Health care education, delivery, and quality
Update review
Stress and atopic disorders
Rosalind J. Wright, MD, MPH Boston, Mass
Evidence linking psychological stress to the expression of
asthma and atopy continues to grow. Examining the underlying
molecular mechanisms linking stress to asthma and other
allergic phenomena is an active area of research. Evidence is
reviewed for the influence of stress on neuroimmunoregulation
and oxidative stress pathways, which, in turn, may affect
biological hypersensitivity to environmental stimuli
characteristic of atopic disorders. Critical periods of
development, including in utero environment, are underscored.
The role of genetics and gene-by-environment interactions is
also discussed. (J Allergy Clin Immunol 2005;116:1301-6.)
Key words: Asthma, atopy, psychological stress, oxidative stress,
psychoneuroimmunology, genetics
Asthma and other allergic diseases have long been
considered psychosomatic disorders. Indeed, before we
better understood the underlying inflammatory basis of
asthma, it was among the disorders believed to be purely
psychogenic in origin, commonly referred to as asthma
nervosa in early medical texts.1
Atopy may be defined as a genetically and environ-
mentally determined predisposition to clinically expressed
disorders, including allergic rhinitis, atopic dermatitis or
eczema, and allergic asthma, regulated through immune
phenomena in which many cells (ie, mast cells, eosino-
phils, and T lymphocytes) and associated cytokines,
chemokines, and neuropeptides play a role. Overlapping
mechanisms of inflammation central to the pathophysiol-
ogy of these atopic disorders involve a cascade of events
that include the release of immunologic mediators trig-
gered by both IgE-dependent and IgE-independent
mechanisms. Biological hypersensitivity to environ-
mental stimuli is a central feature of atopic disorders.
Increasingly, atopy has been conceptualized as an epi-
demic of dysregulated immunity. The exploration of host
and environmental factors that may alter neuroimmune
From the Channing Laboratory, Department of Medicine, Brigham and
Women’s Hospital, Harvard Medical School; and the Department of
Society, Human Development, and Health, Harvard School of Public Health.
Supported by the National Heart, Lung, and Blood Institute: R01 ES10932,
R01 HL64108, and U01 HL072494.
Received for publication June 2, 2005; revised September 27, 2005; accepted
for publication September 29, 2005.
Reprint requests: Rosalind J. Wright, MD, MPH, Channing Laboratory,
181 Longwood Ave, Boston, MA 02115. E-mail: rosalind.wright@
channing.harvard.edu.
0091-6749/$30.00
© 2005 American Academy of Allergy, Asthma and Immunology
doi:10.1016/j.jaci.2005.09.050
Abbreviations used
CNS: Central nervous system
CRH: Corticotrophin-releasing hormone
HPA: Hypothalamic-pituitary-adrenocortical
ROS: Reactive oxygen species
SAM: Sympathetic and adrenomedullary
expression and potentiate the expression of atopic dis-
orders is an active area of research. Both genetic and
environmental factors affecting maturation of the immune
system during childhood set the stage for the inflammatory
processes and altered reactivity to stimuli that are charac-
teristic of atopic disorders. Psychological stress may thus
play an important role in both the onset of these disorders
and the exacerbation of existing atopic disease.
It is helpful to begin the discussion by summarizing key
aspects of how psychological stress has been conceptual-
ized in human research.2 Three broad traditions of assess-
ing the role of psychological stress in disease risk have
been distinguished (ie, environmental, psychological,
Health care education,
delivery, and quality
and biological). The environmental tradition focuses on
assessment of events associated with adaptive demands,
whereas the psychological tradition focuses on the subjec-
tive evaluation of one’s ability to cope with these de-
mands. If environmental demands are found to be taxing
or threatening, and coping resources are viewed to be in-
adequate, individuals perceive themselves as being under
stress.3 This perception is presumed to result in negative
emotional states (eg, fear, anxiety, posttraumatic stress
symptoms, depression). Finally, the biological tradition
focuses on activation of specific physiological systems.
Behavioral and emotional changes that follow the effort
to adapt to stressors are accompanied by complex patterns
of neuroendocrine and immunologic alterations.4
Typical stressors considered in health research include
factors such as major life events, trauma, and abuse, as
well as less intense chronic psychological pressure in-
duced during work and personal relationships.2 Exposure
to acute stress generates an adaptive individual response,
such as ‘‘fight or flight.’’ Chronic stress is generally
thought of as the chronic load of day-to-day stressors.
