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Immunol Allergy Clin North Am. Author manuscript; available in PMC 2012 February 1.

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Published in final edited form as:

Immunol Allergy Clin North Am. 2011 February ; 31(1): 5568. doi:10.1016/j.iac.2010.09.009.

Stress and Allergic Diseases


Ninabahen D. Dave, MBBS[Clinical fellow], Lianbin Xiang, MD[Assistant Professor of
Medicine], Kristina E. Rehm, PhD[Postdoctoral Research Fellow], and Gailen D. Marshall
Jr., MD, PhD[Professor of Medicine and Pediatrics]
Laboratory of Behavioral Immunology Research, Division of Clinical Immunology and Allergy,
Department of Medicine, The University of Mississippi Medical Center, 2500 North State Street,
Jackson, MS 39216-4505, (6010 815-5527 FAX (601) 815-4770
Ninabahen D. Dave: ndave@umc.edu; Lianbin Xiang: lxiang@umc.edu; Kristina E. Rehm: krehm@umc.edu; Gailen D.
Marshall: gmarshall@umc.edu

Summary
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Allergy describes a constellation of clinical diseases that affect up to 30% of the worlds
population. It is characterized by production of allergen specific IgE which bind to mast cells and
initiate a cascade of molecular and cellular events that affect the respiratory tract (rhinitis and
asthma) skin (dermatitis, urticaria) and multi systems (anaphylaxis) to a variety of allergens
including pollens, mold spores, animal danders, insect stings, foods and drugs. The underlying
pathophysiology involves immunoregulatory dysfunctions similar to those noted in highly stressed
populations. The relationships in terms of potentials for intervention are discussed.

Keywords
allergy; asthma; stress; immunoregulation

Introduction

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Allergic diseases such as asthma, allergic rhinitis, food allergies, and insect sting allergies
have been described since early in recorded history. A clinical condition with asthma-like
symptoms was described 3500 years ago in an Egyptian manuscript dubbed the Ebers
Papyrus1. In 1906, Austrian pediatrician Clemens Von Pirquet first used the word allergy to
describe the strange, non-disease-related symptoms that some diphtheria patients developed
when treated with a horse serum antitoxins2. Subequently the field of clinical allergy
developed, based upon multiple discoveries: the clinical effectiveness of allergen
immunotherapy3, mast cell granules as the major source of histamine in humans 4,
identification of IgE as the allergen-specific initiator of allergic reactions5 and the
lipoxygenase- based leukotriene cascade as the clinically described slow reacting substance
of anaphylaxis6 . These and other discoveries have ushered in the modern day practice of
allergy and clinical immunology that cares for up to 30% of people in western societies who
suffer with various allergic diseases including hay fever (allergic rhinitis), asthma , atopic
dermatitis, food allergy, drug allergy and the life threatening systemic mast cell-mediated
reaction known as anaphylaxis.

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Allergy has been defined as the result of immune reaction to specific types of mostly protein
antigens known as allergens. Atopy, genetically mediated predisposition to produce specific
IgE following exposure to allergens, is clinically defined as having evidence of allergic
sensitization to at least one environmental allergen. Atopy is a fundamental component of
the pathogenesis of allergic disorders. Although the clinical manifestations can be distinct
between affected organs in a patient and even the same organ among different patients,
allergic diseases share a common pathophysiology resulting from immune dysregulation and
subsequent potentially harmful inflammation (so called hypersensitivity disease).
In recent decades, many studies have shown multiple links between nervous, endocrine and
immune systems. The field of psychoneuroimmunology (PNI) has and continues to describe
various links between behavior, neuroendocrine functions, immune responses and health.
Excessive psychological stress and allergic disorder have been linked together in clinical
practice for centuries. Many allergic conditions have long been considered psychosomatic
disorders which had worsened outcomes in patienst with high levels of psychosocial stress.
For example, asthma was commonly referred to in most early medical texts as asthma
nervosa based upon the belief that , in many children, it was the result of a conversion
reaction from living with a histrionic mother8. Early descriptions of atopic dermatitis used
the term neurodermatitis due to belief that the itch and scratch cycle which results in a
rash, was related primarily to nerves and emotion.

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Thus it is not surprising that allergy, one of the most prevalent of all human disease
categories and psychological stress are related. This chapter will explore the relationships
between allergic diseases and stress and suggest future mechanism-based research directions
to develop therapeutic and even prophylactic approaches to disease management with stressbased interventions.

Stress

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Stress can be thought of as a psychophysiological process that is a product of both the


appraisal of a given situation to assess potential adversity and the ability (either perceived or
actual) to cope with that potentially adverse situation8. The events/situations posing the
potential threat are called stressors. Situations can be experiences in daily life, including
daily hassles (ordinary stressors from interactions with family, neighborhood and/or school/
in the work place) as well as major life events, which may be either positive or negative
such as a large promotion that requires significantly increased physical and mental effort or
losing ones job resulting in financial crisis. Based on their duration, stressors are often
considered acute (minutes to hours), subacute (less than one month duration) or chronic
(months to years). Intensity of the stress, even when acute, may have longer lasting effects
that can ovelap with a less intense stressor lasting for a longer period of time. Further,
repetitive acute stressors (the same ones or even different ones) may, with time and
intensity, have similar effects to that of a single long term stressor.
PNI research focuses primarily on the understanding of the relationships between
psychological stress perception (both conscious and subconscious) and downstream
behavior, endocrine and immune changes occurring in response to that stress perception.
The brain perceives and responds to stressors and determines both the behavioral and
physiological responses. The typical host response to isolated episodes of acute stress is
adaptive for the protection of the host whereas chronic stress can lead to dysregulation of the
mediators and exacerbate underlying inflammatory disease pathophysiology. There are
multiple reported factors that can impact this cause-and-effect relationship including genetic
background (which may include gender and racial differences) , previous life experiences

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and past/present environmental exposures. Of note, the same factors have been reported to
impact the incidence and severity of allergic diseases as well.

