Stress and Atopic Disorders: Asthma and the Seasonal Allergic Response
Rosalind J. Wright, M D MPH
Sheldon Cohen, PhD
Upon completion of this Cyberounds®, the participant should be able to:
• Define atopy and give examples of three associated clinical disorders
• Describe the effects of stress on neuroimmunoregulation and the consequent
modulation of the hypersensitivity response
• Describe the pathophysiology of chronic stress and effects on the HPA
• Describe local pulmonary interactions between the immune system and autonomic
nervous system in the response to stress
• Describe relationships between psychological stress and oxidative stress
• Describe the potential role of stress and glucocorticoid resistance in asthma
• Describe genetic modification of the risks of psychological stress and asthmatic
• Discuss treatment strategies for modifying the relationship between stress and the
Atopy can be considered a genetically and environmentally determined predisposition to a
number of clinically expressed disorders including allergic rhinitis (AR), atopic dermatitis (AD)
or eczema, and allergic asthma (AA) regulated through immune phenomena in which many
cells (i.e., mast cells, eosinophils, and T lymphocytes) and associated cytokines, chemokines
and neuropeptides play a role. Overlapping mechanisms of inflammation central to the
pathophysiology of these atopic disorders involve a cascade of events that include the release
of immunologic mediators triggered by both immunoglobulin E (IgE)-dependent and
-independent mechanisms. Biological hypersensitivity to environmental stimuli is a
fundamental feature of atopic disorders. Increasingly, atopy has been conceptualized as an
epidemic of dysregulated immunity 1. The exploration of host and environmental factors that
may alter immune expression and potentiate the expression of atopic disorders is an active
area of research.
Mechanisms linking psychological stress, personality, and emotion to neuroimmunoregulation
as well as increased risk of atopy have been increasingly elucidated. Hormones and
neuropeptides released into the circulation when individuals experience stress are thought to
be involved in regulating both immune-mediated and neurogenic inflammatory processes 2,3.
Dysregulation of normal homeostatic neural, endocrine, and immunologic mechanisms can
occur in the face of chronic stress leading to chronic hyperarousal and/or hyporesponsiveness
that may impact atopic disease expression 4,5,6. This Cyberounds® will discuss our
understanding of the role of psychological stress in 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 similar pathways.
Q1. Biological hypersensitivity to environmental stimuli is a fundamental feature of atopy
predisposing to a number of clinically expressed disorders including allergic rhinitis (AR),
atopic dermatitis (AD) or eczema, and allergic asthma (AA).
Psychological Stress and the Endocrine System
Psychological stress has been associated with the activation of the sympathetic and
adrenomedullary (SAM) system and the hypothalamic-pituitary-adrenocortical (HPA) axis (as
discussed in previous Cyberounds®, the nervous system is the interpreter of which events are
"stressful" and determines the behavioral and physiological responses to the stressor).
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. It is the disturbed balance of these
systems that is relevant to disease. Immune, metabolic, and neural defensive biological
mechanisms important for the short-term response to stress, may produce long term damage
if not checked and eventually terminated. The potential detrimental cost of such
accommodation to stress has been conceptualized as allostatic load, (i.e. wear-and-tear from
chronic under- or overactivity of the allostatic system)5. For example, shifts in the circadian
rhythm of cortisol have been found among persons under chronic stress7.
A number of altered neuroendocrine and immune changes in response to stress have been
demonstrated in subjects with AD, i.e., altered responsiveness of the HPA axis and the SAM
system8, increased eosinophil counts and elevated IgE expression9. More recently increased
responsiveness of the HPA axis in response to a heel prick stressor in newborns with a family
history of atopy or elevated levels of cord blood IgE has been demonstrated10. Whether the
altered HPA responsiveness will lead to increased risk of developing atopy in later life remains
to be seen.
Allergen-mediated inflammation with T lymphocyte activation is central to the allergic
asthmatic response11. In one working paradigm T-helper (Th) cells have been phenotypically
divided into two profiles of differentiated cell function having different profiles of cytokine
release upon activation (e.g., Th1 and Th2)12. Th1 cells tend to express interleukin-2 (IL-2)
and interferon gamma (IFN-() and Th2 cells tend to express IL-4, IL-5, and IL-1313. Allergy
and asthma expression may also be influenced by cytokines produced through pathways or
inflammatory processes not necessarily directly related to the TH1:Th2 dichotomy14. For
example, some proteins are secreted both by Th1 and Th2 cells [e.g., tumor necrosis factor
alpha (TNF-∀)]. Studies suggest that TNF-∀, produced by both lymphocytes and
macrophages, is involved in the atopic response15,16. Activation of Th2 lymphocytes
underlying allergen sensitization is associated with increased IgE production through release of
Th2 cytokines17. Seroepidemiological studies have shown an association between increased
total IgE levels in early childhood and allergic asthma which increases in magnitude and
significance over the first four to six years of life18.
Recent animal data suggest that increased maternal stress prenatally is associated with an
elevated cortisol response to stress in the newborn affecting Th1 /Th2 cell differentiation 19.