Researchers have long recognized that stress may protect
the body, but when more chronic, can also damage it. 5
Furthermore, there appear to be individual or host differ-
ences in the body’s response to similar levels and duration
of stress.6,7 An individual’s response to acute challenges is
1301
 1302 Wright
FIG 1. Model of the stress process designed to illustrate the
integration of psychological responses to environmental stressors,
which, in turn, may influence the expression of atopic disorders.
altered when superimposed on chronic stress. 8,9 The rea-
sons behind such individual differences in susceptibility
may be key in understanding the functional consequences
of chronic psychological stress. These central themes in stress
research need to be considered when interpreting studies link-
ing psychological stress and emotion to health outcomes.
Mechanisms linking psychological stress, personality,
and emotion to neuroimmunoregulation10-12 as well as in-
creased risk of atopy13 have been increasingly elucidated.
Advances in our understanding of psychoneuroimmuno-
logy and the bidirectional links among the central nervous
system (CNS), autonomic nervous system in the periphery,
endocrine system, and immune system have been critical.
Hormones and neuropeptides released into the circulation
when individuals experience stress may also regulate
Health care education,
delivery, and quality
both immune-mediated and neurogenic inflammation.
Our current understanding of the role of psychological
stress in atopy is discussed. Note that this review focuses
specifically on proposed physiological mechanisms link-
ing stress to asthma as summarized in Fig 1. The expres-
sion of asthma may also be influenced by behavioral
stress responses that have been reviewed previously.14
PSYCHOLOGICAL STRESS AND
THE ENDOCRINE SYSTEM
Psychological stress has been associated with the acti-
vation of the sympathetic and adrenomedullary (SAM)
system and the hypothalamic-pituitary-adrenocortical
(HPA) axis (see detailed review14). It is the disturbed bal-
ance of these systems that is relevant to disease. Immune,
metabolic, and neural defensive biological mechanisms
important for the short-term response to acute stress may
produce long-term damage if not checked and eventually
terminated in the face of more chronic stress.5 Negative
emotional responses to environmental stressors disturb
the regulation of the HPA axis and the SAM systems;
that is, in the face of stress, physiological systems may
operate at higher or lower levels than during normal
homeostasis. The central notion is that some optimal level
of these mediators is necessary to maintain a functional
J ALLERGY CLIN IMMUNOL
DECEMBER 2005
balance, and the absence of this optimal balance in levels
of glucocorticoids and catecholamines (for example) al-
lows other immune mediators to overreact and increases
the risk of autoimmune and inflammatory disorders. The
direction of the HPA response to chronic stress may
depend on the nature of the stressor (ie, with respect to
duration, severity, controllability, and predictability).
Moreover, a well-known characteristic of stress axis
functioning is the marked interindividual variability of
responses to challenge,6 and the understanding of the
relevance of this neuroendocrine system in asthma and
allergy pathophysiology requires the identification of the
determinants of this variability. Genetic factors, in utero
and postnatal environmental factors, and the timing of
exposures likely affect differentiation of this response.
Although hormones of the sympathetic and adrenal
medullary and HPA systems (eg, cortisol, epinephrine) are
those most often discussed as the biological substances
involved in stress responses, alterations in a range of other
hormones, neurotransmitters, and neuropeptides dem-
onstrated in response to stress may also play a part.
Regulatory pituitary (ie, corticotrophin) and hypothalamic
hormones (ie, corticotrophin-releasing hormone [CRH]
and arginine vasopressin) of the HPA axis have systemic
immunopotentiating and proinflammatory effects. Mast
cell mediators are responsible for many of the immediate
symptoms of nasal allergy and manifestations of atopic
dermatitis. Acute psychological stress (immobilization in
rats) has been shown to result in skin mast cell degranu-
lation, an effect inhibited by anti-CRH serum adminis-
tered before stress. Mechanisms linking stress and mast
cell function have been extensively reviewed recently.15
For example, stressor-associated increases in substance
P, growth hormone, and prolactin secreted by the pituitary
gland and in the natural opiate b-endorphins and enkeph-
alins released in the brain are also thought to play a role in
immune regulation. Although these factors have been less
well studied to date, increasing attention has been given
to the role of substance P in mediating inflammatory
responses in the lung.