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Adverse Impact of Stress on Health

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A common clinical observation is the often adverse relationship between stress and human
diseases10. Various sources have estimated that up to 75% of all visits to physicians offices
are stress-related. This appears to be particularly true in relationship to other immune-based
dysfunction such as increased susceptibility to infections and various autoimmune diseases.
Stress is also implicated in morbidity and mortality of other inflammatory based diseases
such as cancer, HIV/AIDS, inflammatory bowel disease and even immune senescence
associated with aging. Stress may also cause persistent increases in sympathetic nervous
system activity, including increase blood pressure, heart rate and catecholamine secretion as
well as platelet aggregation which may explain, at least in part, the known association
between stress, immune alteration and cardiovascular disease. In addition, altered sleep can
modulate stress-health relationship. Sleep disturbance have been associated with adverse
physical health outcomes including increase morbidity and mortality compared to
population with adequate pattern and duration of sleep. Other pathologies associated with
allostatic overload from chronic stress include depression11, tendencies towards unhealthy
behavior12, diabetes13, dyslipidemia13; irritable bowel syndrome14 and cerebrovascular
accidents15.

Stress and Allergic Disease


Stress-induced exacerbation of existing allergic disease
Clinical observations implicating the adverse effects of psychological stress on disease
activity in allergic patients is supported by studies that have demonstrated that allergic
responses can be modulated by mood and psychological stressors. Gauci et al found a
correlation between the Minnesota Multiphasic Personality Inventory distress related scales
and skin reactivity in response to allergen challenge 16. In addition, different studies have
shown that the impact of life event, negative support and current mood disorder were
associated with increased rate of asthma hospital admission17 and negative life event and
negative rumination were associated with asthma morbidity18. Further, behavior problems
and family conflicts preceded the development of asthma in multiple pediatric
populations19, 20.

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Another study showed enhancement of allergic inflammatory responses with natural stress
exposure21. Sputum eosinophils levels in 20 otherwise healthy college students with asthma
were evaluated before and after an allergen challenge. Although there were no baseline
differences before antigen challenge at low (mid semester) and high (during final
examinations) stress exposures, sputum eosinophils counts rose higher and persisted longer
in response to allergen challenge during final examinations. Additionally blood eosinophils
levels were significantly higher both before and after challenge during final examinations
compared to mid semester samples.
Stress and incidence of allergic disease
The potential for adverse impact of maternal stress on immunity in a developing fetus and
possible postnatal disease occurrence is concerning. Psychological maternal stress is
increasingly considered a possible perinatal programming agent. Perinatal programming
occurs when characteristics of the in utero environment, independent of genetic
susceptibility, influence fetal development to permanently organize or imprint physiological
systems. Intrauterine stress hormone levels (both maternal and fetal) are thought to rise with
prenatal maternal stress. Since fetal immunity initially is involved primarily in self-nonself
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programming to prevent future autoimmunity, such prenatal stress hormone exposure may
alter natural immunoregulatory mechanisms such that the child has increased risk for
developing various inflammatory diseases including allergy and asthma. Various animal and
human studies have shown linkage between maternal stress and immune dysregulation in
children. Wright et al reported that increased stress in early childhood was associated with
an atopic immune profile in children predisposed to atopy-asthma (i.e. positive family
history for atopy) 22. They have also shown that caregiver stress can increase the incidence
of early childhood wheeze independent of caregiver smoking, breast-feeding behaviors,
allergen exposure, birth weight or lower respiratory tract infections22, 23. These findings
indicate a significant potential impact of psychological stress on childhood wheeze and
subsequent development of clinical allergy and asthma. These studies and others support a
strong role for stress in exacerbation and possible etiology of allergic diseases.

Immunopathophysiology of allergic disease

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IgE-mediated allergic disorders may manifest clinically as any combination of


conjunctivitis, rhinitis, asthma, atopic dermatitis, food and/or drug intolerance and/or
anaphylaxis. It has been well recognized that atopic dermatitis and food allergies are often
the earliest manifestation of atopic predisposition in a young child. Nearly 50% of children
with atopic dermatitis develop asthma and 75% develop allergic rhinitis. The allergic march
is a sequential or sometimes simultaneous expression of two or three of the above mentioned
allergic disorders in an individual progresses from infancy to adolescence and adulthood24.
The prevalence of allergy and asthma has increased in nearly all countries worldwide and is
more common in Westernized and economically developed countries. As many as 1 in 3
individual suffer from some form of allergic disorder25. Development of allergic disorders
involves multiple factors including genetic components (family history) , both indoor (dust
mite, molds, animal danders) and outdoor (pollens, ozone and diesel exhaust) environmental
exposure as well as other life style factors including maternal diet, reproductive
physiology and birth outcomes, breast feeding, child nutrition and vitamin D level, obesity,
physical activity and psychological stress.
Atopic Dermatitis (AD)

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AD is a chronic relapsing inflammatory skin disease commonly associated with respiratory


allergy26. It is the most common chronic skin disease of young children, with lifetime
prevalence in US schoolchildren up to 17%. Itching and scratching are the hallmark of this
disease. Itching is often worse at night leading to chronic sleep disturbance in patient and
immediate family members and is a source of significant psychological and physiological
stress. When patients with AD become upset, they tend to itch even more, probably
secondary to flushing of the skin due to vasodilatation induced by neurogenic peptides,
followed by increased histamine and prostaglandin E2 release 27. Distribution of the rash on
the face and extensor aspects in infant and young children, changing to more flexural surface
involvement in older agesis a classical finding of AD. . About ninety-five percent of patients
with AD become colonized by a ubiquitous pathogen, Staphylococcus aureus which releases
toxins that can act as superantigens and stimulate marked inflammatory responses as well as
specific IgE production. Patients with AD are prone to recurrent bacterial (impetigo), fungal
(tinea) and viral (Herpes Simplex molluscum contagiosum) skin infections. Allergens,
irritants (wool, soap, detergents, heat and humidity with sweating), infections and certain
foods can worsen eczema28, 29. The impact on self esteem and social interactions of both
children and adults with this condition cannot be underestimated and may account for some
of the chronicity commonly seen in these patients30.

