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Acta Derm Venereol 2016; Suppl 217: 3846

REVIEW ARTICLE

Psychoneuroimmunology and the Skin


Juan F. HONEYMAN
Department of Dermatology, University of Chile, Catholic University of Chile, Santiago, Chile

The nervous, immune, endocrine and integumentary influenced by cytokine actions. Several psychiatric
systems are closely related and interact in a number of conditions (depression, schizophrenia, psychosomatic
normal and pathological conditions. Nervous system me- disorders) can cause immunological alteration whilst
diators may bring about direct changes to the skin or behavioural disturbances such as aggression and mood
may induce the release of immunological or hormonal swings are associated with immunological changes.
mediators that cause pathological changes to the skin. Furthermore, they may play a significant role in aller-
This article reviews the psychological mechanisms in- gies and autoimmune collagen ailments, for example,
volved in the development of skin diseases. Key words: systemic lupus erythematous, systemic sclerosis,
melanocyte-stimulating hormones (MSH). rheumatoid arthritis, Sjgrens syndrome and mixed
connective tissue disease. Feelings of helplessness or
Accepted Feb 16, 2016; Epub ahead of print Jun 9, 2016 the suppression of negative emotions can stimulate the
Acta Derm Venereol 2016; Suppl 217: 3846. growth or spread of cancer.
It is worth noting that hypnosis, psychological re-
Juan F. Honeyman, MD, Department of Dermatology, laxation, and classical conditioning treatments have
University of Chile, Catholic University of Chile, 8320000 had positive results with immune system disorders;
Santiago, Chile. E-mail: juanhoneyman@gmail.com relaxation techniques and the placebo effect have been
found to stimulate Th-1 lymphocytes (1, 2).
The nervous and immune systems reciprocally regulate
each other through different cross-reaction mechanisms. ACTION MECHANISMS OF THE SMALL
The link between the central nervous system (CNS) and PROTEIN-LIKE MOLECULES EXPRESSED AND
the immune system is represented by the hypothalamic- PRODUCED BY NEURONS
hypophyseal-adrenal (HPA) axis, which secretes the
corticotrophin releasing hormone (CRH) and the autono- Neuropeptides, neurotrophins, neurotransmitters and
mous nervous system. The CNS and the immune system catecholamines play a significant role in modulating
intercommunicate via neurotransmitters, cytokines and the immune response (2, 3).
endocrine neurotransmitter hormones (adrenalin and
corticoids). The interconnection between the two sys- Neropeptides
tems is complex and the interactions between them are
bidirectional. The human genome contains about 90 genes that
Neurons use many different chemical signals to encode precursors of neuropeptides. About 100 dif-
communicate information. They release neuropeptides, ferent peptides are known to be released by different
neurotransmitters, cannabinoids and even some gases populations of neurons in the mammalian brain (14).
like nitric oxide. Neurons often produce a conventio- There are 3 groups of hormones that act as neuro-
nal neurotransmitter (glutamate, glutamate gamma- peptides: (i) Hypothalamic hormones (somatostatin,
aminobutyric acid (GABA) or dopamine) and one or corticotropin-releasing hormone, gonadotropin-relea-
more neuropeptides. sing hormone, GHRH, orexins, thyrotropin-releasing
The small protein-like molecules generated by neu- hormone, and proopiomelanocortin [ACTH, MSH,
rons function in different ways; they modulate neuronal lipotropin]). (ii) Gastrointestinal hormones (cholecys-
communication by acting on the cell-surface specific tokinin, gastric inhibitory polypeptide, gastrin, motilin,
receptors of other neurons and this can have a number secretin and vasoactive intestinal peptide. Other hor-
of effects on human behaviour. They can also have a mones acting as neuropeptides are calcitonin, oxytocin
biological impact on gene expression, local blood flow, and vasopressin and (iii) protein-like compounds with
synaptogenesis and glial cell morphology. neuropeptide activity [angiotensin, neuropeptide Y,
Most immune cells have surface membrane receptors neuropeptide S, neurotensin, calcitonin gene-related
for neurotransmitters, neuropeptides and hormones and peptide, and kinins (bradykinin, tachykinins]).
they can be directly influenced by these receptors or, Neuropeptides induce the release of hormones (cor-
in the event of CNS activation, they can be indirectly ticotropin, ACTH and glucocorticosteroids), monoa-

