Dermatologic Therapy, Vol. 21, 2008, 22–31 Copyright © Blackwell Publishing, Inc.

, 2008
Printed in the United States · All rights reserved
DERMATOLOGIC THERAPY
ISSN 1396-0296

Psychoneuroimmunology
Blackwell Publishing Inc

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 inter-
ventions have proved to be effective in their therapy.

KEYWORDS: dermatology, neuropeptides, psychoneuroimmunology, stress

Introduction: to warn the innate immune system of an impend-

Psychoneuroimmunology
The study of mind–body interactions can be traced
back to the time of Hippocrates (c. 460 BC–360 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 emer-
gence in the mid 1970s, with the seminal work of
Ader and Cohen (2) and the finding that changes
in immune function could be behaviorally condi-
tioned, 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)”
ing 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 stud-
ies 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

22

lines of evidence have converged over time to
establish the connections as incontrovertible. First,
CNS (hypothalamic) interventions (including lesion-
ing 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)-α. 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
hypothalamo–pituitary adrenal (HPA) axis and the
sympathetic nervous system (SNS). Chrousos (4,5),
Dunn (6), and others (7–9) 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 ceruleus-
noradrenergic 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 brain-
stem 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 adrenocorti-
cotropic hormone, enkephalins, and endorphins.
Adrenocorticotropic hormone induces downstream
release of glucocorticoids from the adrenal cortex.
CRH and noradrenergic neurons in the CNS inner-
vate and stimulate each other. Activation of the
noradrenergic pathways by CRH results in secre-
tion 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
Psychoneuroimmunology
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 neuro-
sensory 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 individual’s 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 vari-
able 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 prolif-
erative 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 spe-
cialized immunological processes, and also func-
tions 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 system–immune 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 hypersen-
sitivity (DTH) responses appear to be in opposite
directions (18). Following a single session of
restraint prior to challenge with 2,4-dinitro-1-
fluorobenzene (DNFB)(2–5 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 group’s
earlier studies indicating that examination stress
was associated with increased antibody produc-
tion to presumably reactivation of latent Epstein-
Barr 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 sig-
nificantly 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 inflam-
mation in peripheral tissues such as the skin (26)
(FIG. 1).
The hypothalamic–pituitary–adrenal (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, neu-
rosensory, and limbic signals. The central compo-
nents of the stress system are the CRH and locus
ceruleus sympathetic neurons of the hypothala-
mus and brain stem, which regulate the peri-
pheral 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 catechola-
mines (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 antigen-
presenting cells (APC), such as monocytes/mac-
rophages, 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)-γ, IL-2,
and TNF-α, which promote cell-mediated immu-
nity; whereas Th2 cells secrete a different set of
cytokines, primarily IL-4, IL-10, and IL-13, which
enhance humoral immunity (31–33) (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 immu-
nity. Thus, IL-12 and IFN-γ 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 eosi-
nophils, the differentiation of B cells into antibody-
secreting B cells, and immunoglobulin switching
to IgE. Importantly, these cytokines also inhibit
macrophage activation, T-cell proliferation, and the
production of proinflammatory cytokines (31–33).
 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 (naïve T Helper cells) towards the
Th2 humoral immune response to the detriment of the Th1 cell-mediated response. APC’s 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 γInterferon 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: Naïve 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 (35–38). 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 β2-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 innerva-
tion; 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 neu-
ropeptides such as calcitonin gene-related peptide,
SP, vasoactive intestinal peptide, and NGF (52–55).
High expression of NGF mediates T-cell and kera-
tinocyte proliferation, mast cell migration, degranu-
lation, and memory T-cell chemotaxis, which are
all hallmarks of psoriasis (52,56–58). 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 success-
ful in the treatment of psoriasis (61,62). For example,
a brief exposure to meditation tapes during pho-
totherapy sessions decreased the length of photo-
therapy; 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 “what-
ever they believed ... would ameliorate their con-
dition.” 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 phar-
macotherapy 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 contribu-
tors 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 envi-
ronmental 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 stres-
sors (72–74). Additionally, these subjects display an
up-regulation of glucocorticoid receptors on periph-
eral 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

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 (78–80) and a redistri-
bution 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 delete-
rious 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 signifi-
cantly 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 develop-
ment 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 infec-
tions (95).
Cancer
Studies have suggested that natural or experimental
stressors can modulate the evolution of malignan-
cies in humans as well as other animals (96–106),
Psychoneuroimmunology
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 explana-
tion 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 relation-
ship 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 evi-
dence to support the effect of the psyche – stress,
in particular – on immune responses and a multi-
tude 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 dis-
eases. Seeking alternative interventions can only
enhance our ability to treat patients.
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