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Epidemiologia e Psichiatria Sociale, 10, 3, 2001
82
Invited paper
How does stress affect you?
An overview of stress, immunity, depression and disease
CLEMENTINE MADDOCK
1
AND CARMINE M. PARIANTE
2
1
Maudsley Hospital, London SE5 8AZ, UK
2
Section of Clinical Neuropharmacology, Institute of Psychiatry, King’s College London, London SE5 8AF, UK
RRIIAASSSSUUNNTTOO.. SSccooppoo ––
Il termine “stress” viene spesso usato come sinonimo di “vita moderna”. In
questa revisione della letteratura abbiamo valutato la relazione tra lo stress e l’insorgenza o il
decorso della depressione maggiore, dei disturbi cardiovascolari e delle malattie tumorali, le
maggiori cause di morbidità e di mortalità nel mondo occidentale. Abbiamo anche discusso come i
cambiamenti nei parametri del sistema immunitario indotti dallo stress possano essere considerati,
almeno in parte, responsabili di questa relazione tra stress e malattia.
MM ee tt oo dd oo ––
Abbiamo
condotto una ricerca su Medline per il periodo 1996-2000, utilizzando i termine
stress
,
disease
(malattia) e
immune system
(sistema immunitario), allo scopo di identificare i più recenti sviluppi
della ricerca in questo campo. Abbiamo anche rintracciato le più importanti pubblicazioni citate in
questi articoli.
RRii ssuu llttaattii
– Gli studi in letteratura confermano il legame tra lo stress e l’insorgenza
della depressione. Lo stress sembra anche avere un effetto negativo sulla prognosi dei disturbi
cardiovascolari e delle malattie tumorali, ed evidenze preliminari suggeriscono che interventi di
gestione dello stress possono migliorare la sopravvivenza in questi pazienti. Situazioni di stress
cronico sono associate ad una soppressione della funzionalità del sistema immunitario, mentre
stress acuti hanno un effetto sia attivante, sia inibitorio. La liberazione di citochine infiammatorie,
mediatori solubili della risposta immunitaria, può indurre la comparsa di sintomi depressivi.
CCoonncc lluu ssii oonnii
– Studi epidemiologici prospettici sono necessari per chiarire il ruolo dello stress
nell’insorgenza, decorso e prognosi delle malattie. L’utilizzo di terapie di gestione dello stress allo
scopo di migliorare la prognosi dei pazienti con disturbi cardiovascolari, malattie tumorali ed altre
malattie croniche, è un’area di ricerca particolarmente interessante. Gli effetti dello stress sul
sistema immunitario sono importanti per capire il legame tra stress e malattia. In particolare,
l’aumentata produzione di citochine infiammatorie durante situazioni di stress costituisce un
possibile meccanismo biologico per spiegare il legame tra stress e depressione.
PAROLE CHIAVE: stress, malattie cardiovascolari, cancro, sistema immunitario, citochine,
depressione.
Indirizzo per la corrispondenza: Dr. C.M. Pariante, Section of Clinical
Neuropharmacology, Institute of Psychiatry, King’s College London, 1
Windsor Walk, Denmark Hill, London SE5 8AF, UK.
Fax: +44-(0)-20-7848.0051
E-mail: spjucmp@iop.kcl.ac.uk
INTRODUCTION
“Stress” is a term that has become synonymous with
modern life. There are many commonly held beliefs about
the adverse effects of stress, but what is the evidence
linking stress and disease? This review will appraise the
evidence linking stress with disease with particular re-
ference to the three major causes of morbidity and mor-
tality in the Western world, depression, cardiovascular
disease and cancer. A Medline search was carried out
for the period 1996-2000 to identify recent findings in
this field using the terms “stress”, “disease”, “immune
system”. Relevant references that were found in all iden-
tified publications were also followed up. The effects of
stress on the immune system are considered, as modu-
lation of the immune response can affect an individual’s
disease status. Finally, an integrated “stress, cytokine,
depression” model is proposed which may be relevant
to the pathophysiology of depression.
