Stress and Atopic Disorders: Asthma and the Seasonal Allergic Response
Rosalind J. Wright, M D MPH
Sheldon Cohen, PhD
Educational Objectives
Upon completion of this Cyberounds®, the participant should be able to:
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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
axis
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
expression
Discuss treatment strategies for modifying the relationship between stress and the
immune response
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).
True
False
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 demonstrated 10. 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 betaendorphins and enkephalins released in the brain are also thought to play a role in immune
regulation 26.
Q2. Shifts in the circadian rhythm of the HPA axis may influence the expression of atopic
disorders.
True
False
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.
True
False
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 eNANC 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 childhood 37.
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
INF-.
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
Cyberounds®.
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 asthmatics 43. 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.
True
False
Genetics
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 marker82. 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
during pregnancy97.
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 response 20.
These authors found the most consistent evidence for hypnotic suggestion and conditioning
interventions being linked to immune modulation.
Summary
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, neuralimmune 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.
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