Clinical and Experimental Allergy, 2001, Volume 31, pages 25±31

REVIEW

Stress effects on immunity and its application to clinical

immunology
S . K . A G A R W A L and G . D . M A R S H A L L J R

Division of Allergy and Clinical Immunology, The University of Texas Houston Medical School, Houston, Texas, USA

Introduction Stressors are further classified into acute (minutes to

hours), subchronic (less than 1 month), and chronic
Various stressors, including both psychological as well as
(months to years). Some investigators have used the terms
physiological, have been demonstrated to influence the
`eustress' and `distress' to describe situations in which
immune response, presumably through activation of the
stressors do not cause harm or alter homeostasis, respec-
hypothalamic-pituitary-adrenal axis and sympathetic ner-
tively. Different types of stressors as well as durations of
vous system. Anecdotal evidence, and retrospective and
stress may elicit different neuroendocrine responses and
prospective studies, have demonstrated an effect of
immune alterations; however, these relationships have not
psychological and physiological stress on immune-based
been conclusively identified.
diseases such as asthma, atopy and infections. Alterations
Psychological stress precipitates a coordinated series of
in immune function, in particular the type-1/type-2
physiological and behavioural responses from the host,
cytokine balance, secondary to increased psychological
known as the stress response, aimed at protecting the host
stress, are thought to mediate these changes in health. The
and restoring homeostasis. The stress response results in
field of psychoneuroimmunology seeks to establish the link
activation of both the hypothalamic-pituitary-adrenal axis
between behaviour, neuroendocrine functions, immune
(H-P-A) and the sympathetic nervous system (SNS)
responses and health. The current review will describe
(Fig. 1) [1,2]. The paraventricular nucleus (PVN) of the
the effect of psychological stress on immune function, the
hypothalamus receives excitatory stimuli from the catacho-
impact of psychological stress on immune-based pathology,
laminergic pathways of the brainstem and limbic forebrain
and the future directions of research to determine the
circuits [3]. The central, medial and cortical amygdaloid
mechanisms and clinical significance of the field of
nuclei connect with the PVN via GABA-containing
psychoneuroimmunology.
neurones in the bed of the nucleus of the stria terminalis
[3].
The PVN may also be activated by aminergic input from
Stress and the stress response the locus coeruleus. Activation of glutamatergic neurones
Stress may be best defined as a psychophysiological in the PVN results in the secretion of corticotropin-
process, usually experienced as a negative emotional state. releasing hormone (CRH) from nerve terminals in the
It is a product of the appraisal of a situation and the median eminence. CRH reaches the anterior pituitary gland
resulting coping ability available to the individual. via the hypophysial portal circulation and stimulates
Stressors, defined as events posing threat, are judged in corticotrophs to release adrenocorticotropic hormone
the context of dispositional and environmental factors. (ACTH) into the peripheral circulation. ACTH subse-
Stressors (Table 1) may be physical (i.e. infection, quently stimulates the production of glucocorticoids by the
chemical exposure), cognitive (death of a loved one, cells of the zona fasciculata and the zona reticularis of the
perception of imminent danger), or a combination of both adrenal cortex. Activation of the SNS causes an increased
physical and cognitive (firefighter on a 24-h shift). secretion of catecholamines in nerve termini as well as the
adrenal medulla. Psychological stress also has effects on
Correspondence: Gailen D. Marshall Jr, The University of Texas ±
Houston Medical School, Department of Internal Medicine, Division of
other neuroendocrine pathways such as the hypothalamic-
Allergy and Clinical Immunology, 6431 Fannin M.S.B. 4.044, Houston, pituitary-gonadal axis, which may result in alterations in
Texas 77030, USA. menstrual cycle regulation [4].
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26 S.K. Agarwal and G.D. Marshall Jr

Table 1 Types of stressors immune function and subsequently alter the course of
immune-based diseases.
Physical Cognitive Chemical