THE CONCEPT OF STRESS
Stress results when environmental demands exceed a
person’s resources to meet those demands (Lazarus & Folk-
man, 1984). Stress has various dimensions (Herbert &
Cohen, 1993). It may be considered in terms of it’s dura-
tion (acute e.g. laboratory stressor vs. chronic e.g. incu-
rable disease); quantity (discrete events e.g. bereavement
vs. cumulative events e.g. daily hassles); and quality (in-
terpersonal event e.g. divorce vs. non-interpersonal event
e.g. earthquake). The perception of, and adaptation to, stres-
sors are accompanied by physiological and behavioural
changes. The two principal biological components of the
stress response are the hypothalamic-pituitary-adrenal axis
and the nor-epinephrine/autonomic (sympathetic) nervous
systems. Corticotrophin-releasing hormone (CRH) activates
the pituitary-adrenal axis and the sympathetic nervous sy-
stem leading to increases in glucose, heart rate, and blood
pressure. Regulation of the immune response occurs along-
side behavioural changes including enhanced arousal and
vigilance, and suppression of feeding and reproductive
behaviour. This response is temporarily beneficial and
without adverse consequences if acute or of a limited du-
ration (Chrousos & Gold, 1992).
DOES STRESS MAKE YOU ILL?
Much attention has been focused on the effects of stress
on the two major causes of mortality and morbidity in
the Western world, cardiovascular disease and cancer.
Identification of risk factors for these diseases and pos-
sible mechanisms for modifying such factors is thus an
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
83
How does stress affect you? An overview of stress, immunity, depression and disease
SSUUMMMMAARRYY –– OObbjj ee cc ttiivvee..
Stress is a term that has become synonymous with modern life.
This review aims to appraise the evidence linking stress with disease with particular reference to
the major causes of morbidity and mortality in the Western World, cardiovascular disease, cancer,
and depression. Changes in immune parameters in stressful situations were reviewed as a possible
pathophysiological mechanism for such effects.
MMee tthhoodd ––
A Medline search was carried out for
the period 1996-2000 to identify recent findings in this field using the terms “stress”, “disease”,
“immune system”. Relevant references that were found in all identified publications were also
followed up.
RReessuull ttss ––
There is evidence to link stress with the onset of major depression and with
a poorer prognosis in cardiovascular disease and cancer. Few small studies suggest that stress
management strategies may help to improve survival. Chronic stress appears to result in
suppression of the immune response, whereas immune activation and suppression have been
associated with acute stress. Inflammatory cytokines, soluble mediators of the immune response,
can result in symptoms of depression.
CCoonncc lluu ssiioonn ––
Further prospective epidemiologically based
studies are needed to clarify the role of stress on disease onset, course, and prognosis. Stress
management strategies, aimed at prolonging survival in patients with cardiovascular disease,
cancer, and possibly other chronic illnesses, are an exciting area of further research. Immune
system changes may account for the relationship between stress and disease. We propose the
“stress, cytokine, depression” model as a biological pathway to explain the link between stressful
life events and depression.
KEYWORDS: stress, cardiovascular disease, cancer, immune system, cytokines, depression.
Ricevuto il 2.5.2001 – Accettato il 14.05.2001.
area of considerable public health concern. In addition,
stress has been linked to exacerbation of diseases rela-
ted to the immune system including asthma, rheumatoid
arthritis, and multiple sclerosis (Wright et al., 1998;
Walker et al., 1999; Mohr et al., 2000).
Coronary heart disease
There has been widespread interest in the role of stress
as a risk factor for coronary heart disease (CHD). One of
the most well known studies in this field is that of Fried-
man & Rosenman (1959) who described “Type A” per-
sonality characteristics i.e. excessive competitive drive,
aggressiveness, impatience, hostility, and time urgency.
Such personality features would seem to create frequent
episodes of acute stress for the “type A” individual. CHD
incidence was investigated in a prospective epidemiolo-
gical study of 3,524 men aged 39 to 59 years living in Ca-
lifornia. At 8 and a half years follow-up, type A beha-
viour pattern was strongly related to CHD incidence, an
association that remained when other risk factors of pa-
rental history of CHD, smoking, blood pressure, and cho-
lesterol levels were controlled for (Rosenman et al., 1975).
A more recent prospective study investigated whether li-
fe events occurring in “Type A” individuals increased the
risk of cardiovascular disease. These investigators failed
to find such a link with cardiovascular disease although
unexpectedly there was an increased mortality from can-
cer in this group (Hollis et al., 1990).
