Dermatologic Therapy, Vol.

21, 2008, 2231

Printed in the United States All rights reserved

Copyright Blackwell Publishing, Inc., 2008

DERMATOLOGIC THERAPY
ISSN 1396-0296

Blackwell Publishing Inc

Psychoneuroimmunology

FRANCISCO TAUSK*, ILIA ELENKOV & JAN MOYNIHAN

*Department of Dermatology, University of Rochester, Rochester, New York,
Institute of Neurobiology and Molecular Medicine, Rome, and Department
of Psychiatry, University of Rochester, New York

ABSTRACT: Psychoneuroimmunology (PNI) is a discipline that has evolved in the last 40 years to
study the relationship between immunity, the endocrine system, and the central and peripheral
nervous systems. In this manner, neurotransmitters, hormones, and neuropeptides have been found
to regulate immune cells, and these in turn are capable of communicating with nervous tissue
through the secretion of a wide variety of cytokines. Of critical importance is the effect of products of
the CNS and nerves on the maintenance of the delicate balance between cell-mediated (Th1) and
humoral (Th2) immune responses. A good example of how this concept operates in vivo becomes
evident when analyzing the effects of stressors. Chronic stress affects significantly the function of the
immune system as well as modifies the evolution of a variety of skin diseases, as psychosocial interventions have proved to be effective in their therapy.
KEYWORDS: dermatology, neuropeptides, psychoneuroimmunology, stress

Introduction:
Psychoneuroimmunology
The study of mindbody interactions can be traced
back to the time of Hippocrates (c. 460 BC360 BC),
although this early work appeared to have been
focused more on body-to-brain regulation rather
than on brain regulation of physical health (1).
The discipline of psychoneuroimmunology (PNI)
can be argued to have formally begun its emergence in the mid 1970s, with the seminal work of
Ader and Cohen (2) and the finding that changes
in immune function could be behaviorally conditioned, in a manner analogous to the classical
conditioning studies of Pavlov and his canine
subjects. From a practical perspective, that the
central nervous system (CNS) might regulate
immune function, and further, that the immune
system might communicate with the CNS, seems
quite logical and to have clear adaptive value.
For example, it would makes sense for the brain
Address correspondence and reprint requests to: Francisco
Tausk, MD, Department of Dermatology, University of
Rochester, 601 Elmwood Ave., BOX 697, Rochester, NY 14642, or
email: Francisco_Tausk@URMC.Rochester.edu.
Adapted from Tausk et al., with permission from Gaspari A,
Tyring S, Clinical Immunodermatology London: Springer; 2007
(In press)

22

to warn the innate immune system of an impending wound to be inflicted by a predator, and for
lymphocytes to become mobilized to the skin in
anticipation. As the brain functions as the control
center for the entire body, it is entrusted with
maintaining constant communication with all other
bodily systems, resulting in integrated function of
all systems. However, as our understanding of
immunology largely unfolded in the Petri dish,
immunologists had become quite convinced that
the cells of the immune system function often
autonomously, and are regulated only by each
other. Although it is indeed the case that immune
responses can be elicited in vitro, and such studies have been critical for our understanding of
mechanisms of immune function, immunologists
were resistant to the consideration that immune
responses in vivo take place in an environment
that contains nerve fibers, neurotransmitters, and
hormones. Thus, the early days of PNI were
fraught with tension, as the hard evidence for
brain-behavior-immune system interactions was,
initially, scant.
At the present time, there is no longer much
question that the nervous and immune systems
are tightly connected. In addition to growing
support for behavioral conditioning of a variety of
types of immune responses, four additional important

Psychoneuroimmunology

lines of evidence have converged over time to

establish the connections as incontrovertible. First,
CNS (hypothalamic) interventions (including lesioning studies) alter immunologic reactivity, and the
elicitation of an immune response alters CNS
activity. Second, there is sympathetic innervation
of spleen and other lymphoid organs, including
the skin. Third, changes in hormone or transmitter
levels produce changes in immune function, and
vice versa. Finally, lymphoid cells express receptors
for a variety of hormones and transmitters. Thus,
lymphoid cells are exposed to neurochemical
ligands, and express the receptors necessary to
bind them. Although it is beyond the scope of this
article, it is important to acknowledge that the
communication between brain and immune
system is bidirectional, with signaling back to the
brain via the vagus nerve (3), and via soluble
cytokines, including interleukin (IL)-6, IL-1, and
tumor necrosis factor (TNF)-. To date, the majority
of the PNI literature has focused on the role of
major neural pathways activated by internal or
external neurosensory signals or stressors: the
hypothalamopituitary adrenal (HPA) axis and the
sympathetic nervous system (SNS). Chrousos (4,5),
Dunn (6), and others (79) have elegantly reviewed
stressor-induced activation of these pathways.
Briefly, neurosensory signals are ultimately
processed in the paraventricular nucleus (PVN) of
the hypothalamus and in the locus ceruleusnoradrenergic center. In response to stressors, the
hypothalamus secretes corticotropin-releasing
hormone (CRH) and arginine vasopressin (AVP).
From the PVN, CRH-containing neurons have
efferent pathways to the median eminence, and
projections to noradrenergic centers in the brainstem and spinal cord. CRH release further activates
the HPA axis, leading to release of peptides from
the pituitary produced by the differential cleavage
of pro-opiomelanocortin, most notably adrenocorticotropic hormone, enkephalins, and endorphins.
Adrenocorticotropic hormone induces downstream
release of glucocorticoids from the adrenal cortex.
CRH and noradrenergic neurons in the CNS innervate and stimulate each other. Activation of the
noradrenergic pathways by CRH results in secretion of norepinephrine (NE) by the peripheral
SNS and release of NE and epinephrine (EPI) from
the adrenal medulla. The activation of these two
neurochemical pathways and release of hormones
and transmitters can have profound downstream
effects on immune function (reviewed in (10))
Arguably, every one of the hormones/transmitters
secreted by these nervous system regions has
been shown to have the potential, either in vivo or