Trauma/injury Anxiety Environmental toxins Immune-health link

Exercise/exhaustion Depression Diet The balance between cell-mediated immunity (CMI) and
Pain Anger Medications
humoral immunity is largely regulated by cytokines
Infection Major life events Recreational drugs
produced by subpopulations of CD41 T-helper cells, Th1
Hyper-/hypothermia Daily `hassles' Occupational exposures
and Th2 [8]. Th1 cytokines (interferon-gamma (IFN-g) and
IL-12) support CMI for host defence against intracellular
parasites such as viruses. Th2 cytokines (IL-4, IL-5, IL-10,
The autonomic nervous system and the H-P-A axis IL-13) support humoral immunity for host defence against
provide an interface between psychological stress and other extracellular parasites [9]. It is now appreciated that other
organ systems [5]. The stress-induced release of hormones populations of immune cells in addition to T-helper cells,
mediates, at least in part, the effects of stressors on immune including cytotoxic T-lymphocytes (CTL) and dendritic
function. Such effects appear to occur in both health and cells, secrete these cytokines in similar patterns. Therefore
disease. The neuroendocrine mediators reach the cells of the nomenclature, type-1 (Th1-like) and type-2 (Th2-like),
the immune system either through the peripheral circulation is commonly used to delineate a systemic response to
or through direct innervation of lymphoid organs. Primary antigen challenge.
and secondary lymphoid organs are innervated by sympa- Dysregulation of the type-1/type-2 cytokine production
thetic nerve fibers [6]. Lymphocytes and monocytes is thought to be involved in the pathogenesis of several
express receptors for several stress hormones, including infectious, atopic and asthmatic diseases [10±12]. As will
CRH, ACTH, cortisol, norepinephrine and epinephrine [7]. be discussed later, the involvement of the type-1/type-2
Therefore it is reasonable to conclude that the neuroendo- cytokine balance in the pathogenesis of these diseases may
crine hormones released during a stressful event could alter render them vulnerable to the adverse effects of psycho-
logical stress. The type-1/type-2 cytokine balance is
important in the maintenance of an adequate CMI against
HIV and is believed to be altered during the progression of
HIV infection. As HIV infection progresses, the type-1/
type-2 cytokine balance shifts from a predominant type-1
cytokine profile towards a type-2 cytokine profile [10,13].
Plasma from HIV1 patients with more advanced disease
has increased total IgE levels [10,14] and increased type-2
cytokines with concurrent decreased type-1 cytokines [10].
These studies suggest that HIV progression is associated
with a type-2 cytokine shift.
Dysregulation of the type-1/type-2 cytokine balance also
plays a significant role in the pathogenesis of asthma and
atopic diseases. Bronchial biopsies, bronchoalveolar lavage
cells, and peripheral blood mononuclear cells (PBMC)
obtained from asthmatics, contain increased IL-4, IL-5 and
IL-13 mRNA and protein [12,15]. Furthermore, antigen-
specific T-cell clones from atopic and allergic subjects are
more polarized towards the Th2 type compared to T-cell
clones from healthy subjects [16]. IL-4 is necessary for the
isotype switch from IgM to IgE, functions as a mast cell
growth factor, and upregulates the expression of eosino-
phil-related adhesion molecules on lung fibroblasts [17,18].
Eosinophil chemotaxis, differentiation and survival are all
supported by IL-5 [19,20]. IL-13, in conjunction with IL-4,
contributes to the IgE isotype switch and elicits some of the
pathological findings of asthma independent of IL-4 [21±
Fig. 1. The stress response. ! ˆ activation; ´´´´´ ˆ inhibition. 24]. Therefore, conditions that increase type-2 cytokine
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 Stress effects on immunity 27