Acta Derm Venereol Suppl 217 2016 The Authors. doi: 10.2340/00015555-2376
Journal Compilation 2016 Acta Dermato-Venereologica. ISSN 0001-5555
Psychoneuroimmunology and the skin 39

mine neurotransmitters (epinephrine, norepinephrine, Antimicrobial peptides. Monocytes can release the anti-
dopamine), free radicals, cytokins (IL-1, IL-6, TNF), microbial peptides proenkephalin and chromogranin
opioids, peptides, endogenous opiates and endocan- B that are able to stimulate immune cells (1, 2). They
nabinoid antimicrobial peptides (proenkephalin, chro- stimulate the chemotaxis and phagocytosis of the ma-
mogranin B). crophages and provoke the release of pro-inflammatory
Lymphocytes have receptors for neuropeptides cytokines (IL-1, IL-6, etc.).
released by the peripheral nervous system; examples These peptides can also activate T lymphocytes that
would be substance P, somatostatin, VIP and opioids. induce cytotoxic cell proliferation and the secretion of
They also have catecholamine receptors. The activation immunoglobulins by the plasmacells. They are also able
of 1, 2 and 2 catecholamine receptors are able to to activate NK cell cytotoxicity.
induce humoral immunity stimulation and can increase Proenkephalin and chromogranin B can activate neu-
specific IgM antibodies. trophils and release antimicrobial peptides, for example,
Neuropeptides also activate cell-mediated immunity, defensine. They also cause central nervous pain.
stimulating the release of T lymphocytes cytokines (e.g. Autonomous nervous system (ANS) mediators. The
IL-2), macrophage proliferation, natural killer (NK) cell autonomous nervous system is composed of the
activity and the endothelial adhesion of lymphocytes (4). sympathetic (noradrenergic) and the parasympathetic
Along with the autonomous nervous system, opioid (cholinergic) systems. Chronic stress stimulates ACTH
and antimicrobial peptides are important for regulating secretion that activates the secretion of corticoids, adre-
immune responses. nalin and noradrenalin that suppress the production of
Opioid peptides. Opioid peptides are neuropeptides of IL-12 by the antigen-presenting cells, the main Th1 cell
short sequences of amino acids that mimic the effect response-inducing stimulus (13). Corticoids have a
of opiates in the brain (13). Depending on the type direct impact on Th2 cells, increasing the production of
of peptide, the concentration, the peptide receptor and IL-4, IL-10 and IL-13. This gives rise to a Th1/Th2 im-
the contact time of the peptide with the immune cell, balance in favour of a Th2-cell-mediated response with
they regulate immune responses. Brain opioid peptide the deregulation of the neuroimmunologic homeostatic
systems are known to have a significant influence on mechanisms that are secondary to chronic stress. This
motivation, emotions, attachment behaviour, the re- affects cytokine expression and favours an allergic
sponse to stress and pain and the control of food intake. inflammatory response. In addition to the stimulation
Examples of opioid peptides are: dynorphin; endo- of immediate hypersensitivity reactions, chronic stress
morphin; endorphin; enkephalin; nociceptin; VGF, depresses cell-mediated immunity.
(non-acronymic genes generated in vivo by neurotro
phins nerve growth factor (NGF), brain derived Neurotrophins
growth factor and glial-derived growth factor).
Opioid peptides that act as neuropeptides are: cocaine Neurotrophins are a family of proteins that act as NGFs
and amphetamine-regulated transcript; bombesin, gast- that induce the survival, development and function of
rin releasing peptide, carnosine, delta sleep-inducing neurons (5, 6). They may be considered as new cyto-
peptide, FMRF amide, neurophysins, galanin, galanin- kines. Several cells have neurotrophin receptors and
like peptide, neuromedin (B,N,S,U), pancreatic poly- may be activated by these proteins.
peptide, opiorphin, and the pituitary adenylate cyclase One of the cell receptors is Pan-neurotrophine P75
activating peptide. that is of low affinity. Another receptor is Tyrosine
Opioid peptides may be produced by the body or di- Kinase (trkA trkB trkC of high affinity) which may act
gested in food. Some endogenous opioid peptides (with as receptor of the NGF, the brain-derived neurotrophic
more than 8 amino acids) are: -endorphin; enquefalins; factor (BDNF) and neurotrophins-3 and -4. Other neu-
dinorfins (originally enkephalin B); and, probably, en- rotrophins have different receptors: GDNF; neurturin;
domorfin. The human genome contains 3 homologous artemin; persephin (GDNF receptor); and Neuregulin
genes that code the endogenous opioid peptides. (14), GMF, CNTF, PACAP (other receptors).
The human gene for proopiomelanocortin codes for Neurotrophins with high affinity to tyrosine kinase
endorphins such as -endorphin and gamma-endorphin. cell receptors (trkA trkB trkC) are the BDNF, neurotro
Enkephalins have a specific gene. Opiorphin (human phins-3 and -4 and the NGF.
saliva) is an enkephalinase inhibitor, i.e. it prevents the The BDNF and neurotrophins-3 and -4, are neu-
metabolism of enkephalins. rotrophics that increase the Th2-mediated response
Exogenous opioid food peptides are: casomorphin (production of IgE) and reduce the Th1 response.
(in milk), gluten exorphin (in gluten), gliadorphin/glu- The NGF released by the sympathetic or sensory
teomorphin (in gluten), rubiscolin (in spinach). There neurons may cause: proliferation of T lymphocytes
are also microbial opioid peptides deltorphin I and II and cytokines release; activation of B lymphocytes and
(fungal) and dermorphin (from an unknown microbe). plasma cell antibody production; degranulation and