in vitro, to alter some aspect of immunity (e.g.,

(11,12)) Furthermore, not only do lymphoid cells
respond to neurochemicals via receptor-mediated
interactions, but T cells, in particular, have been
demonstrated to express either immunoreactive
protein or mRNA for hormones with an historical
nervous system function, including CRH, AVP, and
prolactin (13,14).
Lymphoid cells, then, live and function in a
fluctuating sea of neuroendocrine substances,
with levels of many of these hormones changing
diurnally, and as a function of either acute and/or
chronic stimuli. Not surprisingly, then, a review of
the stress literature clearly shows that stress effects
on immune function are not unidirectional and
can also vary in magnitude. At the very least, three
broad categories of variables interact with neurosensory signals to ultimately affect changes in
immune and/or infectious disease outcomes: the
experimental subject (e.g., the age, sex, strain, and
previous history of the subject), the nature of the
stimulus itself (e.g., the intensity, duration, and
the individuals perception of the stimulus), and
the immune response that is examined.
One of the best, and now classic, illustrations
that stress effects on immune function are not
unidirectional comes from the work of Lysle and
colleagues (15), using a tail-shock paradigm with
rats. In this paradigm, a single shock session
(composed of 16 tail shocks delivered on a variable basis over 60 minutes) was associated with a
very robust suppression of both splenic and
peripheral blood T-cell proliferative responses. Of
interest is that with three or five daily equivalent
sessions, the response of splenic T cells returned
to that of the control levels, whereas T-cell proliferative responses in the peripheral blood remained
dramatically suppressed. Thus, the effects of stress
differed as a function of both chronicity and the
lymphoid organ examined.
Relevant to this article are studies that have
focused on PNI and the skin. As the principal
barrier to environmental insults, the skin has specialized immunological processes, and also functions as an important component of the diffuse
brain (16). An array of neuropeptides is localized
in the skin, including substance P, calcitonin
gene-related peptide, vasoactive intestinal peptide,
and nerve growth factor (NGF). These peptides have
been implicated in modulating immune function
in the skin, and appear to play roles in development
of skin diseases, particularly psoriasis (17), which
will be discussed later in this article.
Nervous systemimmune system interactions
(as in blood and other secondary lymphoid organs)

23

Tausk et al.

are also not unidirectional in the skin. As an

example, a decade ago, Dhabhar and colleagues
observed that the effects of acute versus chronic
restraint stress of rats on delayed-type hypersensitivity (DTH) responses appear to be in opposite
directions (18). Following a single session of
restraint prior to challenge with 2,4-dinitro-1fluorobenzene (DNFB)(25 hours of restraint), DTH
responses in skin (as measured by ear swelling)
were enhanced, but following chronic (daily for 3
weeks) restraint sessions, DTH responses were
suppressed compared to control mice (19). The
investigators further showed that adrenally derived
corticosterone and EPI may mediate these effects;
that is, the enhanced DTH response was abrogated
by adrenalectomy (20). Dhabhar proposed that acute
stress may induce redeployment of peripheral
blood lymphocytes to the skin and that this would
be an adaptive response during the fight-flight
response.
Another noteworthy example of the interplay
among psychologic factors, physiologic factors,
and processes within the skin comes from the
work of Kiecolt-Glaser et al. Following the groups
earlier studies indicating that examination stress
was associated with increased antibody production to presumably reactivation of latent EpsteinBarr virus (21), and to a slower time to seroconvert
following hepatitis B vaccinations (22) in normal,
healthy medical students, the investigators also
found that time to heal a mucosal wound was
approximately 3 days slower in dental students at
the time of examination (23).
More recently, Kiecolt-Glaser and colleagues
investigated the relationship between the quality
of marital relationships and the partners time to
heal a dermal blister wound. For those couples who
engage in hostile interactions, the median time to
wound healing was 2 days longer than for those
couples who have non-hostile interactions (7 vs. 5
days) (24), 2005 2705/id}. A related study was
published in older adults (mean age of 65), who,
in general, heal wounds slower than young adults.
In this study, participants who were randomized
to an exercise intervention (3 days/weeks, 30 minutes
cardio work) healed a 3.5 mm dermal wound significantly faster than participants in a nonexercise
group (29.2 vs. 40 days, on average) (25). Thus, the
process of wound healing is affected by stressful
life conditions, and can be improved through
intervention and/or changes in lifestyle. It remains
to be determined, however, through what specific
mechanisms the nervous system, both central and
peripheral, can alter innate and cellular immunity
in the skin in response to a wound.