production may lead to a worsening of asthmatic and atopic However, recent data have suggested that a dysregulation
symptoms. of the type-1/type-2 cytokine balance may play a more
significant role in stress-associated immune alterations
[42]. Using the academic stress model, we recently
Stress-immune link
demonstrated that PBMC production of IFN-g, a type-1
The impact of psychological stress on immune function has cytokine, was decreased with a concurrent increase in IL-
been the subject of extensive research efforts. Many 10, a type-2 cytokine, production during an examination
models, such as bereavement, marital discord, caregiving period compared with a period of lower stress. Further-
for a relative with a chronic disease, living with a cancer more, the increase in IL-10 production and the decrease in
diagnosis, and academic exam stress, have been utilized to the IFNg:IL-10 ratio correlated with the level of psycho-
investigate the affect of chronic stress on immune function logical distress as measured by the Hassles Scale. These
[25±30]. Using these models, it has been reported that data suggest that chronic stress does not simply suppress
stress is associated with a suppression of NK cell the immune system, but induces a shift in the type-1/type-2
cytotoxicity, lymphocyte proliferation, and PBMC produc- cytokine balance towards a type-2 cytokine response. A
tion of IL-2 and IFN-g [25,30±34]. Psychological stress is stress-associated alteration in the type-1/type-2 cytokine
also associated with a higher rate of hypoergy to the balance may better explain the fluctuations in the clinical
common recall delayed type hypersensitivity antigens [35]. course of several immune-based diseases (discussed
These studies suggest that psychological stress suppresses below).
various components of CMI responses. In vitro models are currently being utilized to investigate
The effects of psychological stress on latent herpes virus the mechanisms of the in vivo stress-associated immune
reactivation have also been investigated in both animal and dysregulation. Glucocorticoids and catecholamines, at
human models [36,37]. Plasma obtained from volunteers concentrations observed during periods of stress, decrease
during medical student exams contained elevated levels of IFN-g production and increase IL-4 and IL-10 production
immunoglobulins specific for the EBV viral capsid antigen, by human PBMC, indicating a shift in the type-1/type-2
indicating reactivation of EBV [32,34,38]. In addition, cytokine balance towards a type-2 response [43,44]. In
stress inhibited EBV-stimulated PBMC proliferation and addition, in vitro exposure to cortisol analogs, ACTH,
EBV-specific CTL activity [32,36]. In another study, somatostatin and CRH causes a viral production in cell
Glaser and colleagues demonstrated that caregivers of lines latently infected with EBV [45] and HIV [46]. These
patients with Alzheimer's disease had significantly higher data demonstrate the ability of the neuroendocrine
antibody titres to herpes simplex virus type-1 (HSV-1) and hormones to directly modulate immune function and may
lower HSV-1 specific PBMC proliferation than matched in part explain the type-1/type-2 cytokine alterations and
controls [39]. These changes in latent virus expression are latent virus reactivation observed in subjects during periods
thought to be secondary to the stress-associated inhibition of increased psychological stress.
of CMI.
Psychological stress has also been reported to alter the
Stress-health link
immune response to vaccines [39±41]. A lower rate of
seroconversion after the first hepatitis B vaccine injection A common clinical observation is the adverse relationship
has been associated with higher levels of psychological between stress and human disease [47]. Although the
stress [39]. In addition, students with greater social support effects of stress on health have been difficult to
had higher serum antibody titres to hepatitis B surface demonstrate due to the difficulty in assessing stress levels,
antigen (HBsAg) and PBMC proliferation to a HBsAg than the number of potential confounding variables, and the low
those with lower levels of social support [39]. In another incidence of an illness in study populations, several
study, caregivers of Alzheimer's patients had lower investigators have demonstrated a significant interaction
influenza-specific antibody titres and influenza-stimulated between psychological stress and health. This association
IL-2 production by PBMC following influenza virus appears to be particularly true with regards to immune-
vaccination compared to the control subjects. Therefore, based diseases such as increased susceptibility to infections
chronic psychological stress can have a significant adverse [48,49], atopic diseases [50±52] and asthma [53,54]. Stress
impact on the immune response against vaccines. is also suspected of playing a role in morbidity and
Based on the stress-associated alterations in in vitro mortality in other immune-based diseases such as cancer
immune responses, latent virus reactivation, and vaccine [55], HIV disease [56], and the immune senescence
responses discussed above, the postulated mechanism most associated with ageing [57,58]. The adverse effects of
often advanced to explain these results involves immuno- stress on health are potentially mediated by the stress-
suppression as a fundamental effect of stress [34]. associated type-1/type-2 cytokine alterations [42].
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28 S.K. Agarwal and G.D. Marshall Jr