While the ability to activate an increase 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 developmental stage20. Chronic stress may induce a state of hyporesponsiveness of the
HPA axis whereby cortisol secretion is attenuated, leading to increased secretion of
inflammatory cytokines typically counterregulated by cortisol. A state of stress induced HPA
hypo responsiveness has been demonstrated in some research subjects with chronic
inflammatory disorders21 including atopic disorders22. 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 individuals. Further studies are needed to examine relationships between
individual patterns of cortisol response to stress across different developmental periods and
the subsequent expression of atopy.
Other regulatory pituitary (i.e., corticotrophin) and hypothalamic hormones [i.e.,
corticotrophin releasing hormone, (CRH ) and arginine vasopressin (AVP)] of the HPA axis
have systemic immunopotentiating and proinflammatory effects23. For example, acute
psychological stress (for example, immobilization in rats) results in skin mast cell
degranulation, an effect inhibited by anti-CRH serum administered prior to stress 24. Mast-cell
mediators, in turn, are responsible for many of the immediate symptoms of nasal allergy and
manifestations of atopic dermatitis. Mechanisms linking stress and mast cell function have
been extensively reviewed recently25. Although hormones of the sympathetic and adrenal
medullary and HPA systems are those most often discussed as the biological substances
involved in stress responses, alterations in a range of other hormones, neurotransmitters, and
neuropeptides found in response to stress may also play a part in the health effects of stress
and need to be further studied. For example, stressor-associated increases in growth
hormone and prolactin secreted by the pituitary gland and in the natural opiate beta-
endorphins and enkephalins released in the brain are also thought to play a role in immune
Q2. Shifts in the circadian rhythm of the HPA axis may influence the expression of atopic
Q3. Chronic stress may induce a state of imbalance of the HPA axis whereby cortisol secretion
is attenuated or increased, leading to increased secretion of inflammatory cytokines typically
counterregulated by an optimal level of cortisol in the body.
Stress and Autonomic Control of Airways
The balance between functional parasympathetic and functional sympathetic activity in
relation to stress, emotional stimuli, and immune function may also be important for the
expression of asthma and allergic rhinitis. Local interactions between the immune system
and the autonomic nervous system are only partially understood27. Increased activity of the
parasympathetic nervous system was once thought to be the dominant mechanism
responsible for the exaggerated reflex bronchoconstriction (airway narrowing) that occurs in
asthmatic subjects, although more recent work challenges this idea28. In the initial phases,
narrowing of the airways in asthma is thought to result primarily from inflammation. Evidence
suggesting a number of cholinergic anti-inflammatory pathways triggered through vagus nerve
activation including inhibition of macrophages and secretion of TNF-alpha29 complicate our
understanding and need to be explored in the context of atopy.
More recent evidence demonstrating nerve-mast cell communication 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 asthma30. Tachykinins derived from e-
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 inflammation31 and regulation of stress hormonal pathways32 as well
as being implicated in asthma33,34 and neurogenic skin disorders35. Recent data from a mouse
model suggested that stress-induced airway hyperreactivity and enhanced allergic
inflammation (OVA sensitization) was mediated by tachykinins36.
Stress and Immune Function
Atopic inflammation is thought to be orchestrated by activated T-lymphocytes and the
cytokines they produce. The T helper cell Th-2 cytokine phenotype promotes IgE production,
with subsequent recruitment of inflammatory cells that may initiate and/or potentiate allergic
inflammation6. For most children who become allergic or asthmatic, the polarization of their
immune system into an atopic phenotype probably occurs during early childhood37.
These findings have sparked vigorous investigation into the potential influence 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 between birth and one year38. This relationship led to speculation that
stress may trigger hormones in the early months of life which may in turn influence Th-2 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 expression, mitogen- and allergen-specific lymphocyte proliferative response,
and subsequent cytokine expression (INF-(, TNF-∀, IL-10, and IL-13) was carried out in the
same prospective birth-cohort mentioned above when the children were 2-3 years of age39.
In adjusted analyses, higher caregiver stress in the first 6 months after birth was associated
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-∀ and reduced
This sort of pattern deviates from the working Th1/Th2 paradigm. These data suggested to us
that although the Th1-Th2 paradigm remains an important functional dichotomy to consider
when interpreting quantitative differences in cytokine expression in response to environmental
stimuli like stress, examination of other mechanisms (e.g., oxidative stress pathways, innate
immune factors, neural-immune interactions) or a broader range of cytokines produced by
cells both within and outside the immune system may better delineate the true complexity of
the underlying mechanisms linking stress to allergic sensitization and asthma. Overlapping
evidence points to some other mechanisms as discussed in the remainder of these
Stress and Glucocorticoid Resistance
An alternative hypothesis linking stress, neuroendocrine and immune function and
inflammatory disease expression considers a glucocorticoid resistance model40. As we have
come to understand the central role of airway inflammation and immune activation in asthma
pathogenesis, asthma treatment guidelines have focused on the use of anti-inflammatory
therapy, particularly oral and inhaled glucocorticoids or steroids. Asthmatics, however, have a
variable response to glucocorticoid therapy41. Although the majority of patients readily
respond, a subset of patients have difficult to control asthma even when treated with high
doses of oral steroids. Our current understanding of the cellular and molecular mechanisms
underlying steroid resistance in asthma and other inflammatory diseases have been recently
reviewed42. 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 activation. 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. For example, studies have shown that allergen exposure
effects glucocorticoid receptor binding affinity in T lymphocytes from atopic asthmatics43. 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 stimulated lymphocytes and
consequent downregulation of the expression and/or function of glucocorticoid receptors
leading to functional steroid resistance40.