Acta Derm Venereol Suppl 217


40 J. F. Honeyman

proliferation; and differentiation of mast cells. It further The molecules that act as neurotransmitters can be
activates monocytes and macrophages, quimiotaxis and removed from the synaptic cleft of the glial cells (ast-
the survival of cytotoxicity of eosinophils and basophil rocytes remove neurotransmitters).
differentiation and cytokines release (Table I). In humans, the sympathetic nerve system can release
A new neurotrophin-1(NNT-1), a cytokine of the catecholamins (epinephrine and norepinephrine). Their
interleukin-6 family, can produce B-cell activation via effect on immune regulation is different, depending
gp130 receptor stimulation. on the organ and the concentrations; there are also dif-
ferences in the effect on animal models and humans.
Neurotransmitters In rats, the stimulation of 2 adrenergic receptors and
norepinephrine provokes predominant TH responses.
Neurotransmitters are endogenous chemicals that relay, In humans, the stimulation of 2 adrenergic receptors
amplify, and modulate signals between a neuron and provokes predominant TH-2 responses.
another cell (3, 5, 6). Several chemicals and over 50 Acute exposure to -adrenergic agonists in low
neuroactive peptides act as neurotransmitters. Not all concentrations increases NK cells (number and acti-
neurotransmitters are equally important. vity) and blood lymphocytes T CD8+ (number but not
Monoamines that act as neurotransmitters are: activity). Catecholamins also decrease lymphocytes T
acetylcholine; dopamine; norepinephrine; epinephrine; CD4+ but do not affect B lymphocytes. However, chro
serotonin (5-HT); histamine; melatonin; adenosine; and nic exposure to high concentrations in the lymphoid
anandamide. Other molecules with neurotransmitter organs (that are more sympathetic), lowers, or does
activity are GABA, glycine and aspartate. not change, the number of lymphocytes and NK cells.
Neuroactive peptides also have neurotransmitter
activity; examples are: bradykinin, beta-endorphin,
bombesin, calcitonin, cholecystokinin, enkephalin, PSYCHO-PHYSIOLOGICAL DISORDERS
dynorphin, insulin, gastrin, substance P, neurotensin, Psycho-physiological disorders (reactive emotional
glucagon, secretin, somatostatin, motilin, vasopressin, states) develop when an emotional or psychological
oxytocin, prolactin, thyrotropin, angiotensin II, sleep condition causes or exacerbates the physical symptoms
peptides, galanin, neuropeptide Y, thyrotropin-releasing of a disease in a direct or an indirect form (111). They
hormone, gonadotropin-releasing hormone, growth represent the relationship between mental (psyche) and
hormone-releasing hormone, luteinizing hormone, and physical (physiological) processes due to the interac-
vasoactive intestinal peptide. tion between the mind and the body.
Soluble gases (nitric oxide, carbon monoxide and There are two main types of psycho-physiological
zinc single ions) are not neurotransmitters but can have disorders, differentiated by the physical symptoms: in
neurotransmitter activity. the first type, sometimes known as somatoform disor-
The vast majority of psychoactive drugs exert their ders, the physical symptoms have no physical cause; in
effects by altering the actions of the neurotransmitter the second type, the physical symptoms have a physical
system and work through transmitters other than glu- cause but they are made worse by psychological issues.
tamate or GABA. For example, the addictive drugs, Specific emotional conflicts and specific personality
cocaine, amphetamine and heroin primarily affect the structures could be related to a certain psychosomatic
dopamine system. diseases.
There are psychological and physiological reac-
Table I. Cells with neurotrophins receptors tions to internal or external disturbances. They may
be directly caused by psychological or psychological
Neutrophins NGF BDNF NT-3 P57 trkA trkB trkC
pathologies or by an alteration of the autonomic nervous
Neural cells system. Psycho-physiological disorders can also be
Neurons Yes Yes Yes Yes Yes Yes Yes
Schwan cell Yes Yes Yes Yes Yes Yes Yes caused indirectly, by a psychological condition, active
Glial cell Yes Yes Yes Yes Yes Yes Yes hormones or mixed immunological reactions (1).
Keratinocytes Yes Yes Some of the more common emotional states respons
Immune cells ible for the development of illness are anxiety, stress,
LTh-1 Yes Yes Yes Yes
LTh-2 Yes Yes Yes and fear. Common psychosomatic ailments are: migrai-
Activated TL Yes Yes Yes nes; attention deficit hyperactivity disorder; ulcerative
B cells Yes Yes Yes colitis; and heart disease. Hypertension is made worse
Basophils
by stress and there are many other conditions that are
Eosinophils Yes
Mast cells Yes Yes Yes either made worse or caused by psychological problems.
Macrophages Yes Yes Yes Yes Minor and major stress factors are very important in
NGF: nerve growth factor; BDNF: brain-derived neurotrophic factor; NT: the onset and course of rheumatoid arthritis, juvenile
neurotrophin; trk: tyrosine kinase. chronic arthritis, and systemic lupus erythematous.