STRESS AND AUTONOMIC CONTROL
OF AIRWAYS
The balance between functional parasympathetic and
functional sympathetic activity in relation to stress, emo-
tional stimuli, and immune function may also be important
for the expression of asthma and allergic rhinitis. Local
interactions between the immune system and the auto-
nomic nervous system are only partially understood. 16,17
Increased activity of the parasympathetic nervous system
was once thought to be the dominant mechanism re-
sponsible for the exaggerated reflex bronchoconstriction
(airway narrowing) that occurs in subjects with asthma,
although more recent work challenges this idea. Evidence
suggesting several cholinergic anti-inflammatory pathways
triggered through vagus nerve activation18 complicate our
understanding and need to be explored in the context of atopy.
J ALLERGY CLIN IMMUNOL
VOLUME 116, NUMBER 6
Evidence demonstrating nerve–mast cell communi-
cation in response to stress and the potential import of
these interactions in the respiratory system suggests this
may be a fruitful area of research relative to stress and
allergic asthma.17 Tachykinins derived from nonadre-
nergic noncholinergic (NANC) nerves influence airway
smooth muscle contraction, mucus secretion, vascular
leakage, and neutrophil attachment. In experimental
studies, tachykinins, especially substance P, have been
linked to neurogenic inflammation and regulation of
stress hormonal pathways and have been implicated in
asthma and neurogenic skin disorders.17
When immune cells (ie, T cells, mast cells, dendritic
cells, and macrophages) are activated locally (eg, in the
airways) and release proinflammatory molecular media-
tors, these signals not only influence cells of the innate and
adaptive immunological system in the periphery but also
activate sensory pathways that relay information to the
CNS.16 The precise mechanisms by which the peripheral
immune system signals the CNS is only partially under-
stood. Stimulation of sensory nerves in the airways—
specifically ascending vagus nerve fibers as well as pain
sensory pathways (vagal nonmyelinated lung C fibers
and Ad rapidly adapting receptors)—results in CNS reflex
responses consistent with asthma symptoms (eg, broncho-
constriction, cough, mucous secretion). These neural
inflammation-sensing pathways can function at low
thresholds of detection and activate responses even when
inflammatory mediators are present in the airway tissues
in quantities too low to reach the brain through the blood-
stream. Both animal studies and human imaging data have
identified neurobiological correlates that shed further light
on neuroimmunological mechanisms underlying the lung-
brain link. Airways function in response to stimuli, includ-
ing irritants, allergens, and inflammatory mediators. Chen
et al19,20 have demonstrated the ability of the nucleus trac-
tus solitarius, a CNS region containing neurons that pro-
cess lung sensory signals, to undergo marked changes in
excitability in the face of extended exposure to irritants
(ie, allergen exposure, ozone exposure, and tobacco
smoke). These toxicants share commonalities in the
responses they may illicit in the airways (eg, local release
of inflammatory mediators, oxidative stress, and activa-
tion of sensory neurons) that may contribute to the respi-
ratory inflammatory and motor response. These processes
may be mediated, in part, through substance P.21 A logical
extension of this work in the context of this discussion is
whether extended episodic exposures to psychological
stressors would change the neural behavior of neurons
in the CNS and also influence the CNS neural contribution
to asthma and the allergic airway response. Further research
into the neurobiological correlates of atopy may lead to a
more complete understanding of the lung-brain link.
STRESS AND IMMUNE FUNCTION
Atopic inflammation is thought to be orchestrated by
activated T lymphocytes and the cytokines they produce.
Wright 1303
The TH2 cytokine phenotype promotes IgE production,
with subsequent recruitment of inflammatory cells that
may initiate and/or potentiate allergic inflammation. For
most children who develop allergies or asthma, the polari-
zation of their immune system into an atopic phenotype
probably occurs during early childhood. These findings
have sparked vigorous investigation into the potential in-
fluence of early life environmental risk factors for asthma
and allergy on the maturation of the immune system, in
the hopes of understanding which factors will potentiate
(or protect from) this polarization. There is evidence that
parental reports of life stress are associated with subsequent
onset of wheezing in children in early childhood22 (also see
references within article22). This relationship led to specu-
lation that stress may trigger hormones in the early months
of life, which may in turn influence TH2 cell predominance,
perhaps through a direct influence of stress hormones on
the production of cytokines that are thought to modulate
the direction of differentiation. Further examination of
the relationships between caregiver stress on markers of
early childhood immune response including IgE expres-
sion, mitogen-specific, and allergen-specific lymphocyte
proliferative response, and subsequent cytokine expression
(IFN-g, TNF-a, IL-10, and IL-13) was performed in the
same prospective birth cohort mentioned23 when the chil-
dren were 2 to 3 years of age. In adjusted analyses, higher
caregiver stress in the first 6 months after birth was asso-
ciated with increases in the children’s allergen-specific
proliferative response (a marker of the allergic immune
response), higher total IgE levels, and increased production
of TNF-a and reduced IFN-g.