24

Stress and immunity

Stress hormones influence numerous physiologic
processes; however, it is becoming clear that the
way they regulate inflammatory diseases is through
their effects on the balance between cell-mediated
and humoral immunity and on neurogenic inflammation in peripheral tissues such as the skin (26)
(FIG. 1).
The hypothalamicpituitaryadrenal (HPA) axis
and the SNS represent the peripheral limbs of the
stress system (27,28), whose activation occurs within
the CNS in response to distinct blood-borne, neurosensory, and limbic signals. The central components of the stress system are the CRH and locus
ceruleus sympathetic neurons of the hypothalamus and brain stem, which regulate the peripheral activities of the HPA axis and the SNS,
respectively (28,29). The stress-induced release of
hypothalamic CRH leads ultimately to systemic
secretion of glucocorticoids (GCs) and catecholamines (CAs) (mainly EPI and NE), which in turn
influence immune responses. Immune challenges
such as infections with bacteria release bacterial
lipopolysaccharides (LPS), which induce the nuclear
factor (NF)kB mediated secretion of IL-1 and IL-6,
which stimulate the hypothalamic stress response
(27,28,30).
Immune responses are regulated by antigenpresenting cells (APC), such as monocytes/macrophages, dendritic cells, and other phagocytic cells
that are components of innate immunity, and by
the helper T-lymphocyte subclasses Th1, Th2, and
Treg that are components of adaptive immunity.
Homeostasis within the immune system is largely
dependent on cytokines, the chemical messengers
between immune cells, which play crucial roles in
mediating inflammatory and immune responses.
Th1 cells primarily secrete interferon (IFN)-, IL-2,
and TNF-, which promote cell-mediated immunity; whereas Th2 cells secrete a different set of
cytokines, primarily IL-4, IL-10, and IL-13, which
enhance humoral immunity (3133) (FIG. 1). Naive
T cells (Th0) are precursors of Th1 and Th2 cells,
and IL-12 (produced by APCs) is the major inducer
of Th1 differentiation and, hence, cellular immunity. Thus, IL-12 and IFN- inhibit Th2, whereas
IL-4 and IL-10 inhibit Th1 cell activities. IL-4 and
IL-10 promote humoral immunity by stimulating
the growth and activation of mast cells and eosinophils, the differentiation of B cells into antibodysecreting B cells, and immunoglobulin switching
to IgE. Importantly, these cytokines also inhibit
macrophage activation, T-cell proliferation, and the
production of proinflammatory cytokines (3133).

Psychoneuroimmunology

FIG. 1. Effects of Stress on Immunity and Inflammation.

The information of the presence of a stressor is processed through the Hypothalamus resulting in the release of CRH,
ACTH, NE and eventually cortisol. The latter hormones mediate the differentiation of Th0 (nave T Helper cells) towards the
Th2 humoral immune response to the detriment of the Th1 cell-mediated response. APCs secrete cytokines that mediate Th1
differentiation, however the presence of bacterial products such as LPS that bind to Toll-like Receptors induce the production
of IL-1 and IL-6, which cross the blood-brain barrier and trigger the hypothalamic CRH-stress response. In this manner, a
blood borne stressor of infectious nature can activate the HPA axis. Th1 effects are mediated by the cytokines IL-12,18,2
and Interferon and T cells and Macrophages. Th2 responses are mediated by IL-4,6,13 and B Cells, Eosinophils and Mast Cells.
CRH: Corticotropin releasing Hormone; NE: Norepinephrin; Th0: Nave Helper cells; APC: Antigen Presenting Cell; LPS:
Lipopolysaccharide; HPA: Hypothalamic-Pituitary-Adrenal Axis.

25

Tausk et al.

Each subset of T cells (Th1 and Th2) is mutually

exclusive.
Both GCs and CAs systemically mediate a Th2
shift by up-regulating Th2-cytokine production
and also by suppressing APCs and Th1, cytokine
synthesis (34). Thus, GCs and CAs suppress the
production by APCs of IL-12, the main inducer
of Th1 responses (3538). GCs also have a direct
effect on Th2 cells by up-regulating their IL-4,
IL-10, and IL-13 production (36,39). Because
catecholamine-binding 2-adrenoceptors are only
present in Th1 cells (40), CAs do not directly affect
Th2 cells.

Stress and skin diseases

Diseases of the skin more than any other organ
appear to be influenced by emotional factors, and
most dermatologists encounter patients who report
a temporal relationship between disease flares and
stressful life events. Emotional stressors have been
linked to the development or evolution of a variety
of cutaneous diseases including acne (41), vitiligo
(42,43), alopecia areata (44), lichen planus (45),
seborrheic dermatitis, herpes simplex infections
(46), pemphigus (47), urticaria (48), psoriasis, and
atopic eczema (26).
Psoriasis
Emotional stressors have been reported to precede
the onset of psoriasis (49), as well as precipitate
flares (50,51). Farber attempted to explain this
phenomenon when he encountered patients who
suffered traumatic severance of sensory innervation; he observed that the plaques of psoriasis
present in the areas innervated by the sectioned
nerves resolved, and only reappeared when nerve
fibers regenerated and the sensitivity returned.
This observation highlighted the role played by
sensory cutaneous nerves, leading to the proposal
that locally secreted neuropeptides contributed to
the maintenance of psoriatic disease. Subsequently,
it was found that psoriatic plaques display increased
nerve fiber density and altered content of neuropeptides such as calcitonin gene-related peptide,
SP, vasoactive intestinal peptide, and NGF (5255).
High expression of NGF mediates T-cell and keratinocyte proliferation, mast cell migration, degranulation, and memory T-cell chemotaxis, which are
all hallmarks of psoriasis (52,5658). Psoriasis patients
who reported stress-related exacerbations had an
inherited dysfunction in the HPA axis, responding
to experimental stressors with a decreased pro-