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Psychoneuroimmunology and the skin 41

Stress can also affect clotting and induce psychogenic Timing: Immuno-enhancement is observed when
purpura, ecchymosis and recurrent bruising (predomi- acute stress is experienced during the early stages
nates in women). Clotting problems have been repor- of an immune response while immuno-suppression
ted in cases of: emotional lability, depression, sexual may be observed at late stages. The type of immune
problems, obsession, anxiety, aggression and hostility, response (protective, regulatory/inhibitory, or patho
hypochondria, feelings of guilt, masochism, and hys- logical) that is affected determines whether the ef-
teria (1, 8, 9). Stress has been shown to retard wound fects of stress are ultimately beneficial or harmful
healing by impairing immune responses (1). for the organism.
Fibromyalgia syndrome (2) represents a failed at- Negative emotional states produce several immuno-
tempt of the autonomic nervous system to adjust to logical alterations that may cause other pathologies.
a hostile environment. There is a sympathetic hypo- Alcohol, cigarette smoking, lack of physical activity and
reactivity to stress that produces an allostatic load. It has sleep disturbances exacerbate immunological changes.
been suggested that dorsal root ganglia are important Mitogen tests have shown that discussing marital dif-
sympathetic-nociceptive short-circuit sites (10). ficulties can result in a decrease in NK activity, macro
Psychoneuroimmunology is the study of how psy- phages, immunity levels and can increase some T cells
chological factors influence the immune system and and blood levels of Epstein-Barr virus (EBV). Marital
immune functioning (1, 1214). There is a physiological problems, divorce and separation have been shown to
connection between the CNS and the immune system. decrease lymphocyte function, T-cell effectiveness and
For example, the sympathetic nervous system inner- to increase virus levels in the blood. Internal or external
vates the immune organs of the thymus, bone marrow, difficulties that alter or lead to personal problems and
spleen, and even the lymph nodes. failure to resolve them are all causes of stress.
There are 3 types of mental disorders that may affect
General adaptation syndrome (7). There is an asso-
the immune system: (i) psycho-physiological disorders
ciation between a natural stressor and alterations of
or reactive emotional states; (ii) primary psychiatric
immunity levels that may be due to the effect of neu-
disorders; and (iii) secondary psychiatric disorders
rotransmitters and hormones secreted during stress or
(diseases of other organs that cause psychological
due to indirect causes: poor nutrition, consumption of
psychiatric illnesses).
(legal or illegal) drugs, poor personal care, etc.
(i) Stress can suppress or dysregulate immune function Stress provokes neuronal activation of the CNS and
and increase susceptibility to disease. Several factors the paraventricular nucleus; it releases the corticotro
influence the enhancing or suppressive effects of stress phin hormone (CHR) that inhibits T- and B-cell re-
on immune function (1517): sponses, NKT cells and causes periphery inflammation.
Duration: Acute stress may activate an immune Stress also produces adrenalin and noradrenalin that
response and enhance innate and adaptive immune increase white blood cells and depress cell mediated
responses. Chronic stress can suppress or dysregu- immunity (Th1 responses).
late immune function. Adrenergic and cholinergic neurons release vasoac-
Leukocyte distribution: During acute stress, tissues tive intestinal peptide (VIP), somatostatin and other
that are enriched with immune cells (e.g. the skin) hormones that decrease cell-mediated immunity and NK
show immuno-enhancement; endogenous stress cells. Somatostatin also inhibits antibody production.
hormones enhance skin immunity by increasing The activation of the hypotalamus-hypophysis-
leukocyte trafficking and cytokine gene expres- adrenal axis releases opioid peptides that decrease or
sion at the site of antigen entry. On the other hand, increase immunological responses, depending on the
depletion of leukocytes (e.g in the blood) leads to receptors, the tissue and the amount. Activation of this
immuno-suppression. axis induces ACTH and the release of glucocortids that
Physiological and pharmacological stress hormo- decrease cellular and humoral immunity and have anti-
nes: Endogenous hormones in physiological con- inflammatory effects. ACTH also decreases antibody
centrations can have immuno-enhancing effects. production and IFN and increases numbers of B and
Synthetic hormones and endogenous stress hormo- NK cells. Low amounts of ACTH regulate immunity.
nes released during HPA axis activation at pharma- Corticotrophin and glucocorticosteroids chronically
cological concentrations are immuno-suppressive. affect the hypophysis-thyroid axis, resulting in lower T3
They inhibit the production of lymphocytes, the and T4 production and reduced secretion of the growth
white blood cells that circulate in the bodys fluids hormone that activates immune responses (7).
and are important for the immune response. Chro- There are 3 categories of stressors: (i) Physical (electric
nic exposure to corticosterone or acute exposure shocks, swimming in cold water, physical exercise, loss
to dexamethasone significantly suppresses skin of sleep, hunger, dehydration, surgical intervention, im-
delayed-type hypersensitivity reactions. mobility etc.); (ii) Social (parental separation, isolation,