Researchers have also investigated whether life events
predict cardiovascular risk. A prospective study of 752
Swedish men aged 50 found that at 7 years follow-up,
men who had experienced 3 or more life events in the
past year had a significantly greater mortality from all
causes (Rosengren et al., 1993). Adequate emotional sup-
port appeared to be a protective factor. However, the num-
ber of deaths was too small to analyse specific causes of
death. The pathological processes involved in CHD are
likely to have progressed over many years. Thus it is
perhaps not surprising that an acute stressor such as a li-
fe event will not predict outcome 1 year later. It may be
that more chronic stressors may contribute to such a pro-
cess. Indeed, a prospective study found that acute and
chronic stressors predicted a 3-year re-infarction rate in
patients initially admitted with an acute ischaemic event,
with chronic stressors and those involving goal frustra-
tions seeming most important (Tennant et al., 1994). Mo-
reover depression, which is associated with a chronic stress
response in some patients as measured by HPA axis ac-
tivation (Checkley, 1996), is associated with a much hi-
gher risk of both cardiovascular morbidity and mortality
(O’Connor et al., 2000).
Finally, there is evidence to suggest that stress reduc-
tion strategies may be beneficial in patients with CHD. A
cohort of 107 patients with coronary ischaemia were ran-
domly assigned to receive usual care, stress management,
or exercise training (Blumenthal et al., 1997). At 38 months
follow-up the stress management group had the lowest com-
bined rates of death, non-fatal myocardial infarction, and
re-vascularisation than the other two groups.
Stress and cancer
Similar study methods have been utilised to investi-
gate a possible link between stress and cancer. Much of
this research has focused on breast cancer.
A recent meta-analysis examined whether stressful li-
fe events are a risk factor for cancer (Petticrew et al.,
1999). 29 studies met the inclusion criteria. These in-
cluded 14 case-control studies, one prospective cohort
study, and 14 limited prospective studies in which wo-
men awaiting the results of a breast biopsy are interviewed
before the results are known. This attempts to control
for recall bias in case control studies in which women
are aware of their diagnosis and may be more likely to
over-report stressful life events as a result of their ill-
ness. The authors found no significant relationship
between bereavement and risk of breast cancer (OR 0.9;
CI 0.57 to 1.45) or adverse life events and risk of brea-
st cancer (OR 0.8; CI 0.61 to 1.06). Clearly, most of the-
se studies question about life events in the preceding 2,
5, or 10 years and the causative factors for breast can-
cer act many years, perhaps 20 or more, before the on-
set of symptoms or the diagnosis of disease (McGee et
al., 1996). This could explain why stress does not seem
to be a risk factor for breast cancer. However, there are
reports that stress may affect outcome of the disease.
A number of studies have demonstrated that interven-
tions to reduce psychological stress improve cancer sur-
vival. Spiegel et al. (1989) treated women with metasta-
tic breast cancer by means of weekly group therapy. The
intervention focused on encouraging a discussion of how
to cope with cancer, and the expression of feelings about
illness and its physical consequences. Relationships, whi-
ch developed amongst group members, provided increa-
sed social support. A randomised study compared one year
of the psychosocial treatment versus a control group. Both
groups received routine oncological care. After 10 years
of follow-up, the survival time of patients in the intervention
group was almost double that of the controls; 36.6 months
Clementine Maddock and Carmine M. Pariante
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
84
versus 18.9 months starting from the onset of the inter-
vention. A similar group therapy approach was utilised in
the treatment of patients with malignant melanoma (Fawzy
et al., 1990a, b; 1993). The intervention consisted of a 6-
week course focusing on health education, enhancement
of problem solving skills, stress management with relaxation
techniques, and psychological support. At six months fol-
low-up the intervention group, compared to a randomly
selected control group, exhibited lower levels of psycho-
logical distress (Fawzy et al.., 1990a). Furthermore, after
5-6 years of follow-up the psychosocial intervention group
had a lower rate of death and cancer recurrence than con-
trols (Fawzy et al., 1993.)
One possible mechanism whereby stress may be af-
fecting cancer survival is via changes in immune para-
meters. Natural killer (NK) cells are a distinct sub-po-
pulation of lymphoid cells that have spontaneous cytolytic
activity against a variety of tumour cells and some nor-
mal cells. Furthermore, they have a role in resistance to
infection with viruses and other microbes (Herberman
& Ortaldo, 1981). NK cell function is thus implicated in
an individual’s ability to combat cancer. Fawzy et al.
(1990b) found an increase in NK cell percentage and NK
cytotoxic activity in patients with malignant melanoma
who were receiving psychological therapy at six months
follow-up. Baseline NK cell activity was found to be pre-
dictive of recurrence of malignant melanoma in this
cohort. However, the change in NK cell percentage over
time was not correlated with the course of illness, and
NK activity was not predictive of survival.