Psychological Stress and Oxidative Stress
Another possible mechanism linking stress to atopy and asthma is through oxidative stress
pathways. A central feature of inflammation is that it is frequently mediated by reactive
oxygen species (ROS), either acquired exogenously or as byproducts of normal metabolism.
Individuals differ in their ability to deal with oxidant burdens, either due to 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 once exposed to an environmental trigger. It has been
speculated 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 mechanisms44. Suggested
factors which predispose susceptible subjects to allergic inflammation and asthma include
chronic exposure to oxidative toxins (tobacco smoke, air pollution). An extension of the
oxidative stress hypothesis is that psychological stress may be an additional environmental
factor that augments oxidative toxicity and increases airway inflammation.
There is evidence that psychological stress has pro-oxidant properties that augments oxidative
processes45,46,47. Irie and colleagues 48 used classical conditioning to illustrate the role of
chronic stress and oxidative damage. In these experiments, rats treated with ferric
nitrilotriacetate, an oxidant, and conditioned to associated treatment with taste aversion
therapy, had increased 8-OhdG with further taste therapy than unconditioned animals.
Evidence also supports the notion that psychological stress modifies the host response to
other inflammatory oxidative toxins49,50,51,52. Recent animal data support a role for
oxidative/antioxidative imbalance influencing a shift toward a Th2 phenotype in a model of
autoimmunity in the rat53.
Environmental exposures that may interact with stress through these pathways include air
pollution and tobacco smoke. While epidemiologic evidence suggests that asthma symptoms
can be worsened by air pollution, air pollution has not been clearly associated with increased
risk of sensitization and induction of disease54. Several investigators have suggested that the
ability of air pollution to generate reactive oxidative species may explain its role in asthma and
other respiratory diseases55,56,57. Ultrafine particles (<0.1 micron in diameter) have been
demonstrated to increase oxidatively mediated inflammation in the lungs of rats58,59. In vitro
studies demonstrate that PM10 is responsible for the production and release of inflammatory
cytokines by the respiratory tract epithelium as well as the activation of the transcription
factor NF kappa B and that these properties are mediated by the production of reactive
oxygen species59. Air pollution contains other oxidative toxins, such as reactive quinones and
polycyclic aromatic hydrocarbons57. Tobacco smoke also contains a number of compounds with
oxidative potential, at least 50 of which are pro-carcinogens60. These include polycyclic
aromatic hydrocarbons (PAH)60,61,62. Elevated levels of biomarkers linked to oxidative stress
have been found among smokers relative to nonsmokers63,64. Young children are exposed to
environmental tobacco smoke have increased levels of 8-OhdG, a biomarker of oxidative
toxicity in infants65. Factors which produce oxidative stress (including psychological stress)
are likely to be synergistic in their effects on adverse health outcomes49. Given that both
tobacco smoke and air pollution contain toxins metabolized by enzymatic biotransformation to
generate ROS, stress may interact with these exposures to augment oxidative toxicity leading
to increased expression of asthma and allergic rhinitis6.
Q4. The effects of environmental toxins (air pollution, tobacco smoke) on atopy and asthma
may be mediated by the common pathway of oxidative stress, a process that may be
potentiated by chronic psychological stress.
Most advances in our knowledge of the genetic and molecular events underlying the
neurobiology of the stress response have occurred in animal models 66. These animal data
together with the preliminary discussions started above suggest that studies to determine the
role of genetics in modifying the risk of the social/physical environment experienced through
psychological stress may further inform pathways through which stress may impact asthma
expression. Genetic factors of potential import include those that 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 activity67. A number of studies
demonstrate the influence of genetic factors on variation in the cortisol awakening response 68
and baseline cortisol levels in both adults69 and children70. Other studies strongly suggest that
genetic factors contribute to variability in cortisol 71. Variants of the glucocorticoid receptor
(GR) gene may contribute to interindividual variability in HPA axis activity and glucocorticoid
sensitivity in response to stress72,73. In a recent study examining the impact of the three GR
gene polymorphisms, BclI, N363S, and ER22/23EK on cortisol response to psychosocial stress,
Wust et al.74 found that compared to subjects with the wild-type GR genotype (i.e., BclI CC
and N363S AA, n = 36), 363S allele carriers showed significantly increased salivary cortisol
responses to stress, whereas the BclI genotype GG was associated with a diminished cortisol
response. Additional presumably good candidates include polymorphisms in the genes coding
for factors involved in the feedback mechanisms in the glucocorticoid response to stress such
as corticotrophin-releasing hormone (CRHRI and CRHR2) 75,76 tumor necrosis factor alpha
(TNF-alpha),77 and other cytokine loci. Studies suggest that TNF-∀ is involved in the atopic
response15,16. In addition, genetic polymorphisms of the TNF-alpha promoter region have been
linked to differential risk for asthma78. Pro-inflammatory cytokines (including TNF-∀) are
considered the principal messengers between the central nervous system (CNS) and immune
system in the biological stress response. Elevated TNF-∀ can activate the HPA axis79 and has
been associated with increased cortisol. In chronic stress, more persistently elevated TNF-∀
may result in dysregulation of the HPA axis80, which may in turn play a role in the
development of childhood asthma. Moreover, many effects of TNF-∀ are mediated by the
induction of a cellular state consistent with oxidative stress 81. A recent study examined
polymorphisms of the TNF-alpha promoter region (TNF-∀308G/A) and linked specific variants
to increased C-reactive protein (CRP), a proinflammatory marker 82. By considering genetic
factors that may be relevant to both the stress response and asthma, we may better elucidate
the mechanisms underlying the link between stress, the HPA axis, and HPA-related clinical
states (e.g., asthma/atopy).