26

duction of cortisol, elevated blood pressure, heart

rate, and EPI levels (59,60).
Numerous psychosocial interventions aimed at
the reduction of stress have proved to be successful in the treatment of psoriasis (61,62). For example,
a brief exposure to meditation tapes during phototherapy sessions decreased the length of phototherapy; the subjects in the intervention group
cleared their psoriasis significantly faster (by 50%)
when compared to those that received phototherapy
only (63,64). Psoriasis patients improved significantly
during hypnosis sessions, where they received
suggestions that they were being exposed to whatever they believed ... would ameliorate their condition. This observation, in addition to the high
rates of placebo responses in some clinical trials
for psoriasis drugs, may suggest that the placebo
effect could be harnessed and used in the pharmacotherapy of these patients (65,66).
Atopic dermatitis
Atopic dermatitis (AD) exemplifies the relationship of
the delicate balance between genetic, environmental,
and psychosocial factors, and evolution of a
skin disease. Patients with AD have a severe
impairment in their quality of life resulting in
significant emotional distress (67). This relationship
is bidirectional, as stressors are important contributors to the flares and exacerbation of the disease
(68,69). Experimental stressors have been found to
impair the recovery of transepidermal water loss
(70), thus playing a detrimental role in the skin
barrier function. This in turn, creates increased
susceptibility to cutaneous inoculation with environmental agents (e.g., allergens as dust mites,
dander, bacteria, and viruses), which are potential
precipitants of atopic flares (71).
Patients with AD have an inherited deficiency
in the function of the hypothalamus, resulting in a
blunted response of the HPA axis. When exposed
to experimental stressors or to the injection of CRH,
they respond with a blunted production of cortisol,
which could help explain flares during taxing stressors (7274). Additionally, these subjects display an
up-regulation of glucocorticoid receptors on peripheral leukocytes (74), making them hyperreactive
to steroid stimulation. Thus, in spite of a blunted
HPA axis response to stress, effector cells that are
exquisitely sensitive to systemic glucocorticoid
release may respond in a hyperreactive fashion to
stress-induced cortisol elevations, accentuating the
cytokine shift from Th1 to the Th2 immune response.
Stress-induced local and systemic secretion of
EPI or its metabolites may also play a role in the

Psychoneuroimmunology

worsening of AD, as these patients have increased

mononuclear cell activation of intracellular type 4
phosphodiesterases (75). This may result from
elevated levels of NE (76) found in these individuals,
leading to the secretion of IL-13 and IL-4 (77), and
Th2 differentiation. Stressors shift the immune
response, impairing TH1 and favoring the Th2
humoral immune response (7880) and a redistribution of lymphocytes and eosinophils (81,82).
Pharmacologic doses of corticosteroids are also
able to suppress the production of IL-4, which is
an agent of differentiation toward Th2 cells (79,83
86), explaining the beneficial effect of systemic or
topical application of these agents.
Urticaria
The relationship between stress and some forms
of urticaria is supported by numerous anecdotal
observations. Patients suffering from adrenergic
urticaria report that their symptoms invariably
follow acute stressful events. The finding that stress
mediates the degranulation of mast cells via CRH
and neuropeptides (87), and the up-regulation of
mast cell CRH receptors (88) supports its putative
role in the pathogenesis of urticaria.
Infections
Numerous studies have demonstrated the deleterious effects of stressors on the evolution of
infections (89), including experimental bacterial
infections of the skin (90,91) and recurrent herpetic
infection precipitated by psychiatric illness, life
events, and disgust (92). Stress appears to significantly modulate the evolution of human infection
with herpes simplex virus (92). Experimental
restraint stress correlates with the reactivation of
latent herpes simplex virus infection in the dorsal
root ganglion neuron of rats. Human studies show
that persistent, but not single or acute, stressors
are associated with the frequency of recurrences,
which is in agreement with findings that chronic,
but not acute stress, correlates with the development of experimental viral infections in normal
volunteers (46,93,94). Furthermore, psychosocial
interventions have been shown to decrease the
frequency of recurrences of herpes simplex infections (95).
Cancer
Studies have suggested that natural or experimental
stressors can modulate the evolution of malignancies in humans as well as other animals (96106),

suppressing lymphocyte proliferation (107) and

natural killer cell activity (108,109).
We recently reported a model of stress-induced
carcinogenicity (110), where UV-treated mice exposed
repeatedly to the presence of a predator scent
developed squamous cell carcinomas significantly
earlier (week 8) compared to nonstressed controls
(week 21), an observation that was subsequently
confirmed by others (111).
Stress reduction interventions have been shown
to significantly prolong the survival of individuals
with metastatic neoplasms (112). For example,
patients with metastatic melanoma were found
to benefit from limited sessions of psychosocial
interventions, thereby significantly increasing their
6 years survival rate (113). One possible explanation for the benefit of these interventions could
be the modulatory effect of stress and stress
reduction on NK cell function, presumed to represent
one of the first innate lines of immune defense
against foreign (including cancerous) cells (114).
Another example is relaxation training, which
significantly increased older adults cytotoxic function
(115), even though chronic stress has been shown
to suppress NK activity (116,117).

Conclusions
Psychoneuroimmunology is an evolving area of
science that will help us understand the relationship between the mind and the body. The past 30
years of research in the field of PNI have validated
the close relationship between the CNS and the
immune system. There is a growing body of evidence to support the effect of the psyche stress,
in particular on immune responses and a multitude of skin conditions. The effects of stress on
shifting the immune response are not completely
understood; however, research has shown that
stress modifies the delicate balance between health
and disease. Just as interesting are the numerous
studies demonstrating that a nonpharmacologic
approach can ameliorate certain dermatologic diseases. Seeking alternative interventions can only
enhance our ability to treat patients.

References
1. Medicine NLo. Emotions and Disease: an exhibition at
the National Library of Medicine. Friends of the National
Library of Medicine 1997.
2. Ader R, Cohen N. Behaviorally conditioned immunosuppression. Psychosom Med 1975: 37: 333340.
3. Watkins LR, Maier SF, Goehler LE. Cytokine-to-brain

27

Tausk et al.

4.

5.

6.

7.
8.

9.

10.

11.

12.
13.

14.

15.

16.

17.

18.

19.
20.

21.

22.

23.