proliferation, decreased numbers of NK cells and CTL, and

increased latent viral expression in HIV1 subjects [65,66].
In addition, asymptomatic HIV1 subjects reporting
increased psychological stress levels had lower CD41 T-
lymphocyte numbers that were moderated by an active
coping style [67,68]. Finally, several reports have demon-
strated beneficial effects of interventions that decrease
stress levels, on immune function and CD41 T-lympho-
cyte numbers of HIV1 subjects [69±71]. These studies
suggest that stress-associated immune alterations, particu-
larly during the early stages of HIV infection, may place
patients at increased risk for rapid progression. Additional
studies utilizing more sensitive surrogate markers (e.g. viral
load) are necessary to better define the relationship between
stress and HIV.
Fig. 2. The stress-distress-immune-health paradigm.
Stress and asthma
Stress and viral infections
Anecdotal evidence supports a relationship between
Psychological stress has been associated with increased increased emotional states and asthma exacerbations.
susceptibility and/or risk of infectious diseases, including Indeed, compared to healthy controls, asthmatics have
upper respiratory infections (URI), herpes reactivation and higher levels of life stress and negative emotions, such as
HIV. A recent report demonstrated that persistent stressors panic, fear and irritability [72±76]. Furthermore, some
and anxiety predict recurrence of genital herpes in women asthmatics have been found to have higher levels of
[59]. Graham and colleagues prospectively followed 235 psychological symptoms [77] and depression [78]. While
adults, and found that higher levels of self-reported stress these studies show a relationship between emotion, stress
were associated with increased coryzal symptoms and and asthma they do not adequately define the cause and
confirmed URIs [60]. A subsequent study found that effect relationship. Some studies have shown that the
children with a history of recurrent URI had increased increased psychological symptoms are a result of asthma
levels of distress and lower salivary IgA levels, suggesting exacerbations [79]. On the other hand, other studies suggest
a suppression of local mucosal immunity [61]. In a recent that extreme emotional manifestations can worsen asthma
report, life stress was associated with an increase in URI symptoms [72].
incidence in children that was moderated by social support Recently there have been several studies using the
[62]. academic stress model in teenage asthmatics [80±82].
The studies discussed above suggest an association These studies demonstrated that mild to moderate asthmatic
between stress and URI susceptibility, but do not subjects have immunological changes (decreased NK cell
differentiate between the stress-associated changes in host cytotoxicity and cytokine alterations) in response to exam
resistance or increased exposure to viruses due to changes stress. These immune alterations are consistent with a
in social behaviour. To address this issue, Cohen et al. cytokine milieu that could potentially worsen asthma;
administered an experimental intranasal viral challenge to however, there were no changes in peak flow rates, self-
volunteers who were kept in isolation, to minimize the report asthma symptoms or medication utilization. The lack
effect of prior viral exposure and person-to-person spread. of correlation between stress and asthma symptoms may be
The rates of viral infection as well as coryzal symptoms related to the timing of the visits in relation to the stressor,
correlated with increased psychological stress levels [63]. the duration of the stressor, disease severity, or a lack of
In a subsequent study, only stressors of at least 1 month in accurate self-report data. Alternatively, stress-mediated
duration were sufficient to increase an individual's risk for exacerbations of asthma may require multiple alterations
URIs [64]. These studies suggest that psychological stress by stress, including cytokine dysregulation and/or vagal-
is associated with increased URI susceptibility due to mediated airway hyperresponsiveness.
intrinsic changes in host resistance. A recent intervention study suggests that psychological
The relationship between stress, immune function and stress may play an important role in asthma [83].
health has sparked an interest in the potential adverse Asthmatics who wrote about past stressful experiences
impact of stress on the progression of HIV infection. had an improvement in the predicted FEV1 compared to
Psychological stress is associated with decreased PBMC control groups, which was associated with decreases in
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 Stress effects on immunity 29