Genes expressed in the lung involved in determining the effects of oxidative stress, specifically
the glutathione S tranferases, have been found to be functionally83 and clinically84,85 significant
in recent studies related to atopic risk. Specific GSTP1 variants have been associated with
increased histamine and IgE responses to air pollution oxidants and allergen in vivo86.
Maternal genetics related to oxidative stress genes may influence the child’s atopic risk
beginning in utero87. The fetal immune response is influenced prenatally;88. Seasonal
sensitization of cord blood mononuclear cells to pollens has been demonstrated89,90.
Stress and Dysbiosis
Recently there has been growing interest in the integrity of the indigenous microflora of the
gastrointestinal tract in early life and the relationship to atopic disorders. Epidemiological and
clinical studies suggest that non-pathogenic microbes including Lactobacillus in the gut play a
role in the maturation of the immune system toward a nonatopic phenotype91. Intestinal
dysbiosis, or alterations in the integrity of indigenous microflora in the GI tract is now believed
to be a contributing factor to atopic diseases among others92. Factors including antibiotics,
psychological and physical stress, and dietary components have been found to contribute to
intestinal dysbiosis. A number of prospective intervention studies modifying the gut flora from
birth have yielded results supporting the notion that this may be a promising approach to
primary prevention of atopy in the future 93,94,95. Studies have shown that psychological and
physical stress may disrupt the normal balance of intestinal microflora that may contribute to
later disease. A recent experiment showed that separation of infant monkeys from their
mothers, a psychological stressor, was associated with a significant decrease in protective
fecal flora, particularly Lactobacilli96. This same group demonstrated that this influence may
begin even before birth documenting alteration in the intestinal microflora in newborn and
infant monkeys when their mothers were exposed to an acoustical startle stress paradigm
Evidence suggests that shifts in the population dynamics of enteric bacteria can be modulated
by psychological stress. Stress results in increased bacterial adherence and decreased luminal
lactobacilli in the gut98. These data suggest another pathway through which stress may be
operating to influence risk for atopy.
Insights from Psychological Intervention Studies
Clinical studies demonstrating the efficacy of alternative modalities that reduce stress and
alter mood states in treating atopic disorders add further support to the hypothesized link with
stress99 and suggest alternative treatment approaches. These have been reviewed
elsewhere100. The mind-body paradigm linking psychological stress and affective states to
asthma morbidity provides a useful framework to explore plausible mechanisms through which
psychological interventions may be operating101.
Evidence from overlapping research buttresses the notion that psychological interventions
aimed to reduce stress and modify mood states influence asthma expression. Studies have
demonstrated that the relaxation response is related to decrease in negative affective states,
sympathetic nervous system activity, immune function, and circulating cortisol levels in
healthy adult subjects102,103 . A meta-analysis of clinical outcome studies of autogenic training
and asthma demonstrated effects on mood states, cognitive performance, and physiological
variables104. A recent meta-analysis provides the most thorough review of the evidence
linking a range of psychological interventions to modulation of the human immune response20.
These authors found the most consistent evidence for hypnotic suggestion and conditioning
interventions being linked to immune modulation.
Although the Th1-Th2 paradigm remains an important functional dichotomy to consider when
interpreting quantitative differences in cytokine expression in response to environmental
stimuli like stress, examination of other mechanisms (e.g., oxidative stress pathways, neural-
immune interactions, intestinal dysbiosis) or a broader range of cytokines and neuropeptides
produced by cells both within and outside the immune system may better delineate the true
complexity of the underlying mechanisms linking stress to allergic sensitization and asthma.
Psychological stress should be conceptualized as a social pollutant which can be ‘breathed’ into
the body and disrupt a number of 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 responses to other
environmental factors operating through similar pathways.
1. Umetsu DT, McIntire JJ, Akbari O, Macaubas C, DeKruyff RH. Asthma: an epidemic of
dysregulated immunity. Nature Immunology. 2002;3:715-20.
2. Wright R, Rodriguez M, Cohen S. Review of psychosocial stress and asthma: an integrated
biopsychosocial approach. Thorax. 1998;53:1066-1074.
3. Cohen S. Social Relationships and Health. American Psychologist. 2004:676-684.
4. Ader R, Cohen N, Felten D. Psychoneuroimmunology: interations between the nervous system
and the immune system. The Lancet. 1995;345:99-102.
5. McEwen BS. Protective and damaging effects of stress mediators. New England Journal of
6. Wright RW, Cohen RT, Cohen S. The impact of stress on the development and expression of
atopy. Current Opinions in Allergy and Clinical Immunology. 2004;5:23-9.