28

communication: a review and analysis of alternative mechanisms. Life Sci 1995: 57: 10111026.
Chrousos GP. Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye
Memorial Lecture. Ann N Y Acad Sci 1998: 851: 311335.
Charmandari E, Tsigos C, Chrousos G. Endocrinology
of the stress response. Annu Rev Physiol 2005: 67: 259
284.
Dunn A. Psychoneuroimmunology, stress and infection.
In: Friedman K, ed. Psychoneuroimmunology, stress, infection. Boca Raton, FL: CRC, 1995: 2545.
Sternberg EM. Overview of the conference and the field.
Ann N Y Acad Sci 1998: 840: 1 8.
McEwen BS. Protection and damage from acute and
chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders.
Ann N Y Acad Sci 2004: 1032: 17.
Korte SM, Koolhaas JM, Wingfield JC, McEwen BS. The
Darwinian concept of stress: benefits of allostasis and
costs of allostatic load and the trade-offs in health and
disease. Neurosci Biobehav Rev 2005: 29: 338.
Moynihan JA, Stevens SY. Mechanisms of stress-induced
modulation of immunity in animals. In: Ader R, Felten
DL, Cohen N, eds. Psychoneuroimmunology. New York:
Academic Press, 2001: 227249.
Levite M. Neuropeptides, by direct interaction with T
cells, induce cytokine secretion and break the commitment to a distinct T helper phenotype. Proc Natl Acad Sci
USA 1998: 95: 1254412549.
Khansari DN, Murgo AJ, Faith RE. Effects of stress on the
immune system. Immunol Today 1990: 11: 170175.
Baker C, Richards LJ, Dayan CM, Jessop DS. Corticotropin-releasing hormone immunoreactivity in human T
and B cells and macrophages: colocalization with arginine
vasopressin. J Neuroendocrinol 2003: 15: 10701074.
Gerlo S, Verdood P, Hooghe-Peters EL, Kooijman R. Modulation of prolactin expression in human T lymphocytes
by cytokines. J Neuroimmunol 2005: 162: 190193.
Lysle DT, Lyte M, Fowler H, Rabin BS. Shock-induced
modulation of lymphocyte reactivity: suppression, habituation, and recovery. Life Sci 1987: 41: 18051814.
Urpe M, Buggiani G, Lotti T. Stress and psychoneuroimmunologic factors in dermatology. Dermatol Clin 2005: 23:
609 617.
Saraceno R, Kleyn CE, Terenghi G, Griffiths CE. The role
of neuropeptides in psoriasis. Br J Dermatol 2006: 155:
876 882.
Dhabhar FS, McEwen BS. Acute stress enhances while
chronic stress suppresses cell-mediated immunity in
vivo: a potential role for leukocyte trafficking. Brain Behav
Immun 1997: 11: 286306.
Dhabhar FS. Stress-induced enhancement of cell-mediated
immunity. Ann N Y Acad Sci 1998: 840: 359372.
Dhabhar FS, McEwen BS. Enhancing versus suppressive
effects of stress hormones on skin immune function. Proc
Natl Acad Sci USA 1999: 96: 10591064.
Glaser R, Kiecolt-Glaser JK, Speicher CE, Holliday JE.
Stress, loneliness, and changes in herpesvirus latency. J
Behav Med 1985: 8: 249260.
Glaser R, Kiecolt-Glaser JK, Bonneau RH, Malarkey W,
Kennedy S, Hughes J. Stress-induced modulation of the
immune response to recombinant hepatitis B vaccine.
Psychosom Med 1992: 54: 2229.
Marucha PT, Kiecolt-Glaser JK, Favagehi M. Mucosal
wound healing is impaired by examination stress. Psychosom Med 1998: 60: 362365.

24. Kiecolt-Glaser JK, Loving TJ, Stowell JR, et al. Hostile marital interactions, proinflammatory cytokine production,
and wound healing. Arch Gen Psychiatry 2005: 62: 1377
1384.
25. Emery CF, Kiecolt-Glaser JK, Glaser R, Malarkey WB, Frid DJ.
Exercise accelerates wound healing among healthy older
adults: a preliminary investigation. J Gerontol 2005: 60:
14321436.
26. Sandoz A, Kusnir D, Koenig T, Tausk F Psychocutaneous
medicine. In: Fitzpatricks dermatology in general medicine. New York: Mc Graw-Hill, 2007.
27. Chrousos GP. The hypothalamic-pituitary-adrenal axis
and immune-mediated inflammation. N Engl J Med 1995:
332: 13511362.
28. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve an integrative interface between two supersystems: the brain and the immune system. Pharmacol
Rev 2000: 52: 595638.
29. Besedovsky HO, del Rey AE, Sorkin E. What do the
immune system and the brain know about each other.
Immunol Today 1983: 4: 342346.
30. Besedovsky H, del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986: 233: 652654.
31. Fearon DT, Locksley RM. The instructive role of innate
immunity in the acquired immune response. Science
1996: 272: 5053.
32. Mosmann TR, Sad S. The expanding universe of T-cell
subsets: Th1, Th2 and more. Immunol Today 1996: 17:
138146.
33. Trinchieri G. Interleukin-12 and the regulation of innate
resistance and adaptive immunity. Nature Rev 2003: 3:
133146.
34. Elenkov IJ, Chrousos GP. Stress Hormones, Th1/Th2
patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trends Endocrinol Metab 1999: 10:
359368.
35. Elenkov IJ, Papanicolaou DA, Wilder RL, Chrousos GP.
Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proc Assoc Am Physicians
1996: 108: 374381.
36. Blotta MH, DeKruyff RH, Umetsu DT. Corticosteroids
inhibit IL-12 production in human monocytes and
enhance their capacity to induce IL-4 synthesis in CD4+
lymphocytes. J Immunol 1997: 158: 55895595.
37. Hasko G, Szabo C, Nemeth ZH, Salzman AL, Vizi ES. Stimulation of beta-adrenoceptors inhibits endotoxin-induced
IL-12 production in normal and IL-10 deficient mice. J
Neuroimmunol 1998: 88: 5761.
38. Panina-Bordignon P, Mazzeo D, Lucia PD, et al. Beta2agonists prevent Th1 development by selective inhibition
of interleukin 12. J Clin Invest 1997: 100: 15131519.
39. Ramirez F, Fowell DJ, Puklavec M, Simmonds S,
Mason D. Glucocorticoids promote a TH2 cytokine
response by CD4+ T cells in vitro. J Immunol 1996: 156:
24062412.
40. Sanders VM, Baker RA, Ramer-Quinn DS, Kasprowicz DJ,
Fuchs BA, Street NE. Differential expression of the beta2adrenergic receptor by Th1 and Th2 clones: implications
for cytokine production and B cell help. J Immunol 1997:
158: 42004210.
41. Chiu A, Chon SY, Kimball AB. The response of skin disease to stress: changes in the severity of acne vulgaris as
affected by examination stress. Arch Dermatol 2003: 139:
897900.