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Allergic RhinitisAllergic rhinitis (AR) is a debilitating disease that currently affects up


to 30% of the world population . Classical symptoms of AR include profuse watery
rhinorrhea, sneezing, itchy nose, and congestion. Post nasal drip might be present and cause
cough or persistent throat clearing. Sometimes AR patients can also experience itchy
conjunctiva, ears and throat. . AR is generally classified as seasonal (SAR) and perennial
(PAR), based on presence or absence of seasonality and the source of allergens triggering
the symptoms.but more recently has been classified based on duration and severity of
symptoms as mild intermittent, mild persistent, moderate or severe intermittent, and
moderate or severe persistent to aid with choice of therapy.
Non-allergic triggers like strong odors, tobacco smoke, and temperature changes can
stimulate symptoms in AR patients similar to those induced by allergens., suggesting hyper
responsiveness which is more commonly reported in lower airways. Neural reflex arcs in the
upper airways, when challenged with allergens, can incite lower airway bronchospasm.
These observations gave rise to the concept of one linked airway which addresses the
observed connection between nasal and pulmonary symptoms in allergic individuals.31.
Patient with allergic rhinitis can often have sleep impairment due to nasal obstruction which
typically worsens at night. Fatigue, malaise, and impairment of work and school
performance are common when AR symptoms are severe32. Patients with AR are more
prone to upper respiratory infections during periods of high psychological stress33.

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AsthmaAsthma is defined as a chronic inflammatory disorder of the airways in which


many cells and cellular elements play a role. The chronic inflammation causes an associated
increase in airway hyper responsiveness that leads to recurrent episodes of wheezing,
breathlessness, chest tightness, and coughing, particularly at night or in the early morning.
These episodes are usually associated with widespread but variable airflow obstruction that
is often reversible either spontaneously or with treatment34. Based on 2005 NHIS results, an
estimated 32.6 million Americans have received an asthma diagnosis during their lifetimes,
an increase in prevalence by 16% from 199735. Atopy, particularly to house dust mites and
cockroaches and family history of allergy or asthma are known risk factors for asthma.
Common symptoms described by patients include cough, wheezing, chest tightness, dyspnea
and occasionally chest pain. In up to 15% of asthma patients, dry cough may be the only
presenting respiratory symptom.. Exercise induced bronchospasm is present in almost 90%
of all asthmatics which results from rapid change of airway temperatures with increased
tidal volumes and mouth breathing. Any and all of these symptoms have been reported to be
worsened in asthma patients experiencing high stress levels.

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Acute exacerbation of asthma can be triggered by upper and lower respiratory tract
infections (specially viruses such as rhinovirus, influenza, parainfluenza, respiratory syncital
viruses), changes in weather, significant allergen exposure in sensitized individuals, cold air,
exercise, various stressful situations and hormonal changes related to menses in some
women. Approximately five thousands deaths occur in the United States from asthma
annually.

B. Altered Immunity in Allergic Diseases


For purposes of this discussion, allergy or immediate hypersensitivity describes a series of
immune based reactions occurring as a result of the induction of allergen specific IgE that
binds to mast cells via high affinity FcR1 receptors. Subsequent re-exposure to the inciting
allergen causes a cross-linking of the mast cells-bound IgE with activation and release of the
mast cell contents such as histamine, leukotrines, tryptase, chymase, kininogenase, and
heparin within 560 minutes of exposure. These mediators can induce vasodilatation and
vascular leaks, causing mucosal edema, increased mucus gland secretions, nasal and/or

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bronchial congestion and occlusion resulting in various clinical signs and symptoms. . Late
phase allergic reactions can occur six to twenty-four hours after initial exposure following
the recruitment and migration of inflammatory cells like eosinophils, basophils, neutrophils,
T lymphocytes, and macrophages to the target tissues (skin, nose, lung, gastrointestinal tract,
and/or blood vessels). These result in more persistent symptoms. TH2 cytokines play a
critical role in orchestrating ongoing inflammation.
Chronic changes seen in airways of asthmatics include smooth muscle hypertrophy and
hyperplasia, goblet cell hyperplasia, submucosal gland hypertrophy, neovascularization,
thickening of reticular basement membrane, and fibrotic changes with collagen deposition49.
Airway smooth muscle hyper responsiveness is another hallmark of asthma which might
precede, accompany and sometimes be independent of airway inflammation, suggesting
heterogeneity of asthma phenotypes. While, increase transepithelial water losses, defective
skin barrier function, allergen-and-infection-induced inflammation, and abnormal
regeneration of damaged skin are the characteristics of atopic dermatitis29.

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As already discussed, the production of the IgE is under the direct control of type 2 cytokine
production with IL-4 and IL-13 being responsible for isotype switch from IgM to IgE. IL-4
is also a mast cell growth factor and IL-5 is a major chemotactic, growth and activation
factor for eosinophils, which are a central component of allergic inflammation50. Thus,
clinical allergic diseases can be viewed as immunoregulatory imbalances where Th2
cytokines predominates51.
Dysregulation of Th1 and Th2 cytokine balance play a central role in the immunopathology
of allergic diseases. . Allergen-specific T- cell clones from atopic patients have a much
higher percentage of TH2 or TH0 type compared with healthy individuals, which tend to
have more TH140, 52. Finally, treatment of allergic rhinitis with allergen immunotherapy has
been demonstrated to result in a shifting of overall Th1 and Th2 cytokine levels toward a
more balanced Th1/Th2 response, which correlates with decreases in clinical disease activity
53. These mechanism studies would support the theory that physiological states associated
with type II cytokine environment could exacerbates asthmatic and allergic diseases.
Since we and others have shown that chronic psychosocial stress is associated with an
altered Th1/Th2 balance toward a Th2 predominance, it is not surprising from an immune
standpoint that stress can exacerbate allergic diseases such as AR, AD and asthma. Such
observations lead to interventions for these diseases that are based upon the notion of
managing (if not reducing) stress as a means to control symptoms and, perhaps in the future,
prevent the appearance of allergic diseases in the most susceptible individuals. (Fig 1)

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Management of Allergic Disease


Clinical principles for managing allergic diseases include of
1.