7. Ockenfels MC, Porter L, Smyth J, Kirschbaum C, Hellhammer DH, Stone AA. Effect of chronic
stress associated with unemployment on salivary cortisol: overall cortisol levels, diurnal rhythm,
and acute stress reactivity. Psychosomatic Medicine. 1995;57:460-467.
8. Buske-Kirschbaum A, Geiben A, Hollig H, Morschhauser E, Hellhammer D. Altered
responsiveness of the hypothalamus-pituitary-adrenal axis and the sympathetic adrenomedullary
system to stress in patients with atopic dermatitis. J Clin Endocrinol Metab. 2002;Sep;87:4245-51.
9. Buske-Kirschbaum A, Gierens A, Hollig H, Hellhammer DH. Stress-induced immunomodulation
is altered in patients with atopic dermatitis. J Neuroimmunol. 2002;129:161-7.
10. Buske-Kirschbaum A, Fischbach S, Rauh W, Hanker J, Hellhammer D. Increased responsiveness
of the hypothalamus-pituitary-adrenal (HPA) axis to stress in newborns with atopic disposition.
11. Donovan CE, Finn PW. Immune mechanisms of childhood asthma. Thorax. 1999;54:938-946.
12. Romagnani S. Human TH1 and TH2 subsets: regulation of differentiation and the role in
protection and immunopathologies. International Archives of Allergy and Immunology.
13. Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunology Today. 1991;12:256-7.
14. Mosman TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunology
15. Kim MH, Agrawal DK. Effect of interleukin-1 beta and tumor necrosis factor-alha on the
expression of G-proteins in CD4+ T-cells of atopic asthmatic subjects. Journal of Asthma.
16. Halasz A, Cserhati E, Magyar R, Kovacs M, Cseh K. Role of TNF-alpha and its 55 and 75 kDa
receptors in bronchial hyperreactivity. Respiratory Medicine. 2002;96:262-7.
17. Robinson D, Hamid Q, Bentley A, Ying S, Kay AB, Durham SR. Activation of CD4+ T cells,
increased TH2-type cytokine mRNA expresion, and eosinophil recruitment in bronchoalveolar
lavage after allergen inhalation challenge in patients with atopic asthma. Journal of Allergy &
Clinical Immunology. 1993;92:313-24.
18. Burrows B, Martinez FD, Cline MG, Lebowitz MD. The relationship between parental and
children's serum IgE and asthma. American Journal of Respiratory and Critical Care Medicine.
19. von Hertzen LC. Maternal stress and T-cell differentiation of the developing immune system:
possible implications for the development of asthma and atopy. J Allergy Clin Immunol.
20. Miller GE, Cohen S. Psychological Interventions and the Immune System: A Meta-Analytic
Review and Critique. Health Psychology. 2001;20:47-63.
21. Buske-Kirschbaum A, Jobst S, Wustmans A, Kirschbaum C, Rauh W, Hellhammer D. Attenuated
free cortisol response to psychosocial stress in children with atopic dermatitis. Psychosomatic
22. 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.
23. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. New
England Journal of Medicine. 1995;332:1351-1362.
24. Theoharides TC, Singh LK, Boucher W, Pang X, Letourneau R, Webster E, Chrousos G.
Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular
permeability, a possible explanation for its proinflammatory effects. Endocrinology.
25. 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 Sciences.
26. Rabin BS, Cohen S, Ganguli R, Lysle DT, Cunnick JE. Bidirectional interaction between the
central nervous system and the immune system. Critical Reviews in Immunology. 1989;9:279-312.
27. Undem BJ, Weinreich D. Neuroimmune interactions in the lung. In: Bienenstock J, Goetzle EJ,
Blennerhassett MG, eds. Autonomic neuroimmunology. New York: Taylor & Francis;
28. Barnes PJ, Baraniuk JN, Belvisi MG. Neuropeptides in the respiratory tract. American Review of
Respiratory Disease. 1991;144:1187-1198;1391-1399.
29. Tracey KJ. The inflammatory reflex. Nature. 2002;420:853 - 859.
30. van der Kleij HPM, Blennerhassett MG, Bienenstock J. Nerve-mast cell interactins-partnership in
health and disease. In: Bienenstock J, Goetzl JE, Blennerhassett MG, eds. Autonomic
neuroimmunology. New York: Taylor & Francis; 2003:139-70.
31. Weinstock JV. Substance P and the immune system. New York: Taylor & Francis, Inc.; 2003.
32. Jessop DS, Renshaw D, Larsen PJ, Chowdrey HS, Harbuz MS. Substance P is involved in
terminating the hypothalamo-pituitary-adrenal axis response to acute stress through centrally
located neurokinin-1 receptors. Stress. 2000;3:209-20.
33. Ichinose M, Miura M, Yamauchi H, Kageyama N, Tomaki M, Oyake T, Ohuchi Y, Hida W, Miki
H, Tamura G, Shirato K. A neurokinin 1-receptor antagonist improves exercise-induced airway
narrowing in asthmatic patients. American Journal of Respiratory & Critical Care Medicine.