The effect of stress on NK cell activity has also been
investigated in a group of 116 patients treated surgical-
ly for invasive breast cancer (Andersen et al., 1998). Prior
to surgery, subjects completed a questionnaire assessing
intrusive thoughts, avoidant thoughts, and actions con-
cerning cancer, which was used as a measure of psy-
chological stress. An increased stress score was signifi-
cantly associated with a decline in spontaneous NK cell
cytotoxicity. Furthermore, higher stress significantly pre-
dicted a diminished NK cell cytotoxicity after stimula-
tion with interferon-gamma (IFN-gamma). NK cells that
have been activated by cytokines, including IFN-gam-
ma and interleukin-2 (IL-2), known as lymphokine ac-
tivated killer (LAK) cells, are highly cytotoxic against
a wider variety of tumour cells than those lysed by re-
sting NK cells (Whiteside & Herberman, 1990). Thus,
the potential cytotoxic activity of these patients NK cel-
ls appears to be reduced. Finally, Andersen and collea-
gues found that increased stress was significantly asso-
ciated with reduced T-cell responses as measured by the
proliferative response of peripheral blood lymphocytes
to plant lectins and a monoclonal antibody directed
against the T-cell receptor.
So, does stress make you ill?
In summary, there is thus intriguing, albeit limited da-
ta currently available that psychological stress is associa-
ted with the outcome of coronary heart disease, breast can-
cer, and malignant melanoma. Immune parameters, inclu-
ding NK cell cytotoxicity, are also affected by stress le-
vels, and are of importance in the host response to tumour
cells. The relationship between stress, disease and the im-
mune system is thus an exciting field for further research.
STRESS AND THE IMMUNE SYSTEM
The mechanisms whereby psychological stress may
be influencing disease outcome are not clear. We have
summarised some of the findings relating to immune sy-
stem changes in patients with cancer. There have been
several studies investigating the effect of stressful si-
tuations, both acute and chronic, in otherwise healthy
subjects. As outlined below, such stressors have effects
on a large number of immune parameters, which are of
importance in resistance to infection and disease.
The studies below have utilised two kinds of immune
assay; enumerative and functional (Herbert & Cohen,
1993). Enumerative assays count the numbers or percen-
tages of different types of white blood cell in peripheral
blood. Such assays are useful as a certain number of ea-
ch type of immune cell is needed in order to respond ade-
quately to an antigenic challenge. Furthermore, a balan-
ce of the different cell types is needed for an optimal im-
mune response. Enumerative techniques may also mea-
sure immunoglobulin (Ig) levels in saliva or peripheral
blood. As most people have been exposed to the common
herpes viruses e.g. herpes simplex virus type 1 and Epstein-
Barr virus, serum antibody (Ab) to these viruses may be
measured with higher levels indicating higher levels of
virus replication and thus poorer immune functioning.
The functional capacity of human immune cells may
be assessed via the lymphocyte proliferative response and
NK cell cytotoxic activity, which has been briefly men-
tioned above. Lymphocyte proliferation is achieved by
incubating lymphocytes, in-vitro, with substances (mi-
togens) capable of non-specifically inducing T or B-
lymphocytes to divide. It is assumed that the more pro-
liferation that occurs, the more effectively the cells are
functioning. NK cell cytotoxic activity assays determi-
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
85
How does stress affect you? An overview of stress, immunity, depression and disease
Clementine Maddock and Carmine M. Pariante
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
86
ne how effectively NK cells kill damaged or altered (e.g.
infected, cancerous) cells. Immune cells are incubated,
in-vitro, with tumour cells to achieve this measure.
Stressful Life Events
Immune system function, as measured by lymphocy-
te proliferative responses, has been assessed in indivi-
duals who have been exposed to the stressful life event
of bereavement. Initial studies revealed, as perhaps may
be predicted, reduced responses in these individuals. Bar-
trop et al. (1977) conducted one of the first studies sug-
gesting a link between stressful events and the immune
system in humans. Compared with an age, sex, and ra-
ce matched control group, 26 bereaved spouses showed
a reduced lymphocyte proliferative response at 6 weeks
post-bereavement, although there was no difference in
T and B cell numbers. Similarly, a study of 15 spouses
of women with advanced breast carcinoma revealed si-
gnificantly suppressed lymphocyte responses one and two
months following bereavement compared with pre-be-
reavement levels. There was no comparison with a con-
trol group. At 4 to 14 months after bereavement, an in-
termediate response was achieved. Again, no differen-
ces were found in total lymphocyte or T or B cell num-
bers (Schleifer et al., 1983). However, a recent study com-
paring 18 widows to 10 married female controls found
that the widows showed a higher lymphocyte prolifera-
tive response to mitogen at 3 and 7 months post-berea-
vement, compared to the control group (Beem et al., 1999).