Avoidance of exposure to known allergic and non-allergic triggers

2.

Controlled exposure to allergens that cannot be totally avoided (i.e. airborn pollens,
mold spores, dust mite proteins)

3.

Pharmacotherapy to treat mast cell mediated symptoms and reduce allergic


inflammation

4.

Allergen Immunotherapy for upper and lower airway disease in selected individuals

Identification of allergens to which an individual is sensitive is typically accomplished by in


vitro (ImmunoCAP-RAST) or in vivo (skin prick or intradermal skin testing) assays when
feasible, which is correlated with the clinical history of symptoms. Environmental control,

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which includes improve symptoms of susceptible patients with allergic diseases54. The
general goal of pharmacotherapy for any disease is to minimize the impact of the disease on
patients life with minimal adverse side effects of the medications. There are many different
types of medications used to treat allergy and asthmabut corticosteroids are the most
effective anti-inflammatory medications. C exert their anti-inflammatory effects by
suppressing the expression of a host of inflammatory mediators (growth factors, cytokines,
chemokines) and inflammatory enzymes involved in metabolism of arachidonic acid and
nitric oxide (NO). Topical forms of corticosteroids (i.e. inhaled steroids for asthma,
intranasal steroid sprays for allergic rhinitis and topical steroid crmes and ointments for
allergic dermatitis) represent first line therapy in everyday management of allergic diseases.
In addition, short courses of systemic corticosteroids are typically used for acute
exacerbations of allergic diseases . Inhaled bronchodilators (2-agonist) and anticholinergic
are also used in management of acute asthma exacerbations . Antihistamines in oral,
intranasal and ocular forms as well as leukotriene receptor antagonists are also used in
management of various allergic diseases.

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Immunotherapy for inhaled allergens induces regulatory T cells that dampen the allergic
responses to allergens. Two forms of immunotherapy, Subcutaneous Immunotherapy (SCIT)
and Sublingual Immunotherapy (SCIT) are in use currently. SCIT is the conventional
immunotherapy which involves injecting gradually increasing doses of an allergen that a
given patient is sensitized to and has history of problems on exposure followed by a
maintenance therapy with the same. Studies showed that the global assessment of
improvement with SLIT was significantly better than placebo although only half the
difference recorded in the SCIT study55, 56 . Use of recombinant technology in
immunotherapy is under development and in experimental phase.
Immunomodulatory therapy with anti-IgE is a major advancement in the field of allergy and
immunology. It reduces the rate of clinically significant asthma exacerbations irrespective of
baseline oral corticosteroid use, concomitant treatment with other controller medications and
patient characteristics.

Impact of Stress on Immune system

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The link between the brain and immune system involves two main pathways: the autonomic
nervous system (ANS) and the-hyphophyseal-pituitary - adrenal (HPA) axis. Perception of
stress leads to activation of HPA system which begins with the secretion of corticotrophin
releasing hormone (CRH) which in turn induces the secretion of adrenocortictrophic
hormone (ACTH) by the anterior lobe of the pituitary lobe. ACTH activates the secretion of
corticoids by the adrenal cortex and catecholamines (adrenalin and noradrenalin) by the
adrenal medulla. The catecholamines and corticoids suppress the production of IL-12 by the
antigen-presenting cells which is a primary TH1 cytokine-inducing inducing stimulus57.
Corticoids can also exert a direct effect upon TH2 cells thus increasing the production of
IL-4, IL-10 and IL-1358. The end result is the predominance of a TH2 cell mediated
response which would favor an allergic inflammatory response in a susceptible individual.
The ANS is composed of sympathetic (adrenergic, noradrenergic) and the parasympathetic
(cholinergic) systems in the CNS with noradrenalin and acetyl choline as neurotransmitters,
respectively and the non-adrenergic, non-cholinergic (peptidergic) system primarily located
in the gastrointestinal tract. The main peptides of this system are vasoactive intestinal
peptides (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). The
innervation of important organs and systems related to the immune system such as the liver,
spleen, thymus gland, bone marrow, lymph nodes, skin, digestive tract, and respiratory

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apparatus is by postsynaptic ANS59. Most immune system cells have surface membrane
receptors for varying combinations of neurotransmitters, neuropeptides and hormones60.

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The CNS modulates immune system through neurotransmitters (acetyle choline,


noradrenalin, serotonin, histamine, -aminobutyric acid (GABA), glutamic acid),
neuropeptides (ACTH, prolactin, vasopressin, bradykinin, somatostatin, VIP, SP,
neuropeptide Y, encephalin, endorphin), neurological growth factors (neuron growth factor
(NGF)), and hormones (adrenalin and corticoids) whereas the immune system can also
modulate CNS function via various molecules including cytokines (tumor necrosis factor
alpha TNF and TGF), chemokines (interferons) and nitric oxide (NO)61. Perception of
acute stress stimulates the locus ceruleus which secretes noradrenalin. Noradrenalin
activates the sympathetic nervous system leading to decrease production of IL-12 as
described earlier.
Neuropeptides including SP, CGRP and VIP are potent vasodilators and also increases
vascular permeability. SP increases the production of TNF and IL-12 by monocytes and
macrophages. SP and CRH can degranulate mast cells within inflammatory foci. All of the
above processes lead to inflammatory changes62.