34. Tomaki M, Ichinose M, Miura M, Hirayama Y, Yamauchi H, Nakajima N, Shirato K. Elevated
substance P content in induced sputum from patients with asthma and patients with chronic
bronchitis. American Journal of Respiratory & Critical Care Medicine. 1995;151:613-17.
35. Singh LK, Boucher W, Pang X, Letourneau R, Seretakis D, Green M, Theoharides TC. Potent
mast cell degranulation and vascular permeability triggered by urocortin through activation of
corticotropin-releasing hormone receptors. Journal of Pharmacology & Experimental
36. Joachim RA, Sagach V, Quarcoo D, Dinh QT, Arck PC, Klapp BF. Neurokinin-1 receptor
mediates stress-exacerbated allergic airway inflammation and airway hyperresponsiveness in
mice. Psychosom Med. 2004;66:564-71.
37. Yabuhara A, Macaubas C, Prescott SL. Th-2 polarised immunological memory to inhalant
allergens in atopics is established during infancy and early childhood. Clinical & Experimental
38. Wright RJ, Cohen S, Carey V, Weiss ST, Gold DR. Parental stress as a predictor of wheezing in
infancy: A prospective birth-cohort study. American Journal of Respiratory & Critical Care
39. Wright RJ, Finn PW, Contreras JP, Cohen S, Wright RO, Staudenmayer J, Wand M, Perkins DL,
Weiss ST, Gold DR. Chronic caregiver stress and IgE expression, allergen-induced proliferation,
and cytokine profiles in a birth-cohort predisposed to atopy. The Journal of Allergy and Clinical
40. Miller GE, Ritchey AK, Cohen S. Chronic psychological stress and regulation of pro-
inflammatory cytokines: A glucocorticoid-resistance model. Health Psychology. 2002;21:531-41.
41. Lee TH, Brattsand R, Leung DYM. Corticosteroid action and resistance in asthma. American
Journal of Respiratory Cellular and Molecular Biology. 1996;154:S1-S79.
42. Leung DYM. Update on glucocorticoid action and resistance. Journal of Allergy & Clinical
43. Nimmagadda S, Spahn J, Surs W, Szefler S, Leung D. Allergen exposure decreases glucocorticoid
receptor binding affinity and steroid responsiveness in atopic asthmatics. American Journal of
Respiratory & Critical Care Medicine. 1997;155:97-93.
44. Spiteri MA, Bianco A, Strange RC, Freyer AA. Polymorphisms at the glutathione S-transferase,
GSTP1 locus: a novel mechanism for susceptibility and development of atopic airway
inflammation. Allergy. 2000;55:15-20.
45. Adachi S, Kawamura K, Takemoto K. Oxidative damage of nuclear DNA in liver of rats exposed
to psychological stress. Cancer Research. 1993;53:4153-5.
46. Kosugi H, Enomoto H, Ishizuka Y, Kikugawa K. Variations in the level of urinary thiobarbituric
acid reactant in healthy humans under different physiological conditions. Biological &
Pharmaceutical Bulletin. 1994;17:1645-50.
47. Tomei LD, Kiecolt-Glaser JK, Kennedy S, Glaser R. Psychological stress and phorbol ester
inhibition of radiation-induced apoptosis in human peripheral blood leukocytes. Psychiatry
48. Irie M, Asami S, Nagata S, Miyata M, Kasai H. Classical conditioning of oxidative DNA damage
in rats. Neuroscience Letters. 2000;288:13-6.
49. Moller P, Wallin H, Knudsen LE. Oxidative stress associated with exercise, psychological stress
and life-style factors. Chemico-Biological Interactions. 1996;102:17-36.
50. Capel ID. The effect of isolation stress on some hepatic drug and carcinogen metabolising
enzymes in rats. Journal of Environmental Pathology & Toxicology. 1980;4:337-44.
51. Capel ID, Dorrell HM, Smallwood AE. The influence of cold restraint stress on some components
of the antioxidant defence system in the tissues of rats of various ages. Journal of Toxicology &
Environmental Health. 1983;11:425-36.
52. Chen D, Cho SI, Chen C, Wang X, Damokosh AI, Ryan L, Smith TJ, Christiani DC, Xu X.
Exposure to benzene, occupational stress, and reduced birth weight. Occupational and
Environmental Medicine. 2000;57:661-7.
53. Wu Z, Holwill SD, Oliveira DB. Desferrioxamine modulates chemically induced T helper 2-
mediated autoimmunity in the rat. Clinical & Experimental Immunology. 2004;135:194-9.
54. Peden DB. Air pollution in asthma: effect of pollutants on airway inflammation. Annals of
Allergy, Asthma, & Immunology. 2001;87:12-17.
55. Prahalad AK, Inmon J, Dailey LA, Madden MC, Ghio AJ, Gallagher JE. Air pollution particles
mediated oxidative DNA base damage in a cell free system and in human airway epithelial cells in
relation to particulate metal content and bioreactivity. Chemical Research in Toxicology.
56. Ghio AJ, Carter JD, Richards JH, Crissman KM, Bobb HH, Yang F. Diminished injury in
hypotransferrinemic mice after exposure to a metal-rich particle. American Journal of Physiology
- Lung Cellular & Molecular Physiology. 2000;278:L1051-61.
