoattractant factors by injured parenchymal cells.
Cytokines and chemokines — such as IL-1α,
IL-1β, transforming growth factor-β (TGF-β),
vascular endothelial growth factor (VEGF),
TNF and CXC-chemokine ligand 8 (CXCL8;
also known as IL-8) — are important in the
early stages of wound healing. These factors
function as chemoattractants, promoting the
migration of phagocytes and other cells to
the wound site, thereby starting the proliferative phase, which involves the recruitment
and replication of cells that are required for
tissue regeneration and capillary regrowth.
The final step, wound remodelling, might
continue for weeks or months. So, the healing
process is a cascade, and success in the later
stages of wound repair depends to a large
extent on initial events48.
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Immune function has a key role in the
early stages of this cascade (FIG. 2). CXCL8
and pro-inflammatory cytokines, such as IL-1
and TNF, are essential to this effort; they
help to protect against infection and prepare
injured tissue for repair by enhancing the
recruitment and activation of phagocytes49.
Furthermore, cytokines that are released by
recruited cells regulate the ability of fibroblasts and epithelial cells to remodel the
damaged tissue49. IL-1 that is produced early
after tissue injury can regulate the production,
release and activation of metalloproteinases
that are important in the destruction and
remodelling of the wound. IL-1 also regulates
fibroblast chemotaxis and the production of
collagen49. Moreover, IL-1 stimulates the production of other cytokines that are important
for wound healing, including IL-2, IL-6 and
CXCL8 (REF. 49). Accordingly, IL-1 deficits early
in the wound-repair cascade can have adverse
consequences downstream.
Stress disrupts the production of proinflammatory cytokines that are important
for wound healing, a mechanism that produces substantial delays in wound repair.
For example, in a clinical study, women who
were experiencing the long-term stress of
caring for a relative with Alzheimer’s disease
took 24% longer than sociodemographically matched controls to heal a small, standardized dermal wound. Consistent with
these differences in wound repair, peripheralblood leukocytes (PBLs) obtained from carers also produced less IL-1β in response to
lipopolysaccharide (LPS) stimulation50. In a
subsequent study in a different population,
wounds produced in the hard palate 3 days
before important examinations healed an
average of 40% more slowly than identical
wounds made during summer holidays: no
student healed as rapidly during examinations as during the holiday period, and no
student produced as much IL-1β when his or
her PBLs were stimulated with LPS51.
Mouse models have also been developed
to study the effect of stress on wound healing.
These studies have confirmed and extended
the data obtained by studying humans. Mice
that were subjected to restraint stress and had
a standardized 3.5-mm full-thickness cutaneous punch-biopsy wound healed this
wound an average of 27% more slowly than
control mice52. Analysis of the cellularity of
wound sites using cross-sections of dermal
and epidermal layers showed less leukocyte
infiltration of the wound sites in restraintstressed mice at 1 and 3 days after wounding,
compared with controls52. Serum corticosterone levels in the restraint-stressed group
were more than fourfold higher than those
of control animals52. Blocking glucocorticoid receptors in restraint-stressed animals,
using RU40555, resulted in healing rates
that were similar to those of control animals52. Accordingly, these data provide evidence that disruption of neuroendocrine
homeostasis modulates the early stages of
wound healing.
Higher levels of glucocorticoids have several adverse effects on various components of
the wound-healing process. For example,
they might slow wound healing by altering
local levels of pro-inflammatory cytokines.
Hübner et al.48 showed that the strong and
early induction of IL-1α, IL-1β and TNF
expression at the site after wounding was significantly reduced after pretreatment of mice
with glucocorticoids. Similarly, human studies have also shown that stress-induced
increases in glucocorticoids can transiently
suppress IL-1β, TNF and PDGF production53.
Accordingly, dysregulation of glucocorticoid
secretion provides one obvious neuroendocrine pathway through which stress alters
wound healing.
In humans, a suction-blister model
enabled investigators to measure immune
responses that are central to the early stages
of wound healing in vivo and occur at the
wound site, providing key data on the
inflammatory response that have direct clinical relevance54,55. The suction-blister model
provides an excellent mechanism to study
the migration of neutrophils and macrophages and the production of cytokines at
wound sites for the first 2 days after wounding. Commonly, after raising several blisters
and removing their roofs (the epidermis),
plastic templates with wells containing a
salt solution and autologous serum are
placed over the lesions, and cells migrate
to the wound sites and collect in the wells.