Psychoneuroimmunology
42. Papadopoulos L, Bor R, Legg C, Hawk JL. Impact of life
events on the onset of vitiligo in adults: preliminary evidence for a psychological dimension in aetiology. Clin Exp
Dermatol 1998: 23: 243248.
43. Barisic-Drusko V, Rucevic I. Trigger factors in childhood
psoriasis and vitiligo. Coll Antropol 2004: 28: 277285.
44. Gulec AT, Tanriverdi N, Duru C, Saray Y, Akcali C. The
role of psychological factors in alopecia areata and the
impact of the disease on the quality of life. Int J Dermatol
2004: 43: 352356.
45. Chaudhary S. Psychosocial stressors in oral lichen planus.
Aust Dent J 2004: 49: 192195.
46. Cohen F, Kemeny ME, Kearney KA, Zegans LS, Neuhaus
JM, Conant MA. Persistent stress as a predictor of genital
herpes recurrence. Arch Intern Med 1999: 159: 24302436.
47. Goldberg I, Ingher A, Brenner S. Pemphigus vulgaris triggered by rifampin and emotional stress. Skinmed 2004: 3:
294.
48. Berrino AM, Voltolini S, Fiaschi D, et al. Chronic urticaria:
importance of a medical-psychological approach. Allerg
Immunol 2006: 38: 149152.
49. Naldi L, Peli L, Parazzini F, Carrel CF. Family history of
psoriasis, stressful life events, and recent infectious disease are risk factors for a first episode of acute guttate
psoriasis: results of a case-control study. J Am Acad Dermatol 2001: 44: 433438.
50. Fortune DG, Richards HL, Griffiths CEM, Main CJ. Psychological stress, distress and disability in patients with
psoriasis: consensus and variation in the contribution
of illness perceptions, coping and alexithymia. Br J Dermatol 2002: 41: 157174.
51. Fortune DG, Richards HL, Griffiths CEM, Main CJ. Psychologic factors in psoriasis: consequences, mechanisms,
and interventions. Dermatol Clin 2005: 4: 681694.
52. Raychaudhuri SP, Farber FE, Raychaudhuri SK. Role of
nerve growth factor in RANTES expression by keratinocytes. Acta Derm Venereol 2000: 80: 247250.
53. Nickoloff BJ, Schroder JM, von den Driesch P, et al. Is Psoriasis a T-cell disease? Exp Dermatol 2000: 9: 357375.
54. Farber EM, Nall L. Psoriasis: a stress-related disease. Cutis
1993: 51: 322326.
55. Farber EM, Nickoloff BJ, Recht B, Fraki JE. Stress, symmetry, and psoriasis: possible role of neuropeptides. J Am
Acad Dermatol 1986: 14: 305311.
56. Aloe L, Alleva E, Fiore M. Stress and nerve growth factor:
findings in animal models and humans. Pharmacol Biochem Behav 2002: 73: 159166.
57. Raychaudhuri SP, Jiang WY, Farber EM. Psoriatic keratinocytes express high levels of nerve growth factor. Acta
Derm Venereol 1998: 78: 8486.
58. Raychaudhuri SP, Jiang WY, Smoller BR, Farber EM.
Nerve growth factor and its receptor system in psoriasis.
Br J Dermatol 2000: 143: 198200.
59. Richards HL, Ray DW, Kirby B, et al. Response of the
hypothalamic-pituitary-adrenal axis to psychological
stress in patients with psoriasis. Br J Dermatol 2005: 153:
11141120.
60. Schmid-Ott G, Jacobs R, Jger B, et al. Stress induced
endocrine and immunological changes in psoriasis
patients and healthy controls. Psychother Psychosom
1998: 67: 3742.
61. Ginsburg IH. Coping with psoriasis: a guide for counseling patients. Cutis 1996: 57: 323325.
62. Tausk F, Whitmore SE. A pilot study of hypnosis in the
treatment of patients with psoriasis. Psychother Psychosom 1999: 68: 221225.