self-reported distress levels. These results are provocative hormones and their receptors in the immune system. Produc-
in that they demonstrate a relationship between psycholo- tion, processing and action. J Neuroimmunol 1985; 10:31±40.
gical stress and asthma and suggest a role for stress 8 Mosmann TR, Cherwinski H, Bond MW, Giedlin MA,
management in the treatment of complicated asthmatics. Coffman RL. Two types of murine helper T cell clone. I.
Definition according to profiles of lymphokine activities and
secreted proteins. J Immunol 1986; 136:2348±57.
Future directions in psychoneuroimmunology 9 Mosmann TR, Sad S. The expanding universe of T-cell
subsets: Th1, Th2 and more. Immunol Today 1996; 17:138±
As discussed above, extensive research has demonstrated a 46.
marked effect of psychological stress on immunity in 10 Agarwal SK, Marshall GD. In vivo alteration in type-1 and
humans. Currently, it is hypothesized that through activa- type-2 cytokine balance: a possible mechanism for elevated
tion of the H-P-A axis and the SNS, stress induces a total IgE in HIV-infected patients. Hum Immunol 1998;
dysregulation of the type-1/type-2 cytokine. We believe 59:99±105.
that these type-1/type-2 cytokine alterations are a major 11 Kuchroo VK, Das MP, Brown JA, Ranger AM, Zamvil SS,
mechanism of the stress-associated increased susceptibility Sobel RA et al. B7±1 and B7±2 costimulatory molecules
and/or severity of immune-based diseases (Fig. 2). It activate differentially the Th1/Th2 developmental pathways:
remains to be determined whether the effects of psycho- application to autoimmune disease therapy. Cell 1995;
logical stress on immune balance are mediated through 80:707±18.
alterations in type-1/type-2 cellular differentiation, cellular 12 Robinson D, Hamid Q, Bentley A, Ying S, Kay AB, Durham
SR Activation of CD41 T cells, increased TH2-type cytokine
trafficking, chemokine production, and/or adhesion mole-
mRNA expression, and eosinophil recruitment in bronchoal-
cule expression.
veolar lavage after allergen inhalation challenge in patients
Additional prospective studies using clinically relevant with atopic asthma. J Allergy Clin Immunol 1993; 92:313±24.
outcome measures are necessary to further define the 13 Clerici M, Shearer GM. The Th1-Th2 hypothesis of HIV
impact of psychological stress on immune-based diseases. infection: new insights. Immunol Today 1994; 15:575±81.
Better definition of the mechanisms of the stress-associated 14 Israel-Biet D, Labrousse F, Tourani JM, Sors H, Andrieu JM,
immune alterations, the specific nature of the stressors that Even P. Elevation of IgE in HIV-infected subjects: a marker of
adversely impact health, and the clinical course of stress- poor prognosis. J Allergy Clin Immunol 1992; 89:68±75.
mediated alterations in disease, will provide valuable 15 Del Prete GF, De Carli M, D'Elios MM, Maestrelli P, Ricci M,
insight for the development of pharmacological and/or Fabbri L, Romagnani S. Allergen exposure induces the
behavioural interventions to prevent and/or treat the clinical activation of allergen-specific Th2 cells in the airway mucosa
sequelae of stress-associated immune dysregulation. of patients with allergic respiratory disorders. Eur J Immunol
1993; 23:1445±49.
16 Essayan DM, Han WF, Li XM, Xiao HQ, Kleine-Tebbe J,
References Huang SK. Clonal diversity of IL-4 and IL-13 expression in
human allergen-specific T lymphocytes. J Allergy Clin
1 Meyerhoff JL, Oleshansky MA, Mougey EH. Psychologic Immunol 1996; 98:1035±44.
stress increases plasma levels of prolactin, cortisol, and 17 Romagnani S, Del Prete G, Maggi E, Parronchi P, Tiri A,
POMC-derived peptides in man. Psychosom Med 1988; Macchia D et al. Role of interleukins in induction and
50:295±303. regulation of human IgE synthesis. Clin Immunol Immuno-
2 Richter SD, Schurmeyer TH, Schedlowski M, Hadicke A, pathol 1989; 50:S13±S23.
Tewes U, Schmidt RE, Wagner TO. Time kinetics of the 18 Doucet C, Brouty-Boye D, Pottin-Clemenceau C, Canonica
endocrine response to acute psychological stress. J Clin GW, Jasmin C, Azzarone B. Interleukin (IL) 4 and IL-13 act
Endocrinol Metab 1996; 81:1956±60. on human lung fibroblasts. Implication in asthma. J Clin Invest
3 Herman JP, Cullinan WE. Neurocircuitry of stress: central 1998; 101:2129±39.
control of the hypothalamo-pituitary-adrenocortical axis. 19 Dent LA, Strath M, Mellor AL, Sanderson CJ. Eosinophilia in
Trends Neurosci 1997; 20:78±84. transgenic mice expressing interleukin 5. J Exp Med 1990;
4 Chrousos GP, Torpy DJ, Gold PW. Interactions between the 172:1425±31.
hypothalamic-pituitary-adrenal axis and the female reproduc- 20 Sanderson CJ, Warren DJ, Strath M. Identification of a
tive system: clinical implications. Ann Intern Med 1998; lymphokine that stimulates eosinophil differentiation in vitro.
129:229±40. Its relationship to interleukin 3, and functional properties of
5 Wilder RL. Neuroendocrine±immune system interactions and eosinophils produced in cultures. J Exp Med 1985; 162:60±74.
autoimmunity. Annu Rev Immunol 1995; 13:307±38. 21 Punnonen J, Yssel H, de Vries JE. The relative contribution of
6 Felten DL. Direct innervation of lymphoid organs: substrate IL-4 and IL-13 to human IgE synthesis induced by activated
for neurotransmitter signaling of cells of the immune system. CD41 or CD81 T cells. J Allergy Clin Immunol 1997;
Neuropsychobiology 1993; 28:110±12. 100:792±801.
7 Blalock JE, Bost KL, Smith EM. Neuroendocrine peptide 22 Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher
q 2001 Blackwell Science Ltd, Clinical and Experimental Allergy, 31, 25±31
30 S.K. Agarwal and G.D. Marshall Jr