The serial collection of samples from the
wells as time progresses allows for cell
phenotyping and cytokine measurement as
the local immune response evolves. Using
this approach to study stress and wound
healing, women who reported more stress
produced significantly lower levels of two
pro-inflammatory cytokines (IL-1α and
CXCL8) that are important for the early
stages of wound healing54.
Therefore, convergent data from mouse
and human studies have shown that stress has
substantial adverse effects on wound repair. In
agreement with these laboratory findings,
several studies have shown that greater fear or
distress before surgery is associated with
poorer outcomes, including longer hospitalization, more post-operative complications
and higher rates of rehospitalization56,57.
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Stress and inflammation
The pro-inflammatory cytokine IL-6, which
is produced by T cells, B cells, monocytes and
several non-lymphoid cell types, has an
important role in the acute-phase response3.
IL-6 is an important inducer of C-reactive
protein (CRP) by the liver, and the combination of IL-6 and CRP is important in the
process that leads to the development of cardiovascular disease3,58. As previously discussed,
stress induces immune dysregulation partly
through alterations in the production of proinflammatory cytokines. Both physical and
psychological stressors can provoke transient
increases in pro-inflammatory cytokines, particularly in IL-6 (REFS 53,59). In animal models,
both stress and administration of adrenaline
increase levels of IL-6 in the plasma, which is
consistent with evidence that IL-6 production
is stimulated by β-adrenergic receptors, as well
as through other pathways3.
Importantly, negative emotions, such as
depression and anxiety, augment the production of IL-6 (REFS 60–62). Indeed, both stressors
and depression can sensitize the inflammatory response, thereby producing heightened
responsiveness to subsequent stressful events,
as well as to antigen challenge59,61–63. For
example, individuals who reported more
depressive symptoms showed increases in
serum IL-6 levels 2 weeks after vaccination
against influenza-virus infection, whereas
there was little change in IL-6 levels in those
individuals who reported few or no symptoms61. This is consistent with other evidence
of cross-sensitization between cytokines and
stressors in human and animal studies59,62,63.
These stress-related changes have broad implications for health: increased levels of proinflammatory cytokines, such as IL-6, have
been linked to various age-related diseases
and conditions (including cardiovascular
disease, osteoporosis, arthritis, type 2 diabetes, frailty and functional decline) and to
certain cancers (such as chronic lymphocytic
leukaemia)64.
Stress, inflammation and ageing
One recent longitudinal study highlighted the
deleterious longer-term immunological consequences of chronic stress: the average annual
rate of increase in serum IL-6 was about fourfold higher in men and women who were
chronically stressed by caring for a spouse with
dementia than in similar individuals who did
not have caring responsibilities65. Possible
consequences of these different trajectories are
indicated by epidemiological studies of individuals of 65 years of age or older64; within
these population studies, individuals whose
IL-6 values fell within the highest quartile had
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© 2005 Nature Publishing Group
PERSPECTIVES
a twofold greater risk of death within the following 4–5 years compared with those whose
IL-6 values were in the lowest quartile64.
Application of the epidemiological risk values
to the data from carers indicated that carers
would, on average, have values that crossed
into the highest quartile around the age of
75, whereas the IL-6 values of control individuals would not reach that level until after
the age of 90.
Another recent study also supports the
hypothesis that chronic stress might be associated with premature ageing of immune
cells. Telomerase activity and telomere length
— two cellular markers that are associated
with ageing — were measured in peripheralblood mononuclear cells obtained from
mothers caring for a chronically ill child, as
well as from mothers of healthy children66.
Carers reported greater stress than controls,
but reports of a higher level of perceived
stress were associated with lower telomerase
activity and shorter telomere length, regardless of whether the mother’s child was ill or
healthy. Reports of high stress levels were also
associated with higher oxidative-stress activity, as measured by levels of F2-isoprostanes,
another independent measure associated
with ageing66.
Taken together, the data regarding the IL-6
levels of carers of spouses with dementia65
and the data regarding telomerase activity
and length66 provide evidence of mechanisms
through which chronic stressors might accelerate the risk of developing many age-related
diseases by ‘premature ageing’ of the immune
response. Indeed, a prospective populationbased cohort study found that the relative risk
for all-cause mortality over a 4-year period
in strained carers was 63% higher than in
control individuals who were not carers67.