There were no differences in natural killer cell activity
between the bereaved and control groups. It is intere-
sting that this group showed heightened proliferative re-
sponses compared to the control group in this study.
However, the immune responses were tested at 3 and 7
months following bereavement, but no comparisons
between pre-bereavement and post-bereavement were ma-
de. Longitudinally, it is possible that the bereaved subjects
actually showed immune suppression compared with
pre-bereavement responses. Also, this group consisted
solely of women, compared to the previous two studies.
Therefore, it is also possible that the stress affects the
immune system differently in men and women. Indeed,
one study have found that depressed female patients ha-
ve increased NK activity compared to controls, while de-
creased NK activity has been described in old male de-
pressed patients (Pariante & Miller, 1995). One mecha-
nism for this may be the different hormonal milieu. For
example, there is evidence that women taking oestrogen
and progesterone derivatives show heightened immune
activity at times of stress (Maes et al., 1999). Subjects
in the study by Beem et al. (1999) were aged between
50 and 65 and may have been taking hormone replace-
ment therapy. Thus, while these studies demonstrate si-
gnificant changes in immune parameters following be-
reavement, larger prospective designs would clarify the
time course of such changes and control for possible
confounders such as sex, age and health status.
Kiecolt-Glaser & Glaser (1991a) have investigated the
association of a range of stressful life events with the
immune response. This research group initially focused
their attention on academic stress among medical stu-
dents as a commonplace stressful situation. Overall, they
demonstrated impaired immune responses during the fi-
nal examination (stressor) period as compared with pre-
examination baseline responses. Decreases were noted
in NK cell activity, T-cell number, and interferon pro-
duction from activated lymphocytes. Increased antibody
titres to latent herpes viruses, a putative marker of de-
creased immune cell function, were also noted.
Further exploration in this area has revealed that a
subject’s psychological perception of the stressor, along
with social support, may determine the outcome of the
immune response. In a group of 48 medical students re-
ceiving a hepatitis B vaccination on the day of an exa-
mination, those who became immunised after the first
injection were significantly less stressed and anxious than
those who did not (Glaser et al., 1992). Those students
who reported greater social support demonstrated a stron-
ger immune response to the vaccine at the time of the
third inoculation as measured by antibody titres to he-
patitis B surface antigen.
Some studies have found that acute stress may acti-
vate, rather than suppress, some aspects of the immune
response. For example, immune activation, as suggested
by increased numbers of neutrophils, monocytes, B-cel-
ls, and activated T-cells has been observed in students
who showed increases in psychological stress (stress re-
sponders), the day before an exam. The Perceived Stress
Scale was used to measure stress, and results were com-
pared with baseline and post-exam responses (Maes et
al., 1999). However, those students who did not show
increased stress scores (stress non-responders) did not
show many immune system changes. Some of the alte-
rations in immune parameters persisted for several weeks
after the exam stress. Female students taking oral con-
traception containing oestrogen and progesterone deri-
vatives revealed a significantly greater stress induced re-
sponse in the number of leukocytes, neutrophils and B-
cells. Whitehouse et al. (1996) also found evidence of
immune activation at the time of exam stress, as sugge-
sted by increased B-lymphocyte and activated T
lymphocyte counts, increased lymphocyte proliferative
responses, and increased NK cell cytotoxicity. In this
study, some students were trained in self-hypnosis as a
stress management skill. These subjects reported signi-
ficantly less distress and anxiety than their non-inter-
vention counterparts, but the two groups did not differ
with respect to immune function. However, within the
self-hypnosis group, those subjects reporting higher le-
vels of relaxation showed enhanced NK cell cytotoxi-
city over the course of the investigation.
These studies provide evidence for changes in immune
system function in medical students at the time of exami-
nation stress. Both immune suppression and activation ha-
ve been demonstrated. The psychological response of in-
dividuals to exam stress appears to determine whether chan-
ges occur. There is no clear explanation as to why some
studies suggest enhanced immune function and others sup-
pression at the time of an exam stress. It is possible that
subjects in some studies may have experienced chronic stress
resulting in adaptation of the immune response e.g. longer
time spent preparing for the exam, frequent exams. Alter-
natively, some of the exam situations e.g. final exams as
measured in the Kiecolt-Glaser and Glaser studies may ha-
ve been perceived as more psychologically stressful than
year 1 or 2 exams measured in other studies.