Acta Derm Venereol Suppl 217


42 J. F. Honeyman

the presence of an intruder etc.); and (iii) Psychological vaccine. Good humour, happiness and laughter increase
(emotional responses, electric shocks etc.). IgA, the lymphocyte count and lymphocyte activity.
Stress can trigger a number of immunological reac- Hypnosis and relaxation techniques have been found to
tions. Depending on the duration and intensity, stress improve cell effectiveness and NK-cell activity whilst
can be described as acute or chronic. Acute stress may lowering stress hormone levels in blood and retarding
augment the immune system through a moderate rise herpes virus activity.
in the number and activity of NK cells, an increase in Physical and aerobic exercise stimulates production of
lymphocytes, cytotoxic T lymphocytes, neutrophils, white blood cells, endorphins, NK and T cells although it
leucocytes, salivary IgA, IL-6 and IFN. can decrease lymphocyte function (T-cell effectiveness).
Short-term, natural stress can bring about a mode- Similarly, feelings of good group and peer support can
rate increase in IL-6, IL-10, leucocytes and anti EBV result in an increase NK-cell numbers and activity and
antibodies. On the other hand, there may be a moderate the number of lymphocytes but can reduce T-helper cells.
decrease in NK-cell activity, mitogen induced lympho People with an optimistic, practical disposition are
cyte proliferation (Phytohemaglutinin, concavalin A), more likely to be able to counteract the decrease of
citotoxic T lymphocytes, neutrophils, leucocytes, sali- immunity (NK and T lymphocytes activity) induced
vary IgA and IFN. by stressful events and situaitons.
An acutely stressful event (e.g. death of a family mem- Neurogenic stimulation of the autonomous nerve
ber) can cause a mild to moderate decrease of IL-6, IL-10, system and certain drugs (neuroleptics, antihyperten-
leucocytes and anti EBV antibodies; there may also be a sive treatments, psychotropics, anti-histamine H2 and
moderate decrease in NK-cell activity. The body reacts opioids) lead to higher levels of dopamine that inhibits
to natural disasters, for example, earthquakes, with a the production of ACTH (11).
moderate increase in NK cell activity, mitogen induced (ii) Primary psychiatric disorders are rare and should
lymphocyte proliferation (Phytohemaglutinin) and a be treated in conjunction with psychiatrists and psycho-
moderate decrease in T lymphocytes (CD4+ and CD8+). logists. Many mental and emotional disorders involve
Chronic stress increases Th2 responses but decreases physical manifestations that are often the first definitive
T cells, Th1 reactions, NK cells, B cells and raises sign of disease; some examples are obsessive-compulsi-
blood levels of EBV. Pessimistic psychological states ve disorders, control impulses, depression and anxiety.
can lower lymphocyte reactivity and T-cell effective- Immunological changes that have been reported in
ness. Loneliness has been shown to reduce NK activity. patients suffering from depression are (1416): a mo-
Certain forms of chronic stress are associated with an derate increase of circulating neutrophils leucocytes
increased frequency of infections of the upper respiratory and activated T CD8 lymphocytes; a decrease in the
tract (colds, flu, etc.). Stress related to academic demands number and activity of T cells and NK cells (mainly
(e.g. exams) can decrease NK cell and T-cell activity, IgA in men); an increase of IL-6 (Th-2 citokyne); a higher
levels and increase susceptibility to the herpes virus. A number of acute phase proteins (1-glicoprotein, 1-
psychological need for power and control can result in antitripsin, and haptoglobin); c-reactive proteins and the
reduced NK activity and a lower number of lymphocytes. expression of soluble intercellular adhesion molecules
Chronic physical stress (cardiac arrest, disability, that increase endothelial activation (mainly in patients
etc.) causes a mild to moderate reduction in NK-cell with cardiovascular disease).
activity, mitogen-induced lymphocyte proliferation A further alteration observed in depressive patients
(phytohemaglutinin, cytokines production) and there was a Th1 and Th2 cytokine imbalance. TGF-beta1
is a humoral response to viral vaccines. seems to influence the pathophysiology of depression.
In people over 55 years old, chronic stress results Melancholic depressed patients release less IL-1 than
in a decrease in NK-cell activity and mitogen-induced those that are not melancholic.
lymphocyte proliferation. In people younger than 55 Depression also affects the autonomous nervous
there is only a decrease in NK-cell activity. system and hormonal release. There is an activation of
Based on NK-cell activity, hypersensitive reactions the peripheral sympathetic nervous system and elevated
and cell-mediated immunity, an evaluation of the ef- levels of catecholamines and neuropeptide-Y. Immunity
fects of stress on the immune systems of people who against viral infections inside the cells is reduced. Cell
are optimists and pessimists showed that optimists mediated immunity decreases but humeral responses to
manage acute stress better than pessimists. However, bacterial infections outside the cells increases.
in situations of chronic or unmanageable stress, pessi- Hormonal changes are characterised by inhibition
mists have stronger levels of immunity than optimists. of the effects of the corticotrophin-releasing hormone
Positive life conditions: satisfying personal relation (CRH) and the corticoids do not function, due to a defect
ships, a solid social support network etc. can increase of the glucocorticoids receptors.
lymphocyte function, NK activity, immunity (mitogen Depression is associated with lower levels of seroto-
tests) and the immune system response to the hepatitis B nin: a decrease of tryptophan, the precursor of 5-hidroxi-