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SP and CGRP have been identified in bronchial mucosa as neurogenic inflammatory


agents63. In addition, Neurokinin-1, receptor for SP, is located on bronchial vessels,
bronchial smooth muscle, epithelial cells, submucosal glands and immune cells. Stress likely
exerts its effect on bronchial mucosa of asthmatics by varying combinations of impacting
number and function of various immune/inflammatory cells as well as direct action on
bronchial mucosa64.
Increased tissue levels of neurotrophins, acting as nerve growth factors, have been described
in different respiratory and dermatologic allergic disorders. They act on immune cells,
structural cells (keratinocytes, epithelial cells) and can increase angiogenesis65. Eosinophils
and submucosal glands of the nasal mucosa are a major source of neurotrophins66 which
have been shown to regulate eosinophil survival in the lungs, increase production of specific
IgE and change the cytokines profile towards TH2 predominance.
These findings and others demonstrate that interactions between the CNS and immune
systems are complex and bidirectional.

Addressing stress in comprehensive allergic disease management


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Similar to allergic diseases, progression of the other immune-based diseases such as


cardiovascular disease, diabetes mellitus, development of AIDS in HIV+ patients and certain
malignancies has been suggested for high-stress population. Thus it follows that managing
stress in these patients could be expected to have salutatory effects on their underlying
disease course.
Strategies for stress management as part of a comprehensive treatment plan should involve
identification of high-risk population or , ideally, individuals. Current efforts are underway
in our group and others to identify biomarkers that would categorize individuals into risk
categories for adverse effects of psychological stress on their immune system which, in turn,
would effect risk for or activity of underlying immune-based diseases. The categorization
would be followed by (ideally) individualized prophylactic interventions in the highest atrisk individuals to prevent immune based diseases or therapeutic intervention in the diseased
individuals with the intent to minimize the immunoregulatory imbalance that characterizes
chronic stress induced immune changes.

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Stress reduction/elimination would be the most desirable intervention but is often difficult to
achieve in our fast paced, high pressure societies. Accordingly, , methods (psychological,
physiological, pharmacological or some combination) to improve individual coping abilities
to stressful situations are more likely to be clinically valuable as a core of the interventional
strategies for stress management67.
Many studies have shown the encouraging effects of psychological interventions on clinical
outcome in allergic diseases. Smyth et al showed that expressive writing about stressful
events was associated with symptom reduction in asthma patients. Biofeedback as well as
mental imagery has a positive role in asthma management6870. In a systematic review,
Huntley et al. described that relaxation therapy had a positive effect on asthma outcomes71.
While Psychotherapy can reduce the number of asthma exacerbations and ER visits in
depressed asthma patients72. Although evidence suggests that these interventions result in
restoring a more normal Th1/Th2 balance , further research is warranted to prove a direct
link between clinical improvement and immune changes following psychological
interventions in allergic diseases.

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Physiological interventions for allergic diseases include various forms of exercise programs
as well as complementary and alternative medicine techniques such as acupuncture,
chiropractic and applied kinesiology all of which may work, at least in part, by their impact
on the underlying stress of the individual.. So far, well designed studies have not shown a
clear benefit of complementary and alternative medicine interventions, perhaps secondary to
the robust placebo effect with subsequent psychophysiological impact on immunity73, 74
and thus likely on allergic diseases75. Based upon the severity of the underlying dysfunction,
exercise had varied effects on immune function. Exercise training program are well tolerated
in children with mild-to-moderate asthma and improves both aerobic and anaerobic
fitness76. Exercise rehabilitation programs improve aerobic conditioning, ventilatory
capacity as well as decrease hyperpnea of exercise occurred in patients with mild asthma77.
But, as a caution, excessive exercise can lead to an exacerbation of disease in poorly
controlled asthmatic patients.
Reported pharmacological interventions for stress have mainly included psychoactive
agents . Both tricyclic and SSRI antidepressants may have a therapeutic role in asthma by
suppressing production of proinflammatory cytokines, inducing production of antiinflammatory molecules and/or preventing the effects of these inflammatory molecules on
the brain78. Both adult and child/adolescent populations with asthma appear to have a high
prevalence of anxiety disorders79. In addition, anxiolytic drugs may have beneficial in
increasing the quality of asthma therapy in asthmatics with anxiety disorder80.

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Psychological stress increases superoxide release81. This finding suggests a potential


prophylactic role of anti-oxidant agents like Vitamin C and E against stress-induced immune
changes. Studies have shown vitamin C and vitamin E can reduce immunoregulatory
imbalances noted in stressed individuals82.
Thus, many different approaches with proven or likely beneficial effects are available to
modulate stress and thus immune function to have positive effects in allergic patients.

Future directions
Although the adverse role of psychological stress in allergic disease activity has long been
suspected by clinicians, recent research has found more direct mechanistic links between
stress and immunity. Future research should include developing ways to identify high-risk
individuals as well as more accurate assessment of the specific impact of stress on various
regulatory and effector components of the immune system and resulting allergic diseases.
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Concluding remarks
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Based upon the available evidence, it seems apparent that chronic stress in susceptible
individual can favor the manifestation of allergic disease and exacerbate as well as
complicate control of the existing allergic diseases. Current research has delivered
anatomical as well as physiological evidence of intense communication between
neuroendocrine mediators, nerve fibers and immune cells in allergic diseases. There is a bidirectional relationship between psychosocial factors and allergic disorders. This suggests
that optimal management of allergic disorders must involve a multipronged approach
including psychological interventions as well as conventional physical and pharmacological
therapies.