Chronic stressors
Care giving has been used as a model of a chronic
stressor in a number of studies investigating associated
changes in immune function. Those groups studied in-
clude caregivers of patients with Alzheimer’s disease,
handicapped children, and mothers of very low birth-wei-
ght infants. Thus, by their very nature, there is a bias
towards female subjects in these studies. Overall, these
studies have demonstrated down-regulation of several
aspects of the immune response.
Care-giving for patients with Alzheimer’s disease has
been associated with alterations in lymphocyte sub-po-
pulations, increased antibody titres to herpes simplex vi-
rus, decreased proliferative responses to mitogens, more
days of illness from infectious disease compared to mat-
ched controls, impaired antibody responses to an influenza
virus vaccine, and a longer latency in wound healing (Kie-
colt-Glaser et al., 1987; 1991b; 1995; 1996). Caregivers
to patients with Alzheimer’s disease tend to people and
18 age and sex matched controls were compared in terms
of immunological parameters. Caregivers had a signifi-
cantly lower percentage of T-cells, significantly higher per-
centage of T suppressor/cytotoxic cells, and a significan-
tly lower T helper/suppressor ratio. When subjects were
also analysed after division into two groups according to
the median age (45 years), older caregivers actually had
lower numbers of T cells and T helper cells, and higher
antibody titres for cytomegalovirus than their age matched
controls. These alterations in immune parameters may be
relevant to functioning of the immune system. T helper
cells secrete cytokines in order to activate the immune re-
sponse; T cytotoxic cells have the ability to lyse cells to
which they bind; and T suppressor cells act primarily to
suppress the function of other T cells. Therefore, a reduction
in the T helper population in association with an increa-
se in the T suppressor population, as shown in these subjects,
may represent a marker of a decreased immune function.
Moreover, as we have said before, an increase in the an-
tibody titres for a virus has been described in a large num-
ber of stressful situations and is considered to be a marker
of decreased cellular immunity. These results imply that
advancing age is a vulnerability factor for immune sup-
pression, should another chronic stressor be present.
A third group examined as a model of chronic stress
has been mothers of pre-term very low birth weight in-
fants (VLBW). This is a particularly interesting group, who
are not only caregivers but also re-establishing immune
function after the cellular changes of pregnancy, and the-
refore may be more vulnerable to stress induced immune
down-regulation. An American study compared 50 post-
partum women; 25 had pre-term VLBW infants who sur-
vived to be discharged home, and 25 had normal weight
term infants. Mothers of pre-term VLBW infants had de-
creased mitogen responses for the first four post-partum
months compared to mothers of term infants. There we-
re no differences in health behaviours i.e. diet, smoking,
exercise, between the groups. Anxiety and depression fai-
led to account for the relationship and the authors’ po-
stulate that the chronic stressor of caring for a small, fra-
gile infant may have accounted for the changes. There was
no difference in NK cell activity between the two groups
of mothers (Gennaro et al., 1997). This suggests that not
all compartments of the immune system are equally af-
fected by stress. In addition, there may be a time lag befo-
re certain immune components are affected.
CLINICAL RELEVANCE OF IMMUNOLOGICAL
CHANGES AND THE ROLE OF CYTOKINES
Taken together, these data provide convincing eviden-
ce that changes in the immune system occur in response
to stress. However, while these studies demonstrate phy-
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
87
How does stress affect you? An overview of stress, immunity, depression and disease
Clementine Maddock and Carmine M. Pariante
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
88
siological variability in the immune response to stress, they
tell us little about the clinical implications of such chan-
ges. Clearly, a potential consequence of stress-induced chan-
ges in immune response is suppression of host resistance
to infectious agents. This has been suggested by several
studies, including the studies above mentioned by Kie-
colt-Glaser et al.(1991b) showing increased number of days
of illness from infectious diseases in caregivers to Alzhei-
mer’s disease patients. However, more insight into this
topic was obtained by a series of “experimental studies”
conducted by Cohen et al. (1991; 1998; 1999). These stu-
dies found that greater psychological stress is associated
with both an increased incidence of upper respiratory tract
infections (URTI), and more severe symptoms. To con-
trol for exposure to URTI in these studies, participants
were intentionally exposed to a virus and monitored in
quarantine for infection and illness. Psychological stress
was monitored before and during exposure to the virus.