Recent animal data suggest that increased maternal
Health care education,
stress prenatally is associated with an elevated cortisol
delivery, and quality
response to stress in the newborn, affecting TH1/TH2 cell
differentiation.24 Although the ability to activate an in-
crease in cortisol in response to some stimuli in early
life may be adaptive, prolonged exposure to stress may
change the cortisol response if examined at a later devel-
opmental stage. Chronic stress may induce a state of hypo-
responsiveness of the HPA axis whereby cortisol secretion
is attenuated, leading to a shift in the balance of pro-
inflammatory/anti-inflammatory cytokines secreted (ie,
increased production of proinflammatory cytokines
typically counterregulated by cortisol). Several altered
neuroendocrine and immune changes in response to stress
have been demonstrated in subjects with atopic dermatitis:
altered responsiveness of the HPA axis and the SAM
system, increased eosinophil counts, and elevated IgE
expression.25 Whether the altered HPA responsiveness
will lead to increased risk of developing atopy in later
life remains to be seen. A state of stress-induced HPA hy-
poresponsiveness has been demonstrated in some research
subjects with chronic atopic disorders.26 An attenuated
cortisol response has been found among adolescents
with positive skin test reactivity and a clinical history of
allergic rhinitis, atopic dermatitis, or asthma compared
with those with skin test positivity alone or nonatopic in-
dividuals. Further studies are needed to examine relation-
ships between individual patterns of cortisol response to
 1304 Wright
stress across different developmental periods and the
subsequent expression of atopy.
STRESS AND GLUCOCORTICOID
RESISTANCE
An alternative hypothesis linking stress, neuroendo-
crine and immune function, and inflammatory disease
expression considers a glucocorticoid resistance model.27
As we have come to understand the central role of airway
inflammation and immune activation in asthma pathogen-
esis, asthma treatment guidelines have focused on the use
of anti-inflammatory therapy, particularly oral and inhaled
glucocorticoids or steroids. Patients with asthma, how-
ever, have a variable response to glucocorticoid therapy.
Although the majority of patients readily respond, a sub-
set of patients has difficult-to-control asthma even when
treated with high doses. Notably, the majority of subjects
with glucocorticoid-resistant or glucocorticoid-insensitive
asthma have an acquired form of steroid resistance thought
to be induced by chronic inflammation or immune activa-
tion. Thus, it is important to investigate those factors that
may potentiate the development of functional steroid
resistance so that we might intervene to prevent or reverse
it. It has been proposed that chronic psychological stress,
resulting in prolonged activation of the HPA and SAM
axes, may result in a counterregulatory response in stimu-
lated lymphocytes and consequent downregulation of the
expression and/or function of glucocorticoid receptors
leading to functional steroid resistance.27,28 This in part
may be mediated through downregulation of the gene
coding for the expression of the glucocorticoid receptor
Health care education,
delivery, and quality
(Miller G, personal communication, September 2005).
RELEVANCE OF PERINATAL PHYSIOLOGICAL
PROGRAMMING AND EARLY LIFE STRESS
Studies suggest that characteristics of the in utero envi-
ronment, independent of genetic susceptibility, influence
fetal development, including immune development.29,30
The concept that nongenetic factors act early in life to
organize or imprint physiological systems permanently is
known as perinatal programming. Adverse environmen-
tal influences at critical periods of development (ie, stress)
may be important in this regard. The HPA axis seems par-
ticularly susceptible to early life programming.31 Maternal
and fetal stress stimulates placental secretion of CRH,
which in turn may stimulate the fetal HPA axis to secrete
glucocorticoids, amplifying fetal glucocorticoid excess.