Conclusions and future directions
Great strides have been made in the field of
PNI towards understanding some of the
interactions between the CNS, endocrine
system and immune system, as well towards
understanding how distress modulates
these three complex systems. Although the
mechanisms that underlie these interactions are complex, and although it will
probably take many years to fully understand how these three systems interact, there
are already clear translational implications
from laboratory data.
Herpesvirus infections carry substantial
human costs because the latent viruses are
linked to considerable pain and suffering.
Moreover, the evidence that psychological
stressors can reactivate latent herpesviruses
might have the most notable implications for
people who are already immunosuppressed
(such as patients who have received an organ
transplant or patients infected with HIV),
owing to the risk of these individuals developing EBV-associated B-cell lymphomas.
Indeed, reactivation of latent EBV, HSV-1
and CMV is associated with significant morbidity and mortality of immunosuppressed
patients.
Furthermore, on the basis of speculation
that chronic inflammation might be a contributing factor in up to 15% of all cancer
cases68, stress-induced increases in the inflammatory response could be a broader pathway
that links stress with cancer. Although it is
beyond the scope of this article, the possibility
that the physiological changes associated with
stress could be key factors in cancer risk and
progression has recently been reviewed69.
The results of the vaccine studies are particularly important for individuals who might
be at a higher risk of developing complications that are associated with respiratoryvirus infections, such as older individuals for
whom increased susceptibility to pathogens is
a serious health problem: together, influenza
and pneumonia are the fifth leading cause of
mortality in individuals aged 50 or older16.
Biologically, the largest deleterious or enhancing consequences of stress are likely to occur
when biological vulnerability is greatest: that
is, early and late in life70. Older adults seem to
show greater immunological impairments
associated with distress or depression than
younger adults14,57. However, the studies indicate that vaccine efficacy can be compromised
by psychological stress, even in younger adults
— an important public-health finding in its
own right. These studies should be considered
in the planning of clinical studies using cancer
vaccines. The efficacy of such vaccines will
depend on an optimum immune response.
The possibility that stressors might have a
long-term impact on the developing endocrine
and immune systems of infants and young
children is an important question that has not
been well studied in the PNI field. Indeed,
excellent developmental studies of primates
indicate that early stressors can reverberate
for the life of an individual70.
In accordance with the evidence that
stress delays wound healing, more than 200
studies published in the past 3 decades have
shown beneficial effects from pre-surgical
interventions. These beneficial effects include
decreased anxiety and stress reductions when
hospitalized, fewer post-operative complications, better treatment compliance, less pain
and reduced use of analgesics, and alterations
in various physiological indices56,57. Given the
substantial consequences of stress for wound
NATURE REVIEWS | IMMUNOLOGY
repair, even small reductions in anxiety could
have substantial clinical consequences, both
directly and indirectly57.
More broadly, researchers have used several diverse strategies to modulate immune
function, including relaxation, hypnosis, exercise, classical conditioning, self-disclosure and
cognitive behavioural interventions. These
interventions have generally produced positive endocrine and immune changes5,44,71–74.
Although it is not yet clear to what extent
these positive immunological changes translate
into any concrete improvements in relevant
aspects of health, such as alterations in the incidence, severity or duration of infectious and/or
malignant disease, the preliminary evidence
seems to be promising.
The role that genetics might have in these
complex relationships is unknown, and this is
an important new area that deserves exploration. For example, do individuals who have
one or more variants of the polymorphisms
associated with increased production of cortisol show greater immunological dysregulation
when faced with stressful events?
Several studies have provided convincing
evidence linking stress-induced immune
dysregulation with morbidity and mortality.
Animal models that involve viral infections
have confirmed that stress can exacerbate
morbidity that is associated with a viral
infection37,75–77. Stress can also exacerbate
bacterial infections, such as infections with
Listeria monocytogenes78,79. In both humans
and mice, studies of wound healing show a
direct link between stress-associated immune
dysregulation and health outcome, with
well-documented relationships occurring
between stress hormones, the immune
response and the rate of wound healing50–52,54.
Together, these studies support the hypothesis that morbidity can be directly linked to
stress-induced immune dysregulation.
Using a mouse model, it was also shown
that stress-induced immune dysregulation
can cause mortality80. Restraint-stressed mice
infected with Theiler’s murine encephalomyelitis virus (TMEV) had an increased risk
of dying. TMEV is a Picorna virus, which
can cause CNS lesions. Higher titres of the
virus were observed in the stressed mice
compared with the control mice, and the
underlying mechanism that accounted for
the increased mortality in restraint-stressed
mice was related to corticosterone-induced
immune suppression.