In this study, increasing stress was linked to increasing ri-
sk of infection in a dose-response manner (Cohen et al.,
1991). The nature of the stressor is also important in that
acute stress (less than one month long) has not been linked
with developing colds, whereas severe chronic stressors
(1 month or longer) is associated with a greatly increased
risk of disease (Cohen et al., 1998). These findings are in
keeping with the experimental evidence described above
relating chronic stress (e.g. care giving) with suppression
of the immune response.
These studies have further contributed to our under-
standing of the clinical relevance of immunological chan-
ges by describing a possible mechanism for the associa-
tion between stress and symptom severity, namely via an
increased production of the proinflammatory cytokine in-
terleukin 6 (IL-6). Epithelial cells produce IL-6 in-vitro
and in-vivo when exposed to rhinovirus (Zhu et al. 1996).
Cohen et al. (1999) correlated changes in the production
of IL-6 with illness severity. Adult volunteer subjects (n=55)
were experimentally infected with influenza A virus after
completing a measure of psychological stress. Subjects,
in quarantine, were monitored for upper respiratory symp-
toms, mucus production, and nasal lavage levels of IL-6
on a daily basis. Higher psychological stress was asso-
ciated with increased scores on all three measurements.
The authors concluded that these results were consistent
with IL-6 acting as a pathway through which stress re-
sults in increased symptom severity. In fact, exogenous
cytokine administration has been linked with “flu like”
symptoms in animals and humans (Kent et al., 1992).
Interestingly, different studies have found that stress
can induce elevated levels of IL-6 in animals (Zhou et al.,
1993; Le May et al., 1990). Moreover, cytokine produc-
tion in response to stress has also been investigated in hu-
mans. In medical students experiencing the stressor of exa-
minations, the pro-inflammatory cytokines IL-1b (Dob-
bin et al., 1991), and TNF-a (Maes et al., 1998) were found
to be increased. In another study, both patients with mul-
tiple sclerosis, and control subjects, showed increased IL-
1b and TNF-a production in response to an experimental
stressor (Ackerman et al., 1998). Chronic stress, howe-
ver, has been associated with reduced IL-1 measurement
in the local environment of an experimental surgical
wound (Kiecolt-Glaser et al., 1995; Glaser et al., 1999).
The somewhat contradictory nature of these results may
be explained by the nature of the stressor i.e. chronic (ca-
re giving for patients with Alzheimers disease, perceived
level of daily stressors) rather than more acute events su-
ch as a major examination, or an experimental stressor.
Generally, immune suppression has been noted in the stu-
dies of chronic stress described above. As we will see be-
low, an increased production of proinflammatory cytoki-
nes in situations of acute stress may also be one of the
biological pathways by which stress leads to depression.
DOES STRESS MAKE YOU DEPRESSED? THE
“STRESS, CYTOKINE, DEPRESSION” MODEL
Psychological stressors have been linked with onset and
relapse of depression. The classic study by Brown & Har-
ris (1978) demonstrated that excess life events occur in
the six months before a depressive episode starts. This com-
munity based survey in Camberwell, South London, iden-
tified vulnerability factors, which increase the risk of de-
pression if a provoking agent is present. Vulnerability fac-
tors include having 3 or more children at home under the
age of 14, not working outside the home, lack of a confi-
ding relationship, and loss of mother before the age of 11.
A further prospective community based study identified
low self esteem as a major vulnerability factor, and tho-
se showing lack of support from a close tie at the time of
crisis were at greatly increased risk of subsequent depression
(Brown et al., 1986). It thus appears that a person suffe-
ring a chronic stressor (vulnerability factor) and expe-
riencing an acute stressor (life event) is at increased risk
of depression. However, the biological mechanisms for
such an effect have yet to be elucidated.
A “stress, cytokine, depression” model may be one ex-
planation for such an effect. Our hypothesis is that stress
can result in proinflammatory cytokine release, which in
turn induces behavioural and hormonal changes (“sickness
behaviour”) that finally lead to symptoms of depression.