These in utero responses may be adaptive in the short
term (ie, increasing the availability of glucose and other
fuels), geared toward coping with predicted increased en-
vironmental challenges, but they exact a toll in that there is
an increased risk of disease in later life. Moreover, gesta-
tional exposure to maternal stress has been shown to alter
the development of humoral immunocompetence in
offspring as well as their hormonal and immunologic
responses to postnatal stress.32
J ALLERGY CLIN IMMUNOL
DECEMBER 2005
Early childhood environment can also affect these
processes. Studies in both rodents and primates have
shown that environmental manipulations that increase
maternal stress result in elevated cortisol levels and
dysfunctional behaviors in offspring that are evident later
in life, which may be mediated, in part, through effects on
gene expression.33 Numerous retrospective studies in hu-
man HPA functioning suggest that increased reactivity of
the HPA system is associated with early life trauma and
severe deprivation. Studies of infants and toddlers have
linked maternal depression to dysregulation of the child’s
HPA axis in both cross-sectional and longitudinal studies.
Other studies of preschoolers and older children suggest
that children’s cortisol levels are positively correlated
with numerous social stresses and to broader family char-
acteristics known to be associated with higher stress levels
(eg, low socioeconomic status). For example, Essex et al34
examined the relationships of maternal stress beginning in
infancy and concurrent stress on preschoolers’ (age 4.5
years) HPA activity and later mental health outcomes. A
cross-sectional analysis revealed that preschoolers ex-
posed to high levels of concurrent maternal stress had el-
evated cortisol levels. Longitudinal analyses showed that
concurrently stressed children with elevated cortisol also
had a history of high maternal stress exposure in infancy.
Importantly, children exposed only to high levels of con-
current or early stress had cortisol levels that did not
significantly differ from those never exposed to stress.
Also of note, further analysis of the components of stress
indicated that maternal depression beginning in infancy
was the most potent predictor of children’s cortisol.
Preschoolers with high cortisol levels also were more
likely to have greater mental health difficulties in first
grade. Future studies should be designed to examine
whether the link between early stress (specifically mater-
nal stress even starting in pregnancy) and later expression
of asthma/wheeze clinical and immune phenotypes is in
part mediated through dysregulation of the HPA axis.
PSYCHOLOGICAL STRESS AND
OXIDATIVE STRESS
Oxidative stress pathways also play an important role in
the regulation of inflammatory mediators that may be
involved in atopy. Inflammation is frequently mediated
by reactive oxygen species (ROS), either acquired exog-
enously or as byproducts of normal metabolism.
Individuals differ in their ability to deal with oxidant
burdens because of either genetic factors or other
environmental factors that induce or augment oxidative
stress. It has been proposed that differences in host
detoxification provide the basis for either resolution
or progression of inflammation in atopic individuals
and that the inability to detoxify ROS species among
atopic subjects leads to the release of chemotactic factors,
the activation and recruitment of immune effector
cells, prolonged inflammation, and the stimulation of
bronchoconstricting mechanisms.35 Suggested factors that
J ALLERGY CLIN IMMUNOL
VOLUME 116, NUMBER 6
predispose susceptible subjects to allergic inflammation
and asthma include chronic exposure to oxidative toxins
(tobacco smoke, air pollution).36,37
Psychological stress may be an additional environmen-
tal factor that augments oxidative toxicity and increases
airway inflammation. There is evidence that psychological
stress has pro-oxidant properties that augment oxidative
processes. Psychological stress has been noted to decrease
DNA repair and will inhibit radiation-induced apoptosis in
human blood cells, findings suggesting that psychological
stress may increase the likelihood of oxidative stress–
induced pathology. Rats treated with ferric nitrilotriace-
tate, an oxidant, and conditioned to associate treatment
with taste aversion therapy produced increased levels of
8-deoxy-hydroxy-guanosine, a commonly used biomarker
of oxidative stress, with further taste therapy than uncondi-
tioned animals. Perhaps most interestingly with respect to
mechanism, psychological stress has been demonstrated to
increase activity of hepatic enzymes, which activate poly-
cyclic aromatic hydrocarbons in rats. Similarly, chronic
stress has been shown to increase the levels of lipoperox-
ides in rat livers and plasma and decrease levels of reduced
glutathione in erythrocytes and liver. Evidence also sup-
ports the notion that psychological stress modifies the
host response to other inflammatory oxidative toxins.
Recent animal data support a role for an oxidative/antiox-
idative imbalance influencing a shift toward a TH2 pheno-
type in a model of autoimmunity in the rat.38 These studies
have been reviewed elsewhere.13 Given that both tobacco
smoke and air pollution contain toxins that generate ROS
when metabolized, stress may interact with these physical
environmental factors to augment oxidative toxicity, lead-
ing to increased expression of asthma and allergic rhinitis.