63. Benhard JD, Kristeller J, Kabat-Zinn J. Effectiveness of

relaxation and visualization techniques as an adjunct to
phototherapy and photochemotherapy of psoriasis. J Am
Acad Dermatol 1988: 19: 572574.
64. Kabat-Zinn J, Wheeler E, Light T, et al. Influence of a
mindfulness meditation-based stress reduction intervention on rates of skin clearing in patients with moderate
to severe psoriasis undergoing phototherapy (UVB) and
photochemotherapy (PUVA). Psychosom Med 1998: 60:
625632.
65. Ader R. The role of conditioning in pharmacotherapy.
Cambridge: Harvard University Press, 1997.
66. Ader R. Classical conditioning in the treatment of psoriasis. Cutis 2000: 66: 370372.
67. King RM, Wilson GV. Use of a diary technique to investigate psychosomatic relations in atopic dermatitis. J Psychosom Res 1991: 35: 697706.
68. Langan SM, Bourke JF, Silcocks P, Williams HC. An
exploratory prospective observational study of environmental factors exacerbating atopic eczema in children. Br J
Dermatol 2006: 154: 979980.
69. Faulstich ME, Williamson DA, Duchmann EG, Conerly SL,
Brantley PJ. Psychophysiological analysis of atopic dermatitis. J Psychosom Res 1985: 29: 415417.
70. Altemus M, Rao B, Dhabhar FS, Ding W, Granstein RD.
Stress-induced changes in skin barrier function in healthy
women. J Invest Dermatol 2001: 117: 309317.
71. Zane
L.
Psychoneuroendocrinimmunodermatology:
pathophysiological mechanisms of stress in cutaneous
disease. In: Koo JYM, Lee CS, ed. Psychocutaneous medicine. New York: Marcel Dekker Inc., 2003: 6595.
72. Buske-Kirschbaum A, Jobst S, Psych D, et al. Attenuated
free cortisol response to psychosocial stress in children
with atopic dermatitis. Psychosom Med 1997: 59: 419
426.
73. Buske-Kirschbaum A, Geiben A, Hollig H, Morschhauser
E, Hellhammer D. Altered responsiveness of the hypothalamus-pituitary-adrenal axis and the sympathetic
adrenomedullary system to stress in patients with
atopic dermatitis. J Clin Endocrinol Metab 2002: 87:
42454251.
74. Rupprecht M, Rupprecht R, Kornhuber J, et al. Elevated
glucocorticoid receptor concentrations before and after
glucocorticoid therapy in peripheral mononuclear leukocytes of patients with atopic dermatitis. Dermatologica
1991: 183: 100105.
75. Delgado M, Fernndez-Alfonso MS, Fuentes A. Effect of
adrenaline and glucocorticoids on monocyte cAMPspecific phospodiesterase (PDE4) in a monocyte cell line.
Arch Dermatol Res 2002, 190197.
76. Schallreuter KU, Pittelkow MR, Swanson NN, et al. Altered
catecholamine synthesis and degradation in the epidermis of patients with atopic eczema. Arch Dermatol Res
1997: 289: 663666.
77. Chan SC, Brown MA, Willcox TM, et al. Abnormal IL-4
gene expression by atopic dermatitis T lymphocytes is
reflected in altered nuclear protein interactions with IL-4
transcription regulatory element. J Invest Dermatol 1996:
106: 11311136.
78. Kagi MK, Wutrich B, Montano E, Barandun J, Blaser K,
Walker C. Differential cytokine profiles in peripheral
blood lymphocyte supernatants and skin biopsies from
patients with different forms of atopic dermatitis, psoriasis
and normal individuals. Int Arch Allergy Immunol 1994:
103: 332340.
79. Mori A, Yamamoto K, Dohi M, Suko M, Okudaira H.

29

Tausk et al.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

30

Interleukin-4 gene expression in human peripheral

blood mononuclear cells. Int Arch Allergy Appl Immunol
1991: 95: 282284.
Tamir A, Ophir J, Brenner S. Pemphigus vulgaris triggered by emotional stress [letter]. Dermatology 1994:
189: 210.
Schmid-Ott G, Jaeger B, Adamek C, et al. Levels of
circulating CD8(+) T lymphocytes, natural killer cells, and
eosinophils increase upon acute psychosocial stress in
patients with atopic dermatitis. J Allergy Clin Immunol
2001: 107: 171177.
Schmid-Ott G, Jaeger B, Meyer S, Stephan E, Kapp A, Werfel
T. Different expression of cytokine and membrane molecules by circulating lymphocytes on acute mental stress
in patients with atopic dermatitis in comparison with
healthy controls. J Allergy Clin Immunol 2001: 108: 455
462.
Braun CM, Huang SK, Bashian GG, Kagey-Sobotka A,
Lichtenstein LM, Essayan DM. Corticosteroid modulation
of human, antigen-specific Th1 and Th2 responses. J
Allergy Clin Immunol 1997: 100: 400407.
Byron KA, Varigos G, Wootton A. Hydrocortisone inhibition of human interleukin-4. Immunology 1992: 77: 624
626.
Cupps TR, Gerrard TL, Falkoff RJ, Whalen G, Fauci AS.
Effects of in vitro corticosteroids on B cell activation, proliferation, and differentiation. J Clin Invest 1985: 75: 754
761.
Schwiebert LM, Beck LA, Stellato C, et al. Glucocorticosteroid inhibition of cytokine production: relevance to antiallergic actions [published erratum appears in J Allergy
Clin Immunol 1996 Sep; 98(3):718]. J Allergy Clin Immunol 1996: 97: 143152.
Theoharides TC, Donelan JM, Papadopoulou N, Cao J,
Kempuraj D, Conti P. Mast cells as targets of corticotropinreleasing factor and related peptides. Trends Pharmacol
Sci 2004: 25: 563568.
Papadopoulou N, Kalogeromitros D, Staurianeas NG,
Tiblalexi D, Theoharides TC. Corticotropin-releasing
hormone receptor-1 and histidine decarboxylase expression in chronic urticaria. J Invest Dermatol 2005: 125:
952955.
Biondi M, Zannino LG. Psychological stress, neuroimmunomodulation, and susceptibility to infectious diseases in
animals and man: a review. Psychother Psychosom 1997:
66: 326.
Bailey MT, Engler H, Sheridan JF. Stress induces the
translocation of cutaneous and gastrointestinal microflora to secondary lymphoid organs of C57BL/6 mice.
J Neuroimmunol 2006: 171: 2937.
Rojas IG, Padgett DA, Sheridan JF, Marucha PT. Stressinduced susceptibility to bacterial infection during cutaneous wound healing. Brain Behav Immun 2002: 16: 74
84.
Buske-Kirschbaum A, Geiben A, Wermke C, Pirke KM,
Hellhammer D. Preliminary evidence for Herpes labialis
recurrence following experimentally induced disgust.
Psychother Psychosom 2001: 70: 8691.
Cohen S, Frank E, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM Jr. Types of stressors that increase susceptibility to
the common cold in healthy adults [see comments].
Health Psychol 1998: 17: 214223.
Cohen S, Tyrrell DA, Smith AP. Psychological stress and
susceptibility to the common cold [see comments]. N
Engl J Med 1991: 325: 606 612.
VanderPlate C, Kerrick G. Stress reduction treatment of