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Psychoneuroimmunology and the skin 43

triptamine (serotonin) correlates with the severity of the sion; anxiety, aggression and hostility, hypochondria,
depression. Cytokine (IFN-) activation induces indo- feelings of guilt, masochism, and hysteria.
leamine 2 and 3-dioxygenase, a tryptophan degradation
enzyme that leads to tryptophan catabolism and reduces
the availability of tryptophan for serotonin synthesis. INTERACTION OF THE NERVOUS SYSTEM AND
Antidepressant treatment associated with clinical THE SKIN
improvement alters the Th1/Th2 balance through the Recent studies have highlighted the role of emotion
action of TGF1. Tricyclic antidepressants that are asso- dysregulation in several skin diseases. There is a
ciated with clinical improvements increase NK cells and considerable amount of published scientific literature
decrease IL-6 (Th-2 cytokine), causing a shift in Th-1 concerning psychological distress and dermatological
responses. There are several studies on the treatment of diseases. Psychocutaneous diseases are common.
depression; they include the use of IL-1 receptor antago- The skin and the CNS have a similar embryological
nists, anakinra (an IL-1 receptor antagonist), anti-TNF origin. They both release common neuromodulators,
antibodies (infliximab) and receptors (etarnecept) and peptides and biochemical systems. For this reason, the
anti-inflammatory cytokines (IL-10). Other options are skin is an organ that is strongly reactive to psychiatric
the antidepressant targeting of the corticotrophin relea- and psychological conditions and this interaction may
sing factor, therapies targeting monoamine neurotrans- be significant in the pathogenesis of several skin di-
mission with anti depressants inhibitors of indoleamine seases (16, 17).
2,3-dioxygenase, the inhibition of inflammatory signals
with enhancement of glucocorticoid signalling and the Psycho-physiological disorders (18)
use of type 4 phosphodiesterase inhibitors (14, 15).
Schizophrenia is frequently associated with autoim- Psychological illness may alter the evolution of a skin
mune diseases such as rheumatoid arthritis patients disease, precipitating its appearance or exacerbating an
produce less IL-2 and IFN-, there is a switch Th1 to injury. Some examples of psycho-physiological skin
Th2 that alters the availability of tryptophan and se- manifestations are flushing, facial pallor and hyper-
rotonin and a there is a disturbance of the kynurenine hidrosis; a number of dermatoses can be aggravated
metabolism with an imbalance in favour of the produc- by stress and psychological disorders: skin infections
tion of the N-methyl d-aspartate receptor antagonist, (herpes virus, warts, fungi), tumours, allergies, atopy,
kynurenic acid (16). urticaria, angioedema, psoriasis, vitiligo, alopecia,
(iii) Secondary psychiatric disorders (disease of or- acne, seborrhoea, seborrhoeic dermatitis, and rosacea.
gans, causing psychological, psychiatric illnesses) Atopic dermatitis is associated with stress (70% of
(1519) are rare and should be treated in conjunction cases), anxiety, depression and neurosis. Psoriasis is
with psychiatrists and psychologists. These diseases associated with stress (39% of cases), anxiety, depres-
affect appearance and/or alter the quality of life of the sion, obsession, and alcoholism. Hives and angioedema
patient; they may cause feelings of shame, depression, are associated with stress (5177% of cases), hostility,
anxiety, low self-esteem, and suicidal ideation. Patients rage and depression. Alopecia areata is associated with
may have to deal with discrimination and social isola- stress (23% of cases), anxiety, depression and paranoia.
tion. They sometimes have difficulty obtaining work. Chronic stress also weakens the immune system and this
Many psychological and emotional disorders have may affect the incidence of virus-associated cancers,
physical manifestations that are often the first defini- for example, Kaposis sarcoma and some lymphomas.
tive sign of disease: obsessive compulsive disorders,
impulse control, depression, anxiety, body dysmorphic Cutaneous primary psychiatric disorders (19, 20)
disorder, anorexia nervosa, and tobacco dependence These refer to skin conditions that have been self-
(19). inflicted by patients with psychiatric disorders. Examp-
Dysmorphophobia is an abnormal preoccupation les are self-inflicted dermatoses (trichotillomania and
with a real or imagined body image defect. The most onicofagia), factitious injury or neurotic abrasion/exco-
common eating disorders are anorexia nervosa, bulimia, riation (skin-picking), dermatillomania, acne excorie,
and compulsive eating. Burning mouth syndrome (glos- neurotic excoriatio, and psychogenic excoriation.
salgia/glossodynia) is associated with depression and
anxiety (62% of cases) and cancer phobia (2030% of
Secondary psychiatric disorders (21)
cases). It is also symptomatic in personality disorders,
mood swings, anxiety, etc. Skin conditions that affect the psyche may cause
Stress can affect clotting and lead to psychogenic pur- depression, frustration and social phobias. They may
pura, ecchymosis or recurrent bruising (predominates in occur in patients with psychological problems and
women). Clotting problems have been associated with: have a negative impact on their self-esteem and body
emotional lability; depression; sexual problems; obses- image. They include the disfiguring skin disorders:

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44 J. F. Honeyman

severe acne, big lips, rosacea, rhinophyma, angiomas pro-inflammatory cytokines and nitric oxide that cause
and giant hairy pigmentary naevus. destruction of melanocytes, accelerating the depigmen-
tation. Melanocyte damage can also be caused by the
release, by the brain, of the peptide associated with gen-
THE NERVOUS SYSTEM AND SKIN DISEASE
calcitonina (CGRP), which stimulates the neuropeptide
Pruritus (22, 23) and harms the melanocyte. The activated adrenergic
fibres release norepinephrine, epinephrine, dopamine,
Itching is an unpleasant sensation, similar to pain, that metanephrine, and H-indol acetic acid that increase
can be local or generalised. It is a complex sensory and in cases of vitiligo and damaged melanocytes. This is
emotional experience produced by primary psychiatric added to by the fact that type C nerve fibres release
disorders or psycho-physiological disorders such as neuropeptides (NGF) that also harm the melanocytes.
itching of the scalp and trichotillomania, prurigo, and
anal itching. Alopecia areata (26, 27)
Pruritus may be caused by: medication, allergies,
pregnancy, dry skin, poor nutrition, cancer, infection, Stress is an important factor, especially when the di-
psoriasis, diabetes, aging, collagen diseases, and gastro sease itself produces psychological stress. Psychiatric
intestinal disorders. It can also occur in association disorders are observed in 67% of cases (1).
with other conditions like Crohns and Behets disease The high level of psychiatric morbidity plays a
There is a need to define psychogenic pruritus and pathogenic role. Problems of adaptability have been
its diagnostic criteria. Nerve diseases can cause neu- detected in 43.2% of cases; dependent personality
rological itching as with neuropathies, or disorders of (66% of cases); antisocial personality (39%); anxiety
psychic mania, anxiety, sexual problems, psychiatric (41.1%); and depression (32%). In contrast, generalised
conditions, etc. (23). anxiety and a depressive personality are noted in less
Functional brain imaging studies have identified brain than 1% of patients.
regions associated with pruritus and found that several Alopecia areata is an autoimmune disease mediated
regions are activated by itch stimuli. The possible roles by T and B cells. There are immune responses to the
of these regions in itch perception and differences in the antigens of the hair follicles. The auto-antigens of
cerebral mechanisms of healthy subjects and chronic the hair follicle are the peptides associated with me-
itch patients have been discussed. The central itch mo- lanogenesis (trichohyaline and specific keratin). The
dulation system and cerebral mechanisms of contagious condition is associated with HLA or immunogenic and
itch and the pleasurable sensation evoked by scratching neuroendocrine factors.
have also been investigated. The hair follicle has a natural protection against im-
Several nervous system mechanisms might be re- muno-allergic reactions that can cause damage (immune
sponsible for itching. Cholinergic fibres release acetyl- privilege). The hair follicle contains immunosuppres-
choline and produce VIP which causes the eosinophil sive factors (TGF-1 and 2, ACTH and MSH). There
to release histamine and activate the peripheral itching is a small presence of NK cells, lymphocytes CD4+ and
receptors located in the epidermis. The histamine sti- CD8+, and an absence of Langerhans cells and lymph
mulates the H2 and H3 brain receptors and activates the vessels. Immune privilege prevents allergic reactions to
neurons of the CNS which secrete opioid peptides that hair follicle melanocytes and keratinocytes that do not
also stimulate the peripheral itching receptors. More- express MHC I by inhibition of activating molecules.
over, type C sensory nerve fibres, are also activated, Immune privilege may fail due to micro-trauma, fol-
they release the neuropeptides, Neurokinin A, substance licular damage, bacterial superantigens, viral infections
P and the NGF that activates the pruritus receptors. Itch and psychological alterations. The loss of immune pri-
receptors can also be indirectly stimulated by the IL-2 vilege stimulates allergic reactions and the recognition
and prostaglandins. of autoantigens, T lymphocytes and NK cells which
release inflammatory cytokines. Stress inhibits the pro-
duction of ACTH, -MSH and the ACTH-releasing hor-
Vitiligo (2426)
mone, resulting in follicle damage and alopecia areata
In cases of vitiligo, melanocyte damage is produced Another psycho-immunological mechanism that can
by immunological and neurogenic factors and self- cause alopecia areata is the release of the peptide asso-
destruction. The disease is mediated by T cells and ciated with the calcitonin gene (CGRP) by type C and
accelerates with stress, personal trauma, exposure to sympathetic fibres. This peptide stimulates the immune
UVR and mechanical injury. response Th-1 (lymphocytes CD4 helper) and inhibits
The shock protein, caloric HSP70, is released by the Th2 lymphocytes. Stimulation of B lymphocytes that
CNS and damages melanocytes, releasing antigenic produce IgG antibodies originates an immune complex
proteins that activate dendritic cells, inducing a T4 which induces apoptosis in keratinocytes of the hair
and T8-cell immune response and further releasing follicles, causing alopecia.