GENETICS
Variation in genes involved in immune regulation is
associated with biologic and clinical phenotypes in the first
year of life that may increase risk for the subsequent
development of childhood asthma.39 Moreover, gene-
environment interactions influencing the early patterning
of the immune system and the subsequent development
of asthma have been described in the first year of life. By
considering genetic factors that may be relevant to both
the stress response and atopy, we may better elucidate the
mechanisms underlying the links among stress, the HPA
axis, and HPA-related clinical states (eg, asthma/atopy).
Transient changes in the expression of stress responsive
genes and more prolonged aberrant gene regulation may
lead to maladaptive physiologic and behavioral changes to
influence disease.40 Most advances in our knowledge of
the genetic and molecular events underlying the neurobi-
ology of the stress response have occurred in animal
models. Studies to determine the role of genetics in mod-
ifying the risk of the social/physical environment experi-
enced through psychological stress may further inform
pathways through which stress may affect asthma expres-
sion. Genetic factors of potential import include those that
Wright 1305
influence immune development and airway inflammation
in early life, corticosteroid regulatory genes, adrenergic
system regulatory genes, biotransformation genes, and
cytokine pathway genes.
A recent review summarized studies that address the
question to what extent genetic factors contribute to
interindividual differences in HPA axis activity.40 Studies
demonstrate the influence of genetic factors on variation
in the cortisol awakening response and baseline cortisol
levels in both adults and children.40,41 Variants of the glu-
cocorticoid receptor gene may contribute to interindivid-
ual variability in HPA axis activity and glucocorticoid
sensitivity in response to stress. Additional presumably
good candidates include polymorphisms in the genes cod-
ing for factors involved in the feedback mechanisms in
the glucocorticoid response to stress such as corticotro-
phin-releasing hormone (CRHR1 and CRHR2 genes),
TNF-a, and other cytokine loci. Proinflammatory cyto-
kines (including TNF-a) are considered the principal
messengers between the CNS and immune system in the
biological stress response. Elevated TNF-a can activate
the HPA axis and has been associated with increased
cortisol.42 In chronic stress, more persistently elevated
TNF-a may result in dysregulation of the HPA axis.
Moreover, many effects of TNF-a are mediated by the in-
duction of a cellular state consistent with oxidative stress.43
The influence of stress on physiologic programming
may also vary based on an individual’s genetic back-
ground. This is supported by strain differences in hormo-
nal and behavioral responses to stress in rats and mice. For
example, data suggest that feto-placental 11-b-hydroxys-
teroid dehydrogenase type 2 may play an important
Health care education,
role in modulating the programming effects of prenatal
delivery, and quality
endogenous glucocorticoid exposure.44 Interperson and
interstrain (mouse) variability in the expression and effi-
ciency of feto-placental 11-b-hydroxysteroid dehydro-
genase type 2 has been documented.45,46
Genes expressed in the lung involved in determining
the effects of oxidative stress, specifically the glutathione
S transferases, have been found to be functionally and
clinically significant in recent studies related to atopic
risk. Specific glutathione-S-transferase P1 variants have
been associated with increased histamine and IgE re-
sponses to air pollution oxidants and allergen in vivo.
Maternal genetics related to oxidative stress genes may
influence the child’s atopic risk beginning in utero.47
CONCLUSION
Psychological stress should be conceptualized as a
social pollutant that can be ‘‘breathed’’ into the body and
disrupt several physiological pathways, similar to how air
pollutants and other physical toxicants may lead to
increased risk for atopy. Stress may have independent
effects but also may play a role through the enhancement
of neuroimmune and hypersensitivity responses to other
environmental factors operating through overlapping
pathways.
 1306 Wright
REFERENCES
1. Osler W. The principles and practice of medicine. Edinburgh: YJ Pent-
land; 1892.
2. Cohen S, Kessler R, Underwood GL, editors. Strategies for measuring
stress in studies of psychiatric and physical disorders. In: Measuring
stress: a guide for health and social scientists. New York: Oxford Univer-
sity Press; 1995. p. 3-26.
3. Lazarus RS, Folkman S. Stress, appraisal, and coping. New York:
Springer; 1984.
4. Chrousos GP. Stressors, stress, and neuroendocrine integration of the
adaptive response. The 1997 Hans Selye Memorial Lecture. Ann N Y
Acad Sci 1998;851:311-35.
5. McEwen BS. Protective and damaging effects of stress mediators.
N Engl J Med 1998;338:171-9.