96.

97.

98.

99.

100.
101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

severe recurrent genital herpes virus. Biofeedback Self

Regul 1985: 10: 181188.
Yang EV, Glaser R. Stress-induced immunomodulation:
implications for tumorigenesis. Brain Behav Immun 2003:
17 (Suppl. 1): S37S40.
Reiche EM, Nunes SO, Morimoto HK. Stress, depression,
the immune system, and cancer. Lancet Oncol 2004: 5:
617625.
Reiche EM, Morimoto HK, Nunes SM. Stress and depression-induced immune dysfunction: implications for the
development and progression of cancer. International
review of psychiatry (Abingdon, England). Int Rev Psychiatry
2005: 17: 515527.
Lillberg K, Verkasalo PK, Kaprio J, Teppo L, Helenius H,
Koskenvuo M. Stressful life events and risk of breast
cancer in 10,808 women: a cohort study. Am J Epidemiol
2003: 157: 415423.
Riley V. Psychoneuroendocrine influences on immunocompetence and neoplasia. Science 1981: 212: 11001109.
Wu W, Yamaura T, Murakami K, et al. Social isolation
stress enhanced liver metastasis of murine colon 26-L5 carcinoma cells by suppressing immune responses in mice.
Life Sci 2000: 66: 18271838.
Ramirez AJ, Craig TK, Watson JP, Fentiman IS, North WR,
Rubens RD. Stress and relapse of breast cancer [see comments]. Br Med J 1989: 298: 291293.
Havlik RJ, Vukasin AP, Ariyan S. The impact of stress on
the clinical presentation of melanoma. Plast Reconstr Surg
1992: 90: 5761; discussion 24.
Reynolds P, Kaplan GA. Social connections and risk for
cancer: prospective evidence from the Alameda County
Study. Behav Med 1990: 16: 101110.
Jacobs JR, Bovasso GB. Early and chronic stress and their
relation to breast cancer [In Process Citation]. Psychol
Med 2000: 30: 669678.
Grossarth-Maticek R, Eysenck HJ, Boyle GJ, Heeb J, Costa
SD, Diel IJ. Interaction of psychosocial and physical risk
factors in the causation of mammary cancer, and its prevention through psychological methods of treatment.
J Clin Psychol 2000: 56: 3350.
Laudenslager ML, Ryan SM, Drugan RC, Hyson RL, Maier
SF. Coping and immunosuppression: inescapable but not
escapable shock suppresses lymphocyte proliferation.
Science 1983: 221: 568570.
Ben-Eliyahu S, Page GG, Yirmiya R, Shakhar G. Evidence
that stress and surgical interventions promote tumor
development by suppressing natural killer cell activity. Int
J Cancer 1999: 80: 880888.
Ben-Eliyahu S. The promotion of tumor metastasis by
surgery and stress: immunological basis and implications
for psychoneuroimmunology. Brain Behav Immun 2003:
17 (Suppl. 1): S27S36.
Parker J, Klein SL, McClintock MK, et al. Chronic stress
accelerates ultraviolet-induced cutaneous carcinogenesis. J Am Acad Dermatol 2004: 51: 919922.
Saul AN, Oberyszyn TM, Daugherty C, et al. Chronic
stress and susceptibility to skin cancer. J Natl Cancer Inst
2005: 97: 17601767.
Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Effect of
psychosocial treatment on survival of patients with metastatic breast cancer [see comments]. Lancet 1989: 2: 888
891.
Fawzy FI, Fawzy NW, Hyun CS, et al. Malignant melanoma.
Effects of an early structured psychiatric intervention,
coping, and affective state on recurrence and survival 6
years later. Arch Gen Psychiatry 1993: 50: 681689.

Psychoneuroimmunology
114. Herberman RB, Ortaldo JR. Natural killer cells: their
roles in defenses against disease. Science 1981: 214: 24
30.
115. Esterling BA, Kiecolt-Glaser JK, Glaser R. Psychosocial
modulation of cytokine-induced natural killer cell activity
in older adults. Psychosom Med 1996: 58: 264272.
116. Kiecolt-Glaser JK, Garner W, Speicher C, Penn GM,

Holliday J, Glaser R. Psychosocial modifiers of immunocompetence in medical students. Psychosom Med 1984:
46: 714.
117. Glaser R, Rice J, Speicher CE, Stout JC, Kiecolt-Glaser JK.
Stress depresses interferon production by leukocytes
concomitant with a decrease in natural killer cell activity.
Behav Neurosci 1986: 100: 675678.

31