Acknowledgments
Supported in part by grants 1 CPI MP061018-02, 5 R21 AT002938-02 and 1 R21 HL96086-01 from the National
Institutes of Health

References

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1. Ebers, G. Das hermetische buch uber die arzneimittel der slten aegypter. Leipzig: Henrichs; 1875.
2. Bukantz SC. Clemens von Pirquet and the concept of allergie. J Allergy Clin Immunol. Apr; 2002
109(4):724726. [PubMed: 11980437]
3. Noon L. Prophylactic inoculation against hay fever. Int Arch Allergy Appl Immunol. 1953; 4(4):
285288. [PubMed: 13096152]
4. Riley JF, West GB. The presence of histamine in tissue mast cells. J Physiol. Jun 29; 1953 120(4):
528537. [PubMed: 13070225]
5. Kirkpatrick CH. The Ishizakas and the search for reaginic antibodies. J Allergy Clin Immunol. Mar;
2005 115(3):642644. [PubMed: 15753922]
6. Dahlen SE, Hedqvist P, Hammarstrom S, Samuelsson B. Leukotrienes are potent constrictors of
human bronchi. Nature. Dec 4; 1980 288(5790):484486. [PubMed: 6108512]
7. Marshall GD. Neuroendocrine mechanisms of immune dysregulation: applications to allergy and
asthma. Ann Allergy Asthma Immunol. Aug; 2004 93(2 Suppl 1):S1117. [PubMed: 15330008]
8. Osler, W. The principles and practice of medicine. Edinburgh: YJ Pentland; 1892.
9. McEwen BS. Central effects of stress hormones in health and disease: Understanding the protective
and damaging effects of stress and stress mediators. Eur J Pharmacol. Apr 7; 2008 583(23):174
185. [PubMed: 18282566]
10. McEwen BS, Stellar E. Stress and the individual. Mechanisms leading to disease. Arch Intern Med.
Sep 27; 1993 153(18):20932101. [PubMed: 8379800]
11. Clays E, De Bacquer D, Leynen F, Kornitzer M, Kittel F, De Backer G. Job stress and depression
symptoms in middle-aged workers--prospective results from the Belstress study. Scand J Work
Environ Health. Aug; 2007 33(4):252259. [PubMed: 17717616]
12. Muller N, Ackenheil M. Psychoneuroimmunology and the cytokine action in the CNS:
implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. Jan; 1998
22(1):133. [PubMed: 9533165]
13. Golden SH. A review of the evidence for a neuroendocrine link between stress, depression and
diabetes mellitus. Curr Diabetes Rev. Nov; 2007 3(4):252259. [PubMed: 18220683]
14. Blanchard EB, Lackner JM, Jaccard J, et al. The role of stress in symptom exacerbation among IBS
patients. J Psychosom Res. Feb; 2008 64(2):119128. [PubMed: 18222125]
15. Harmsen P, Lappas G, Rosengren A, Wilhelmsen L. Long-term risk factors for stroke: twentyeight years of follow-up of 7457 middle-aged men in Goteborg, Sweden. Stroke. Jul; 2006 37(7):
16631667. [PubMed: 16728686]
16. Gauci M, King MG, Saxarra H, Tulloch BJ, Husband AJ. A Minnesota Multiphasic Personality
Inventory profile of women with allergic rhinitis. Psychosom Med. NovDec; 1993 55(6):533
540. [PubMed: 8310114]

Immunol Allergy Clin North Am. Author manuscript; available in PMC 2012 February 1.

Dave et al.

Page 11

NIH-PA Author Manuscript


NIH-PA Author Manuscript
NIH-PA Author Manuscript

17. Wainwright NW, Surtees PG, Wareham NJ, Harrison BD. Psychosocial factors and incident
asthma hospital admissions in the EPIC-Norfolk cohort study. Allergy. May; 2007 62(5):554560.
[PubMed: 17441796]
18. Wright RJ. Alternative modalities for asthma that reduce stress and modify mood states: evidence
for underlying psychobiologic mechanisms. Ann Allergy Asthma Immunol. Aug; 2004 93(2 Suppl
1):S1823. [PubMed: 15332295]
19. Calam R, Gregg L, Simpson A, Simpson B, Woodcock A, Custovic A. Behavior problems
antecede the development of wheeze in childhood: a birth cohort study. Am J Respir Crit Care
Med. Feb 15; 2005 171(4):323327. [PubMed: 15557132]
20. Stevenson J. Relationship between behavior and asthma in children with atopic dermatitis.
Psychosom Med. NovDec; 2003 65(6):971975. [PubMed: 14645774]
21. Liu LY, Coe CL, Swenson CA, Kelly EA, Kita H, Busse WW. School examinations enhance
airway inflammation to antigen challenge. Am J Respir Crit Care Med. Apr 15; 2002 165(8):
10621067. [PubMed: 11956045]
22. Wright RJ, Finn P, Contreras JP, et al. Chronic caregiver stress and IgE expression, allergeninduced proliferation, and cytokine profiles in a birth cohort predisposed to atopy. J Allergy Clin
Immunol. Jun; 2004 113(6):10511057. [PubMed: 15208584]
23. 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. Feb 1; 2002 165(3):358
365. [PubMed: 11818321]
24. Hahn EL, Bacharier LB. The atopic march: the pattern of allergic disease development in
childhood. Immunol Allergy Clin North Am. May; 2005 25(2):231246. v. [PubMed: 15878453]
25. Peroni DG, Piacentini GL, Alfonsi L, et al. Rhinitis in pre-school children: prevalence, association
with allergic diseases and risk factors. Clin Exp Allergy. Oct; 2003 33(10):13491354. [PubMed:
14519139]
26. Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic
dermatitis. J Clin Invest. Mar; 2004 113(5):651657. [PubMed: 14991059]
27. Ostlere LS, Cowen T, Rustin MH. Neuropeptides in the skin of patients with atopic dermatitis.
Clin Exp Dermatol. Nov; 1995 20(6):462467. [PubMed: 8857337]
28. Leung DY, Bieber T. Atopic dermatitis. Lancet. Jan 11; 2003 361(9352):151160. [PubMed:
12531593]
29. Leung DY, Jain N, Leo HL. New concepts in the pathogenesis of atopic dermatitis. Curr Opin
Immunol. Dec; 2003 15(6):634638. [PubMed: 14630196]
30. Lapidus CS, Kerr PE. Social impact of atopic dermatitis. Med Health R I. Sep; 2001 84(9):294
295. [PubMed: 11565277]
31. Blaiss MS. Rhinitis-asthma connection: epidemiologic and pathophysiologic basis. Allergy
Asthma Proc. JanFeb; 2005 26(1):3540. [PubMed: 15813286]
32. Meltzer EO. Quality of life in adults and children with allergic rhinitis. J Allergy Clin Immunol.
Jul; 2001 108(1 Suppl):S4553. [PubMed: 11449206]
33. Jaber R. Respiratory and allergic diseases: from upper respiratory tract infections to asthma. Prim
Care. Jun; 2002 29(2):231261. [PubMed: 12391710]
34. National Institutes of Health (NIH) NHL. Global Strategy for asthma management and prevention.
Bethesda, MD: NIH; 2002. Global initiative for asthma.
35. NHIS. National health interview survey (NHIS 2005). Hyattsville, MD: National Center for Health
Statistics (NCHS), Centers for Disease Control and Prevention; 2005.
36. Robson NC, Beacock-Sharp H, Donachie AM, Mowat AM. The role of antigen-presenting cells
and interleukin-12 in the priming of antigen-specific CD4+ T cells by immune stimulating
complexes. Immunology. Sep; 2003 110(1):95104. [PubMed: 12941146]
37. Parkhurst MR, Riley JP, Robbins PF, Rosenberg SA. Induction of CD4+ Th1 lymphocytes that
recognize known and novel class II MHC restricted epitopes from the melanoma antigen gp100 by
stimulation with recombinant protein. J Immunother. Mar-Apr; 2004 27(2):7991. [PubMed:
14770079]
38. O'Garra A, Vieira P. Regulatory T cells and mechanisms of immune system control. Nat Med.
Aug; 2004 10(8):801805. [PubMed: 15286781]
Immunol Allergy Clin North Am. Author manuscript; available in PMC 2012 February 1.