F, Rennick DM et al. Requirement for IL-13 independently of Kennedy S, Hughes J. Stress±induced modulation of the
IL-4 in experimental asthma. Science 1998; 282:2261±63. immune response to recombinant hepatitis B vaccine.
23 Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Nelsen TY, Psychosom Med 1992; 54:22±9.
Karp CL, Donaldson DD. Interleukin-13: central mediator of 40 Glaser R, Kiecolt±Glaser JK, Malarkey WB, Sheridan JF. The
allergic asthma. Science 1998; 282:2258±61. influence of psychological stress on the immune response to
24 Parronchi P, De Carli M, Manetti R et al. Aberrant interleukin vaccines. Ann. NY Acad Sci 1998; 840:649±55.
(IL)-4 and IL-5 production in vitro by CD41 helper T cells 41 Jabaaij L, Grosheide PM, Heijtink RA, Duivenvoorden HJ,
from atopic subjects. Eur J Immunol 1992; 22:1615±20. Ballieux RE, Vingerhoets AJ. Influence of perceived psycho-
25 Schleifer SJ, Keller SE, Camerino M, Thornton JC, Stein M. logical stress and distress on antibody response to low dose
Suppression of lymphocyte stimulation following bereave- rDNA hepatitis B vaccine. J Psychosom Res 1993; 37:361±9.
ment. JAMA 1983; 250:374±7. 42 Marshall GD, Agarwal SK, Lloyd C, Cohen L, Henninger EM,
26 Kiecolt-Glaser JK, Fisher LD, Ogrocki P, Stout JC, Speicher Morris GJ. Cytokine dysregulation in healthy medical students
CE, Glaser R. Marital quality, marital disruption, and immune associated with exam stress. Brain Behav Immun 1998;
function. Psychosom Med 1987; 49:13±34. 12:297±307.
27 Esterling BA, Kiecolt-Glaser JK, Bodnar JC, Glaser R. 43 Agarwal SK, Marshall GD. Glucocorticoid±induced type 1/
Chronic stress, social support, and persistent alterations in type 2 cytokine alterations in humans: a model for stress±
the natural killer cell response to cytokines in older adults. related immune dysfunction. J Interferon Cytokine Res 1998;
Health Psychol 1994; 13:291±8. 18:1059±68.
28 Kiecolt-Glaser JK, Dura JR, Speicher CE, Trask OJ, Glaser R. 44 Agarwal SK, Marshall GDJ. beta±Adrenergic modulation of
Spousal caregivers of dementia victims: longitudinal changes human type21/type22 cytokine balance. J Allergy Clin
in immunity and health. Psychosom Med 1991; 53:345±62. Immunol 2000; 105:91±8.
29 Andersen BL, Farrar WB, Golden-Kreutz D, Kutz LA, 45 Glaser R, Kutz LA, MacCallum RC, Malarkey WB. Hormonal
MacCallum R, Courtney ME, Glaser R. Stress and immune modulation of Epstein±Barr virus replication. Neuroendocri-
responses after surgical treatment for regional breast cancer. J nology 1995; 62:356±61.
Natl Cancer Inst 1998; 90:30±36. 46 Marshall GD, Agarwal SK, Glaser R. Enhancement of chronic
30 Kiecolt-Glaser JK, Garner W, Speicher C, Penn GM, Holliday HIV infection in vitro by stress hormones. Neuroimmunomo-
J, Glaser R. Psychosocial modifiers of immunocompetence in dulation 1999; 6:235 (Abstract).
medical students. Psychosom Med 1984; 46:7±14. 47 McEwen BS, Stellar E. Stress and the individual. Mechanisms