6. Cohen S, Hamrick N. Stable individual differences in physiological
response to stressors: implications for stress-elicited changes in immune
related health. Brain Behav Immun 2003;17:407-14.
7. Cohen S, Frank E, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM Jr.
Types of stressors that increase susceptibility to the common cold in
healthy adults. Health Psychol 1998;17:214-23.
8. Pike JL, Smith TL, Hauger RL, Nicassio PM, Patterson TL, McClintick
J, et al. Chronic life stress alters sympathetic, neuroendocrine, and
immune responsivity to an acute psychological stressor in humans.
Psychosom Med 1997;59:447-57.
9. Rich EL, Romero LM. Exposure to chronic stress downregulates
corticosterone responses to acute stressors. Am J Physiol Regul Integr
Compar Physiol 2005;288:R1628-36.
10. Cohen S, Herbert TB. Psychological factors and physical disease from
the perspective of human psychoneuroimmunology. Ann Rev Psychol
1996;47:113-42.
11. Dantzer R. Innate immunity at the forefront of psychoneuroimmunology.
Brain Behav Immun 2004;18:1-6.
12. Kelley KW. From hormones to immunity: the physiology of immunol-
ogy. Brain Behav Immun 2004;18:95-113.
13. Wright RJ, Cohen RT, Cohen S. The impact of stress on the develop-
ment and expression of atopy. Curr Opin Allergy Clin Immunol 2004;
5:23-9.
14. Wright R, Rodriguez M, Cohen S. Review of psychosocial stress
and asthma: an integrated biopsychosocial approach. Thorax 1998;53:
Health care education,
delivery, and quality
1066-74.
15. Theoharides TC, Donelan JM, Papadopoulou N, Cao J, Duraisamy K,
Conti P. Mast cells as targets of corticotropin-releasing factor and related
peptides. Trends Pharmacol Sci 2004;25:563-8.
16. Undem BJ, Kajekar R, Hunter DD, Myers AC. Neural integration and
allergic disease. J Allergy Clin Immunol 2000;106:S213-20.
17. Bienenstock J, Goetzl EJ, Blennerhassett MG, editors. Autononic neuro-
immunology. New York: Taylor & Francis; 2003.
18. Tracey KJ. The inflammatory reflex. Nature 2002;420:853-9.
19. Chen CY, Bonham AC, Schlelegle ES, Gershwin LJ, Plopper CG,
Joad JP. Extended allergen exposure in asthmatic monkeys induces
neuroplasticity in nucleus tractus solitarius. J Allergy Clin Immunol
2001;108:557-62.
20. Chen C-Y, Bonham AC, Plopper CG, Joad JP. Plasticity in respiratory
motor control, selected contribution: neuroplasticity in nucleus tractus
solitarius neurons after episodic ozone exposure in infant primates.
J Appl Physiol 2003;94:819-27.
21. Bonham AC, Sekizawa SI, Joad JP. Plasticity of central mechanisms for
cough. Pulm Pharmacol Ther 2004;17:469-70.
22. Wright RJ, Cohen S, Carey V, Weiss ST, Gold DR. Parental stress
as a predictor of wheezing in infancy: a prospective birth-cohort study.
Am J Respir Crit Care Med 2002;165:358-65.
23. Wright RJ, Finn PW, Contreras JP, Cohen S, Wright RO, Staudenmayer
J, et al. Chronic caregiver stress and IgE expression, allergen-induced
proliferation, and cytokine profiles in a birth-cohort predisposed to atopy.
J Allergy Clin Immunol 2004;113:1051-7.
24. von Hertzen LC. Maternal stress and T-cell differentiation of the devel-
oping immune system: possible implications for the development of
asthma and atopy. J Allergy Clin Immunol 2002;109:923-8.
25. Buske-Kirschbaum A, Fischbach S, Rauh W, Hanker J, Hellhammer D.
Increased responsiveness of the hypothalamus-pituitary-adrenal (HPA)
J ALLERGY CLIN IMMUNOL
DECEMBER 2005
axis to stress in newborns with atopic disposition. Psychoneuroendo-
crinology 2004;29:705-11.
26. Wamboldt MZ, Laudenslager M, Wamboldt FS, Kelsay K, Hewitt J.
Adolescents with atopic disorders have an attenuated cortisol response
to laboratory stress. J Allergy Clin Immunol 2003;111:509-14.
27. Miller GE, Cohen S, Ritchey AK. Chronic psychological stress and the
regulation of pro-inflammatory cytokines: a glucocorticoid-resistance
model. Health Psychol 2002;21:531-41.