57. Donaldson K, Gilmour MI, MacNee W. Asthma and PM10. Respiratory Research. 2000;1:12-15.
58. Oberdorster G. Pulmonary effects of inhaled ultrafine particles. International Archives of
Occupational & Environmental Health. 2001;74:1-8.
59. Baeza-Squiban A, Bonvallot V, Boland S, Marano F. Airborne particles evoke an inflammatory
response in human airway epithelium. Activation of transcription factors. Cell Biology &
60. Ford JG, Li Y, O'Sullivan MM, Demopoulos R, Garte S, Taioli E, Brandt-Rauf PW. Glutathione
S-transferase M1 polymorphism and lung cancer risk in African-Americans. Carcinogenesis.
61. Kelsey KT, Spitz MR, Zuo ZF, Wiencke JK. Polymorphisms in the glutathione S-transferase class
mu and theta genes interact and increase susceptibility to lung cancer in minority populations
(Texas, United States). Cancer Causes & Control. 1997;8:554-9.
62. Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation.
European Respiratory Journal. 2000;16:534-54.
63. Lodovici M. Levels of 8-hydroxydeoxyguanosine as a marker of DNA damage in human
leukocytes. Free Radical Biology & Medicine. 2000;28:13-7.
64. Zhou JF, Yan XF, Guo FZ, Sun NY, Qian ZJ, Ding DY. Effects of cigarette smoking and smoking
cessation on plasma constituents and enzyme activities related to oxidative stress. Biomedical &
Environmental Sciences. 2000;13:44-55.
65. Hong YC, Kim H, Im MW, Lee KH, Woo BH, Christiani DC. Maternal genetic effects on
neonatal susceptibility to oxidative damage from environmental tobacco smoke. Journal of the
National Cancer Institute. 2001;93:645-7.
66. Steckler T. The molecular neurobiology of stress - evidence from genetic and epigenetic models.
Behaviorural Pharmacology. 2001;12:381-427.
67. Wust S, Federenko IS, EF VANR, Koper JW, Kumsta R, Entringer S, Hellhammer DH. A
psychobiological perspective on genetic determinants of hypothalamus-pituitary-adrenal axis
activity. Ann N Y Acad Sci. 2004;1032:52-62.
68. Wust S, Federenko I, Hellhammer DH, Kirschbaum C. Genetic factors, perceived chronic stress,
and the free cortisol response to awakening. Psychoneuroendocrinology. 2000;25:707-20.
69. Bartels M, Van den Berg M, Sluyter F, Boomsma DI, de Geus EJ. Heritability of cortisol levels:
review and simultaneous analysis of twin studies. Psychoneuroendocrinology. 2003;28:121-37.
70. Bartels M, de Geus EJ, Kirschbaum C, Sluyter F, Boomsma DI. Heritability of daytime cortisol
levels in children. Behav Genet. 2003;33:421-33.
71. Federenko IS, Nagamine M, Hellhammer DH, Wadhwa PD, Wust S. The heritability of
hypothalamus pituitary adrenal axis responses to psychosocial stress is context dependent. J Clin
Endocrinol Metab. 2004;89:6244-50.
72. Bamberger CM, Schulte HM, Chrousos GP. Molecular determinants of glucocorticoid receptor
function and tissue sensitivity to glucocorticoids. Endocr Rev. 1996;17:245-61.
73. Diaz R, Brown RW, Seckl JR. Ontogeny of mRNAs encoding glucocorticoid and
mineralocorticoid receptors and 11$-deosysteroid dehydrogenase in prenatal rat brain
development reveal complex contgrol of glucocorticoid action. J Neurosci. 1998;18:2570-2580.
74. 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
psychosocial stress. J Clin Endocrinol Metab. 2004;89:565-73.
75. Challis BG, Luan J, Keogh J, Wareham NJ, Farooqi IS, O'Rahilly S. Genetic variation in the
corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and
association studies with obesity in UK Caucasians. Int J Obes Relat Metab Disord. 2004;28:442-6.
76. Villafuerte SM, Del-Favero J, Adolfsson R, Souery D, Massat I, Mendlewicz J, Van Broeckhoven
C, Claes S. Gene-based SNP genetic association study of the corticotropin-releasing hormone
receptor-2 (CRHR2) in major depression. Am J Med Genet. 2002;114:222-6.
77. Rosmond R, Chagnon M, Bouchard C, Bjorntorp P. G-308A polymorphism of the tumor necrosis
factor alpha gene promoter and salivary cortisol secretion. J Clin Endocrinol Metab.
78. Gentile DA, Doyle WJ, Zeevi A, Howe-Adams J, Trecki J, Skoner DP. Association between TNF-
alpha and TGF-beta genotypes in infants and parently history of allergic rhinitis and asthma.
Human Immunology. 2004;65:347-51.
79. Fukata J, Imura H, Nakao K. Cytokines as mediators in the regulation of the hypothalamic-
pituitary-adrenocortical function. Journal of Endocrinological Investigation. 1993;16:141-155.
80. Chrousos GP. Stress, chronic inflammation, and emotional and physical well-being: concurrent
effects and chronic sequelae. Journal of Allergy & Clinical Immunology. 2000;106:S275-291.