31 Kiecolt-Glaser JK, Glaser R, Strain EC, Stout JC, Tarr KL, leading to disease. Arch Intern Med 1993; 153:2093±101.
Holliday JE, Speicher CE. Modulation of cellular immunity in 48 Sheridan JF, Dobbs C, Brown D, Zwilling B. Psychoneur-
medical students. J Behav Med. 1986; 9:5±21. oimmunology: stress effects on pathogenesis and immunity
32 Glaser R, Pearson GR, Bonneau RH, Esterling BA, Atkinson during infection. Clin Microbiol Rev 1994; 7:200±12.
C, Kiecolt-Glaser JK. Stress and the memory T-cell response 49 Shephard RJ, Shek PN. Infectious diseases in athletes: new
to the Epstein-Barr virus in healthy medical students. Health interest for an old problem. J Sports Med Phys Fitness 1994;
Psychol 1993; 12:435±42. 34:11±22.
33 Dobbin JP, Harth M, McCain GA, Martin RA, Cousin K. 50 Michel FB. Psychology of the allergic patient. Allergy 1994;
Cytokine production and lymphocyte transformation during 49:28±30.
stress. Brain Behav Immun 1991; 5:339±48. 51 Parker CW. Environmental stress and immunity: possible
34 Glaser R, Rice J, Sheridan J, Fertel R, Stout J, Speicher C et al. implications for IgE±mediated allergy. Perspect Biol Med
Stress-related immune suppression: health implications. Brain 1991; 34:197±212.
Behav Immun 1987; 1:7±20. 52 Kodama A, Horikawa T, Suzuki T, Ajiki W, Takashima T,
35 Muller HK, Lugg DJ, Quinn D. Cell mediated immunity in Haroda S, Ichihashi M. Effect of stress on atopic dermatitis:
Antarctic wintering personnel; 1984±92. Immunol Cell Biol investigation in patients after the Great Hanshin earthquake. J
1995; 73:316±20. Allergy Clin Immunol 1999; 104:173±6.
36 Glaser R, Pearson GR, Jones JF, Millhouse J, Kennedy S, Mao 53 Koh KB, Hong CS. The relationship of stress with serum IgE
HY, Kiecolt-Glaser JK. Stress-related activation of Epstein- level in patients with bronchial asthma. Yonsei Med J 1993;
Barr virus. Brain Behav Immun 1991; 5:219±32. 34:166±74.
37 Padgett DA, Sheridan JF, Dorne J, Berntson GG, Candelora J, 54 Busse WW, Kiecolt±Glaser JK, Coe C, Martin RJ, Weiss ST,
Glaser R. Social stress and the reactivation of latent herpes Parker SR. NHLBI Workshop summary. Stress and asthma.
simplex virus type 1 [published erratum appears in Proc Natl Am J Respir Crit Care Med 1995; 151:249±52.
Acad Sci USA 1998; 95(20):12070]. Proc Natl Acad Sci USA 55 Chorot P, Sandin B. Life events and stress reactivity as
1998; 95:7231±35. predictors of cancer, coronary heart disease and anxiety
38 Glaser R, Pearl DK, Kiecolt±Glaser JK, Malarkey WB. disorders. Int J Psychosom 1994; 41:34±40.
Plasma cortisol levels and reactivation of latent Epstein±Barr 56 Evans DL, Leserman J, Perkins DO et al. Stress±associated
virus in response to examination stress. Psychoneuroendocri- reductions of cytotoxic T lymphocytes and natural killer cells
nology 1994; 19:765±72. in asymptomatic HIV infection. Am J Psychiatry 1995;
39 Glaser R, Kiecolt±Glaser JK, Bonneau RH, Malarkey W, 152:543±50.
q 2001 Blackwell Science Ltd, Clinical and Experimental Allergy, 31, 25±31
 Stress effects on immunity 31