28. Chrousos GP, Castro M, Leung DY, Webster E, Kino T, Bamberger C,
et al. Molecular mechanisms of glucocorticoid resistance/hypersen-
sitivity: potential clinical implications. Am J Respir Crit Care Med
1996;154:S39-43, discussion S44.
29. Gluckman PD, Cutfield W, Hofman P, Hanson NA. The fetal, neonatal,
and infant environments—the long-term consequences for disease risk.
Early Hum Dev 2005;81:51-9.
30. Shanks N, Lightman SL. The maternal-neonatal neuro-immune interface:
are there long-term implications for inflammatory or stress-related
disease? J Clin Invest 2001;108:1667-73.
31. Welberg L, Seckl J. Prenatal stress, glucocorticoids and the programming
of the brain. J Neuroendocr 2001;17:113-28.
32. Barker DJ. A new model for the origins of chronic disease. Med Health
Care Philos 2001;4:31-5.
33. Meaney MJ, Szyf M. Maternal care as a model for experience-dependent
chromatin plasticity? Trends Neurosci 2005;28:456-63.
34. Essex MJ, Klein MH, Cho E, Kalin NH. Maternal stress beginning in
infancy may sensitize children to later stress exposure: effects on cortisol
and behavior. Biol Psychiatry 2002;52:776-84.
35. Spiteri MA, Bianco A, Strange RC, Freyer AA. Polymorphisms at the
glutathione S-transferase, GSTP1 locus: a novel mechanism for suscepti-
bility and development of atopic airway inflammation. Allergy 2000;55:
15-20.
36. Donaldson K, Gilmour MI, MacNee W. Asthma and PM10. Respir Res
2000;1:12-5.
37. Zhou JF, Yan XF, Guo FZ, Sun NY, Qian ZJ, Ding DY. Effects of cigarette
smoking and smoking cessation on plasma constituents and enzyme activ-
ities related to oxidative stress. Biomed Environ Sci 2000;13:44-55.
38. Wu Z, Holwill SD, Oliveira DB. Desferrioxamine modulates chemically
induced T helper 2-mediated autoimmunity in the rat. Clin Exp Immunol
2004;135:194-9.
39. Hoffjan S, Ostrovnaja I, Nicolae D, Newman DL, Nicolae R, Gnagnon
R, et al. Genetic variation in immunoregulatory pathways and atopic
phenotypes in infancy. J Allergy Clin Immunol 2004;113:511-8.
40. Wust S, Federenko IS, van Rossum EF, Koper JW, Kumsta R, Entringer
S, et al. A psychobiological perspective on genetic determinants of hypo-
thalamus-pituitary-adrenal axis activity. Ann N Y Acad Sci 2004;1032:
52–62.
41. Wust S, Van Rossum EF, Federenko IS, Koper JW, Kumsta R,
Hellhammer DH. Common polymorphisms in the glucocorticoid
receptor gene are associated with adrenocortical responses to psycho-
social stress. J Clin Endocrinol Metab 2004;89:565-73.
42. Fukata J, Imura H, Nakao K. Cytokines as mediators in the regulation of
the hypothalamic-pituitary-adrenocortical function. J Endocrinol Invest
1993;16:141-55.
43. Glosli H, Tronstad KJ, Wergedal H, Muller F, Svardal A, Aukrust P, et al.
Human TNF-alpha in transgenic mice induced differential changes in
redox status and glutathione-regulating enzymes. FASEB 2002;16:
1450-2.
44. Seckl J. Glucocorticoids, feto-plaental 11-beta-hydroxysteroid dehydro-
genase type 2, and the early life origins of adult disease. Steroids
1997;62:89-94.
45. Stewart P, Rogerson F, Mason J. Type 2, 11beta-hydroxysteroid
dehydrogenase messenger RNA and activity in human placenta and
fetal membranes: its relationship to birth weight and putative role in fetal
steroidogenesis. J Clin Endocrinol Metab 1995;80:885-90.
46. Benediktsson R, Lindsay R, Noble J, Seckl J, Edwards C. Glucocorticoid
exposure in utero: a new model for adult hypertension. Lancet 1993;341:
339-41.
47. Child F, Lenney W, Clayton S, Davies S, Jones PW, Alldersea JE, et al.
The association of maternal but not paternal genetic variation in GSTP1
with asthma phenotypes in children. Respir Med 2003;97:1247-56.