Dave et al.

Page 12

NIH-PA Author Manuscript


NIH-PA Author Manuscript
NIH-PA Author Manuscript

39. Lanzavecchia A, Sallusto F. Dynamics of T lymphocyte responses: intermediates, effectors, and


memory cells. Science. Oct 6; 2000 290(5489):9297. [PubMed: 11021806]
40. Romagnani S. T-cell subsets (Th1 versus Th2). Ann Allergy Asthma Immunol. Jul; 2000 85(1):9
18. quiz 18, 21. [PubMed: 10923599]
41. Trinchieri G, Wysocka M, D'Andrea A, et al. Natural killer cell stimulatory factor (NKSF) or
interleukin-12 is a key regulator of immune response and inflammation. Prog Growth Factor Res.
1992; 4(4):355368. [PubMed: 1364096]
42. Mustafa AS, Oftung F. Cytokine production and cytotoxicity mediated by CD4+ T cells from
healthy subjects vaccinated with Mycobacterium bovis BCG and from pulmonary tuberculosis
patients. Nutrition. SepOct; 1995 11(5 Suppl):698701. [PubMed: 8748256]
43. Parronchi P, De Carli M, Manetti R, et al. IL-4 and IFN (alpha and gamma) exert opposite
regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. J
Immunol. Nov 1; 1992 149(9):29772983. [PubMed: 1401925]
44. DeKruyff RH, Rizzo LV, Umetsu DT. Induction of immunoglobulin synthesis by CD4+ T cell
clones. Semin Immunol. Dec; 1993 5(6):421430. [PubMed: 7907233]
45. Akbari O, Umetsu DT. Role of regulatory dendritic cells in allergy and asthma. Curr Allergy
Asthma Rep. Jan; 2005 5(1):5661. [PubMed: 15659264]
46. Bendelac A, Schwartz RH. Th0 cells in the thymus: the question of T-helper lineages. Immunol
Rev. Oct.1991 123:169188. [PubMed: 1684778]
47. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;
27:485517. [PubMed: 19132915]
48. Trzonkowski P, Szmit E, Mysliwska J, Dobyszuk A, Mysliwski A. CD4+CD25+ T regulatory cells
inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. Clin
Immunol. Sep; 2004 112(3):258267. [PubMed: 15308119]
49. James A. Airway remodeling in asthma. Curr Opin Pulm Med. Jan; 2005 11(1):16. [PubMed:
15591881]
50. Weltman JK, Karim AS. IL-5: biology and potential therapeutic applications. Expert Opin Investig
Drugs. Mar; 2000 9(3):491496.
51. Ngoc PL, Gold DR, Tzianabos AO, Weiss ST, Celedon JC. Cytokines, allergy, and asthma. Curr
Opin Allergy Clin Immunol. Apr; 2005 5(2):161166. [PubMed: 15764907]
52. Romagnani S, Maggi E, Parronchi P, Macchia D, Piccinni MP, Ricci M. Increased numbers of
Th2-like CD4+ T cells in target organs and in the allergen-specific repertoire of allergic patients.
Possible role of IL-4 produced by non-T cells. Int Arch Allergy Appl Immunol. 1991; 94(14):
133136. [PubMed: 1682270]
53. Schmidt-Weber CB, Blaser K. Immunological mechanisms in specific immunotherapy. Springer
Semin Immunopathol. Feb; 2004 25(34):377390. [PubMed: 15007636]
54. Simpson A, John SL, Jury F, et al. Endotoxin exposure, CD14, and allergic disease: an interaction
between genes and the environment. Am J Respir Crit Care Med. Aug 15; 2006 174(4):386392.
[PubMed: 16614348]
55. Khinchi MS, Poulsen LK, Carat F, Andre C, Hansen AB, Malling HJ. Clinical efficacy of
sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized,
placebo-controlled, double-blind, double-dummy study. Allergy. Jan; 2004 59(1):4553.
[PubMed: 14674933]
56. Lima MT, Wilson D, Pitkin L, et al. Grass pollen sublingual immunotherapy for seasonal
rhinoconjunctivitis: a randomized controlled trial. Clin Exp Allergy. Apr; 2002 32(4):507514.
[PubMed: 11972594]
57. Elenkov IJ, Chrousos GP. Stress Hormones, Th1/Th2 patterns, Pro/Anti-inflammatory Cytokines
and Susceptibility to Disease. Trends Endocrinol Metab. Nov; 1999 10(9):359368. [PubMed:
10511695]
58. DeKruyff RH, Fang Y, Umetsu DT. Corticosteroids enhance the capacity of macrophages to
induce Th2 cytokine synthesis in CD4+ lymphocytes by inhibiting IL-12 production. J Immunol.
Mar 1; 1998 160(5):22312237. [PubMed: 9498762]
59. Felten SY, Felten DL, Bellinger DL, et al. Noradrenergic sympathetic innervation of lymphoid
organs. Prog Allergy. 1988; 43:1436. [PubMed: 3059356]

Immunol Allergy Clin North Am. Author manuscript; available in PMC 2012 February 1.