57 Kiecolt±Glaser JK, Glaser R, Williger D et al. Psychosocial Perna F, Schneiderman N. Change in CD41 cell enumeration
enhancement of immunocompetence in a geriatric population. following aerobic exercise training in HIV21 disease:
Health Psychol 1985; 4:25±41. possible mechanisms and practical applications. Int J Sports
58 Finkelstein MS. Aging immunocytes and immunity. Char- Med 1997; 18(Suppl. 1):S56±S61.
acteristics and significance. Clin Geriatr Med 1985; 1:899± 71 Lutgendorf SK, Antoni MH, Ironson G et al. Cognitive±
911. behavioral stress management decreases dysphoric mood and
59 Cohen F, Kemeny ME, Kearney KA, Zegans LS, Neuhaus JM, herpes simplex virus±type 2 antibody titers in symptomatic
Conant MA. Persistent stress as a predictor of genital herpes HIV±seropositive gay men. J Consult Clin Psychol 1997;
recurrence. Arch Intern Med 1999; 159:2430±36. 65:31±43.
60 Graham MB, Braciale VL, Braciale TJ. Influenza virus± 72 Lehrer PM, Isenberg S, Hochron SM. Asthma and emotion: a
specific CD41 T helper type 2 T lymphocytes do not promote review. J Asthma 1993; 30:5±21.
recovery from experimental virus infection. J Exp Med 1994; 73 Dirks JF, Kinsman RA, Staudenmayer H, Kleiger JH. Panic±
180:1273±82. fear in asthma. Symptomatology as an index of signal anxiety
61 Drummond PD, Hewson±Bower B. Increased psychosocial and personality as an index of ego resources. J Nerv Ment Dis
stress and decreased mucosal immunity in children with 1979; 167:615±9.
recurrent upper respiratory tract infections. J Psychosom Res 74 Carr RE, Lehrer PM, Hochron SM. Panic symptoms in asthma
1997; 43:271±8. and panic disorder: a preliminary test of the dyspnea±fear
62 Turner CJ, Steptoe A. Psychosocial influences on upper theory. Behav Res Ther 1992; 30:251±61.
respiratory infectious illness in children. J Psychosom Res 75 Wade S, Weil C, Holden G, Mitchell H, Evans R 3rd,
1998; 45:319±30. Kruszon-Moran D et al. Psychosocial characteristics of
63 Cohen S, Tyrrell DA, Smith AP. Psychological stress and inner±city children with asthma: a description of the
susceptibility to the common cold. N Engl J Med 1991; NCICAS psychosocial protocol. National Cooperative Inner±
325:606±12. City Asthma Study. Pediatr Pulmonol 1997; 24:263±76.
64 Cohen S, Frank E, Doyle WJ, Skoner DP, Rabin BS, Gwaltney 76 Sarafino EP, Dillon JM. Relationships among respiratory
JMJ. Types of stressors that increase susceptibility to the common infections, triggers of attacks, and asthma severity in children.
cold in healthy adults. Health Psychol 1998; 17:214±23. J Asthma 1998; 35:497±504.
65 Ironson G, LaPerriere A, Antoni M, O'Hearn P, Schneiderman 77 Badoux A, Levy DA. Psychologic symptoms in asthma and
N, Klimas N, Fletcher MA. Changes in immune and chronic urticaria. Ann Allergy 1994; 72:229±34.
psychological measures as a function of anticipation and 78 Miller BD. Depression and asthma: a potentially lethal
reaction to news of HIV21 antibody status. Psychosom Med mixture. J Allergy Clin Immunol 1987; 80:481±6.
1990; 52:247±70. 79 Apter AJ, Affleck G, Reisine ST, Tennen HA, Basrows E,
66 Esterling BA, Antoni MH, Schneiderman N, Carver CS, La Wells M et al. Perception of airway obstruction in asthma:
Perriere A, Ironson G et al. Psychosocial modulation of sequential daily analyses of symptoms, peak expiratory flow
antibody to Epstein±Barr viral capsid antigen and human rate, and mood. J Allergy Clin Immunol 1997; 99:605±12.
herpesvirus type26 in HIV21±infected and at±risk gay men. 80 Kang DH, Coe CL, Karaszewski J, McCarthy DO. Relation-
Psychosom Med 1992; 54:354±71. ship of social support to stress responses and immune function
67 Goodkin K, Fuchs I, Feaster D, Leeka J, Rishel DD. Life in healthy and asthmatic adolescents. Res Nurs Health 1998;
stressors and coping style are associated with immune 21:117±28.
measures in HIV21 infection ± a preliminary report. Int J 81 Kang DH, Coe CL, McCarthy DO. Academic examinations
Psychiatry Med 1992; 22:155±72. significantly impact immune responses, but not lung function,
68 Goodkin K, Blaney NT, Feaster D, Fletcher MA, Baum MK, in healthy and well±managed asthmatic adolescents. Brain
Mantero-Atienza E et al. Active coping style is associated with Behav Immun 1996; 10:164±81.
natural killer cell cytotoxicity in asymptomatic HIV21 82 Kang DH, Coe CL, McCarthy DO et al. Cytokine profiles of
seropositive homosexual men. J Psychosom Res 1992; stimulated blood lymphocytes in asthmatic and healthy
36:635±50. adolescents across the school year. J Interferon Cytokine Res
69 Ironson G, Field T, Scafidi F, Hashimoto M, Kumar M, Price 1997; 17:481±7.
A et al. Massage therapy is associated with enhancement of the 83 Smyth JM, Stone AA, Hurewitz A, Kaell A. Effects of writing
immune system's cytotoxic capacity. Int J Neurosci 1996; about stressful experiences on symptom reduction in patients
84:205±17. with asthma or rheumatoid arthritis: a randomized trial. JAMA
70 LaPerriere A, Klimas N, Fletcher MA, Perry A, Ironson G, 1999; 281:1304±09.

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