Proinflammatory cytokines, like IL-1, IL-6, and tu-
mour necrosis factor (TNF) regulate the acute phase reac-
tion, an early immune reaction against invading organi-
sms. The acute phase response aims to limit tissue da-
mage, isolate and destroy the invading organism, and set
repair functions in motion (Miller et al., 2000). Howe-
ver, such immune activation, while containing damage
by invading pathogens, may result in unpleasant and di-
stressing symptoms. In fact, proinflammatory cytokines
exhibit the capacity to induce a group of behavioural
symptoms referred to as “sickness behaviour” (Kent et
al., 1992; Miller et al., 1999). Sickness behaviour com-
monly accompanies serious viral or bacterial infections
and includes fatigue, loss of appetite, sleep disturbance,
social withdrawal, decreased libido, depressed mood, and
general malaise. Sickness behaviour also occurs in pa-
tients undergoing high dose cytokine therapies for neo-
plastic or viral illness (Miller et al., 1999; Pariante et al.,
1999a). The overlap of symptoms in certain psychiatric
disorders (especially major depression) with sickness
behaviour has raised the possibility that cytokines elici-
ted during stress may contribute to the expression of beha-
vioural alterations in stress related disorders like major
depression. This is further supported by studies showing
that proinflammatory cytokines have the capacity to sti-
mulate the release of corticotrophin releasing factor
(CRF) and adrenocorticotrophic hormone (ACTH) (Be-
sedovsky & Del Rey, 1996), thus inducing a state of hy-
peractivity of the HPA axis similar to that described in
major depression. Finally, and in harmony with the theo-
retical model that proinflammatory cytokines may play
a role in major depression, an increased production of
IL-1, TNF, and more consistently IL-6, has been found
in patients with major depression by some (Maes et al.,
1991; Anisman et al., 1999; Lanquillon et al., 2000), but
not all studies (Weizman et al., 1994; Haack et al.,
1999).
CONCLUSION
This review has focused upon the association between
stress, disease, depression, and the immune system. The-
re is currently somewhat conflicting evidence as to
whether stress is a risk factor for cancer and cardiova-
scular disease, and further prospective community ba-
sed studies would clarify this issue. Stress appears to be
associated with a poorer prognosis in both these condi-
tions, and the small numbers of studies available sug-
gest that stress management therapies are associated
with improved survival. Stressful life events and situa-
tions are also related to onset and relapse in major de-
pression. Changes are seen in many immune parameters
examined during stressful situations, both acute, and ch-
ronic. The clinical significance of such changes is not
clear. One study has correlated changes in an immune
parameter (IL-6) with worse clinical symptoms of an up-
per respiratory tract infection (Cohen et al., 1999). So-
me of these changes in immune parameters, namely the
increased production of proinflammatory cytokines, may
have a role spreading beyond the simple regulation of
the immune response into affecting mood and behaviour.
Indeed, the ability of proinflammatory cytokines, namely
IL-1, IL-6, and TNF, to induce “sickness behaviour”,
symptoms which are present in depression, has led to the
concept that cytokines may be a key factor in the
pathophysiology of depression. We have proposed a
“stress, cytokine, depression” model of depression, whi-
ch features cytokines as key mediators in this process
(see figure 1).
Figure 1. - The «stress, cytokine, depression» model.
Our group is currently investigating this model by a
variety of approaches. Firstly, we have investigated the
biological mechanisms by which proinflammatory cy-
tokines may induce depressive symptoms. Specifically,
we have described the molecular step by which the
proinflammatory cytokine IL-1 may induce changes in
the HPA axis that resemble those present in patients with
depression (Pariante et al., 1999b). Of note is that these
molecular changes induced by proinflammatory cytoki-
nes seems to be opposite to those induced by antide-
pressants (Pariante et al., 1997b). Secondly, we have been
looking at the relationship between previous or recent
Epidemiologia e Psichiatria Sociale, 10, 3, 2001
89
How does stress affect you? An overview of stress, immunity, depression and disease
psychiatric history and psychopathological symptoms in-
duced by treatment with interferon-alpha for chronic vi-
ral hepatitis (Pariante et al., 1999a; Carpiniello et al.,
1998). In fact, interferon-alpha also increases proin-
flammatory cytokine production. More recently, we ha-
ve been assessing symptoms of depression, fatigue and
general well being in a prospective cohort study of pa-
tients undergoing a novel formulation (pegylated) of in-
terferon-alpha therapy to treat Hepatitis C. We believe
that the possibility that stressful life experiences may con-
tribute to the onset of depression via the production of
proinflammatory cytokines represents an interesting tho-
retical framework in which further hypotheses regarding
the biological mechanisms of the pathogenesis of de-
pression can be investigated and generated.
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