The field of PNI is improving our understanding of the complex physiological
changes that take place in stressful situations
and providing new insights into various
clinical applications. This research field is
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© 2005 Nature Publishing Group
PERSPECTIVES
also contributing to our knowledge of how
the immune system operates in an environment in which there is bidirectional communication with other bodily systems. Despite
the remarkable complexities of the interactions between the CNS, the immune system
and the endocrine system, the researchers are
making good progress at the molecular, cellular and organ-system levels. And, with that
knowledge, the potential for new approaches
to treatment is evident.
Ronald Glaser is at the Department of Molecular
Virology, Immunology and Medical Genetics,
the College of Medicine and Public Health,
the Institute for Behavioral Medical Research and
the Comprehensive Cancer Center, Ohio State
University, Columbus, Ohio 43210, USA.
Janice K. Kiecolt-Glaser is at the Department of
Psychiatry, the College of Medicine and Public
Health, the Institute for Behavioral Medical
Research and the Comprehensive Cancer Center,
Ohio State University, Columbus, Ohio 43210,
USA.
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e-mail: glaser-1@medctr.osu.edu
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Acknowledgements
We thank J. Sheridan, D. Padgett, R. Bonneau, R. Nelson,
N. Quan and V. Sanders for helpful suggestions. Work on this
paper was supported, in part, by grants from the General
Clinical Research Center (Columbus, United States) and the
Comprehensive Cancer Center, (Columbus, United States).
Competing interests statement
The authors declare no competing financial interests.
Online links
DATABASES
The following terms in this article are linked online to:
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
ACTH | CCL2 | CRH | CRP | CXCL8 | glucocorticoid receptor |
growth hormone | IFN-γ | IL-1α | IL-1β | IL-2 | IL-6 | PDGFs |
prolactin | TGF-β | TNF | VEGF
FURTHER INFORMATION
PNI Research Program: http://pni.psychiatry.ohiostate.edu/jkg/
Access to this interactive links box is free online.
OPINION
Consensual immunity: successdriven development of T-helper-1
and T-helper-2 responses
Pawel Kalinski and Muriel Moser
Abstract | Non-germline-encoded T- and
B-cell receptors allow humans to effectively
deal with rapidly mutating pathogens. Here,
we argue that, in addition to determining the
antigenic specificity of immune responses,
the same receptor systems can also regulate
the T-helper-1/T-helper-2 profile of immunity.
Such a mechanism — based on feedback
from distinct effector cells to dendritic cells,
rather than on instruction from pathogens —
uses the effectiveness of particular effector
cells at targeting and destroying a pathogen
as a reliable, experience-based criterion to
induce and maintain the appropriately
polarized response.
Distinct subsets of CD4+ T cells preferentially
support cell-mediated (type 1) versus
humoral (type 2) immunity1. Type 1 T helper
(TH1) cells promote the cytotoxic effector
functions of natural killer (NK) cells, CD8+
T cells and macrophages. They also promote
antibody-dependent cell-mediated cytotoxicity (ADCC) by supporting B-cell production
of IgG2a in mice and IgG1 in humans. By
NATURE REVIEWS | IMMUNOLOGY
contrast, TH2 cells promote humoral immunity, mediated by B-cell-produced IgG4 and
IgE in humans (and IgG1 and IgE in mice).
Although the proper balance of TH1 and TH2
immunity is as important for the success of
an immune response as its specificity and
overall magnitude1, it still remains unclear
how the TH1/TH2-response profile is matched
to distinct pathogens and to particular
affected tissues.
The previously identified ‘instructive’
mechanisms of the induction of TH1- versus
TH2-dominated responses by dendritic cells
(DCs) use germline-encoded receptors to
identify both distinct sets of conserved
pathogen-specific motifs and endogenous
mediators of tissue damage that are induced
by different pathogen types invading distinct
tissues2–6. Here, we discuss recent evidence for
the existence of an additional highly reliable
mechanism that assures the correctness of
such a match. We propose that the intrinsic
ability of different effector cells to discriminate between different pathogen classes and
to differentially affect DC functions is a
VOLUME 5 | MARCH 2005 | 2 5 1
© 2005 Nature Publishing Group

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