81. Glosli H, Tronstad KJ, Wergedal H, Muller F, Svardal A, Aukrust P, Berge RK, Prydz H. Human
TNF-alpha in transgenic mice induced differential changes in redox status and glutathione-
regulating enzymes. FASEB. 2002;16:1450-1452.
82. Jeanmonod P, von Kanel R, Maly FE, Fischer JE. Elevated Plasma C-reactive protein in
chronically distressed subjects who carry the A allele of the TNF-alpha -308 G/A polymorphism.
Psychosom Med. 2004;66:501-6.
83. Hu X, O'Donnell R, Srivastava SK, Xia H, Zimniak P, Nanduri B, Bleicher R, Awasthi S, Awasthi
YC, Ji X, Singh SV. Active site architecture of polymorphic forms of human glutathione S-
transferase P1-1 accounts for their enantioselectivity and disparate activity in the glutathione
conjugation of 7beta,8alpha-dihydroxy-9alpha,10alpha-ox y-7,8,9,10-tetrahydrobenzo(a)pyrene.
Biochem Biophys Res Commun. 1997;Jun 18;235:424-8.
84. Fryer AA, Bianco A, Hepple M, Jones PW, Strange RC, Spiteri MA. Polymorphism at the
glutathione S-transferase, GSTP1 locus: a new marker for bronchial hyperresponsiveness and
asthma. Am. J. Respir. Crit. Care Med. 2002;161:1437-1442.
85. Aynacioglu AS, Nacak M, Filiz A, Ekinci E, Roots I. Protective role of glutathione S-transferase
P1 (GSTP1) Val105Val genotype in patients with bronchial asthma. British Journal of Clinical
86. Gilliland FD, Li YF, Saxon A, Diaz-Sanchez D. Effect of glutathione-S-transferase M1 and P1
geotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled
crossover study. Lancet. 2004;Jan 10;363:119-25.
87. Child F, Lenney W, Clayton S, Davies S, Jones PW, Alldersea JE, Strange RC, Fryer AA. The
association of maternal but not paternal genetic variation in GSTP1 with asthma phenotypes in
children. Respir Med. 2003;Dec;97:1247-56.
88. Devereux G, Seaton A, Barker RN. In utero priming of allergen-specific helper T cells. Clin Exp
89. Piccinni MP, Mecacci F, Sampognaro S, Manetti R, Parronchi P, Maggi Eea. Aeroallergen
sensitization can occur during fetal life. Int Arch Allergy Immunol. 1993;102:301-3.
90. Van Duren-Schmidt K, Pichler J, Ebner C, Bartmann P, Forster E, Urbanek R, Szepfalusi Z.
Prenatal contact with inhalant allergens. Pediatr Res. 1997;Jan;41:128-31.
91. Kalliomaki M, Isolauri E. Pandemic of atopic diseases--a lack of microbial exposure in early
infancy? Curr Drug Targets Infect Disord. 2002;2:193-9.
92. Hawrelak JA, Myers SP. The causes of intestinal dysbiosis: a review. Altern Med Rev. 2004;Jun;
93. Bjorksten B. Effects of intestinal microflora and the environment on the development of asthma
and allergy. Springer Semin Immunopathol. 2004;Feb;25:257-70.
94. Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in prmary
prevention of atopic disease: a randomis placebo-controlled trial. Lancet. 2001;357:1076-9.
95. Lodinova-Zadnikova R, Cukrowska B, Tlaskalova-Hogenova H. Oral administration of probiotic
Escherichia coli after birth reduces frequency of allergies and repeated infections later in life (after
10 and 20 years). Int Arch Allergy Immunol. 2003; Jul 131:209-11.
96. Bailey MT, Coe CL. Maternal separation disrupts the integrity of the intestinal microflora in infant
rhesus monkeys. Dev Psychobiol. 1999;35:146-55.
97. Bailey MT, Lubach GR, Coe CL. Prenatal stress alters bacterial colonization of the gut in infant
monkeys. J Pediatr Gastroenterol Nutr. 2004;38:414-21.
98. Hart A, Kamm MA. Review article: mechanisms of initiation and perpetuation of gut
inflammation by stress. Aliment Pharmacol Ther. 2002;16:2017-28.
99. Kellner R. Psychotherapy in psychosomatic disorders: A survey of controlled studies. Archives of
General Psychiatry. 1975;32:1021-1028.
100. Wright RJ. Altenative modalities for asthma that reduce stress and modify mood states: evidence
for underlying psychobiological mechanisms. Ann Allergy Asthma Immunol. 2003;92:1-6.
101. Tataryn DJ. Paradigms of health and disease: a framework for classifying and understanding
complimentary and alternative medicine. Journal of Alternative & Complimentary Medicine.
102. McGrady A, Conran P, Dickey D, Garman D, Farris E, Schumann-Brzezinski C. The effects of
biofeedback-assisted relaxation on cell-mediated immunity, cortisol, and white blood cell count in
healthy adult subjects. Journal of Behavioral Medicine. 1993;15.
103. Lehrer PM, Isenberg S, Hochron SM. Asthma and emotion: a review. Journal of Asthma.
104. Stetter F, Kupper S. Autogenic training: a metanalysis of clinical outcome studies. Applied
Psychophysiology and Biofeedback. 2002;27:45-98.