Dave et al.

Page 13

NIH-PA Author Manuscript


NIH-PA Author Manuscript
NIH-PA Author Manuscript

60. Steinman L. Elaborate interactions between the immune and nervous systems. Nat Immunol. Jun;
2004 5(6):575581. [PubMed: 15164017]
61. Mix E, Goertsches R, Zettl UK. Immunology and neurology. J Neurol. May; 2007 254(Suppl
2):II27. [PubMed: 17503123]
62. Elenkov IJ. Neurohormonal-cytokine interactions: implications for inflammation, common human
diseases and well-being. Neurochem Int. Jan; 2008 52(12):4051. [PubMed: 17716784]
63. Lamb JP, Sparrow MP. Three-dimensional mapping of sensory innervation with substance p in
porcine bronchial mucosa: comparison with human airways. Am J Respir Crit Care Med. Nov 1;
2002 166(9):12691281. [PubMed: 12403698]
64. 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. JulAug; 2004 66(4):564571. [PubMed: 15272104]
65. Nockher WA, Renz H. Neurotrophins in allergic diseases: from neuronal growth factors to
intercellular signaling molecules. J Allergy Clin Immunol. Mar; 2006 117(3):583589. [PubMed:
16522457]
66. Wu X, Myers AC, Goldstone AC, Togias A, Sanico AM. Localization of nerve growth factor and
its receptors in the human nasal mucosa. J Allergy Clin Immunol. Aug; 2006 118(2):428433.
[PubMed: 16890768]
67. Barton C, Clarke D, Sulaiman N, Abramson M. Coping as a mediator of psychosocial impediments
to optimal management and control of asthma. Respir Med. Jul; 2003 97(7):747761. [PubMed:
12854624]
68. Lehrer PM, Vaschillo E, Vaschillo B, et al. Biofeedback treatment for asthma. Chest. Aug; 2004
126(2):352361. [PubMed: 15302717]
69. Epstein GN, Halper JP, Barrett EA, et al. A pilot study of mind-body changes in adults with
asthma who practice mental imagery. Altern Ther Health Med. Jul-Aug; 2004 10(4):6671.
[PubMed: 15285276]
70. Freeman LW, Welton D. Effects of imagery, critical thinking, and asthma education on symptoms
and mood state in adult asthma patients: a pilot study. J Altern Complement Med. Feb; 2005 11(1):
5768. [PubMed: 15750364]
71. Huntley A, White AR, Ernst E. Relaxation therapies for asthma: a systematic review. Thorax. Feb;
2002 57(2):127131. [PubMed: 11828041]
72. Lehrer P, Feldman J, Giardino N, Song HS, Schmaling K. Psychological aspects of asthma. J
Consult Clin Psychol. Jun; 2002 70(3):691711. [PubMed: 12090377]
73. Jamison JR. Psychoneuroendoimmunology: the biological basis of the placebo phenomenon? J
Manipulative Physiol Ther. Sep. 1996; 19(7):484487.
74. Rossi EL. Psychosocial genomics: gene expression, neurogenesis, and human experience in mindbody medicine. Adv Mind Body Med. Winter;2002 18(2):2230. [PubMed: 12629875]
75. Markham AW, Wilkinson JM. Complementary and alternative medicines (CAM) in the
management of asthma: an examination of the evidence. J Asthma. Apr; 2004 41(2):131139.
[PubMed: 15115165]
76. Counil FP, Varray A, Matecki S, et al. Training of aerobic and anaerobic fitness in children with
asthma. J Pediatr. Feb; 2003 142(2):179184. [PubMed: 12584541]
77. Hallstrand TS, Bates PW, Schoene RB. Aerobic conditioning in mild asthma decreases the
hyperpnea of exercise and improves exercise and ventilatory capacity. Chest. Nov; 2000 118(5):
14601469. [PubMed: 11083702]
78. Krommydas G, Gourgoulianis KI, Karamitsos K, Krapis K, Kotrotsiou E, Molyvdas PA.
Therapeutic value of antidepressants in asthma. Med Hypotheses. 2005; 64(5):938940. [PubMed:
15780488]
79. Katon WJ, Richardson L, Lozano P, McCauley E. The relationship of asthma and anxiety
disorders. Psychosom Med. MayJun; 2004 66(3):349355. [PubMed: 15184694]
80. Haida M, Itoh K. Clinical effect of alprazolam and trazodone on bronchial asthmatics with anxiety
disorder. Arerugi. Oct; 1997 46(10):10581071. [PubMed: 9404094]
81. Kang DH, McCarthy DO. The effect of psychological stress on neutrophil superoxide release. Res
Nurs Health. Oct; 1994 17(5):363370. [PubMed: 8090947]
Immunol Allergy Clin North Am. Author manuscript; available in PMC 2012 February 1.

Dave et al.

Page 14

82. Wakikawa A, Utsuyama M, Wakabayashi A, Kitagawa M, Hirokawa K. Vitamin E enhances the


immune functions of young but not old mice under restraint stress. Exp Gerontol. Nov; 1999
34(7):853862. [PubMed: 10622420]

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Fig 1.

Stress-Allergic Disease Paradigm

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