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Psychoneuroimmunology and the skin 45

Psoriasis (28, 29) affects an area >100 cm2 it considered as widespread.


Hyperhidrosis can be primary or secondary. Primary
Both internal factors (heredity, hormone metabolism,
hyperhidrosis (or hyperhidrosis of unknown origin) is
the nervous and immune systems) and external factors
more frequent, and usually has a social impact. The con-
(trauma, infections, cutaneous flora, antigens, ultravio-
dition may start in childhood or adolescence it can be-
let radiation, drugs, alcohol, tobacco, etc.) can trigger
come more severe in puberty and persist throughout life.
the condition, which is caused by an increase in the
Secondary hyperhidrosis (or diaphoresis) is associated
proliferation of epidermal keratinocytes. Psychological
with febrile infections, drugs, endocrine problems and
itching and sleep disturbances may occur in 80% of
psychological disorders. Psychiatric or psychosomatic
psoriatic patients. Depression is common in severe
conditions that can accompany hyperhidrosis include:
cases. There is also a direct relationship between stress,
migraine, emotional problems, nervous agitation, night
the severity of cutaneous manifestations and joint
sweats, hysteria, panic, and depression.
commitment in psoriatic arthritis. The prevalence of
To date, the central pathways of emotional sweating
depression in patients with psoriasis is estimated to be
have not been elucidated. The limbic system, inclu-
between 10 and 62%.
ding the amygdala and cingulate cortex, is critical for
Several psycho-neural mechanisms may cause psoria-
emotional processing and many cognitive functions.
sis; sensory nerves release neuropeptides (neurotensin,
Measurement of sweat output on the palm or sole is
somatostatin, substance P and NGF) which activate
useful for evaluating sympathetic function and limbic
the proliferation of keratinocytes. Sensory nerves and
activity in autonomic and psychiatric disorders.
C-fibres also release CGRP (-calcitonin gene-related
peptide), which directly activates keratinocyte prolifera-
tion and stimulates the endothelial cells. The C-fibres Acne (3, 32, 33)
further release nitric oxide and cholinergic fibres pro- Acne involves skin, hormonal, immunological and
duce acetylcholine and the vasoactive intestinal peptide psychological factors. Stress can induce and exacer-
(VIP); all of them are linked to vasodilatation. bate acne lesions. Cutaneous lesions can have a psy-
Neuropeptides activate granulocyte and macrophage chosocial impact and alter the nervous system. Both
(GM-CSF) which attract the macrophages and mono- the peripheral and CNS are associated with cutaneous
cytes that secrete prostaglandin PGE2 and interleukin factors and the action of androgens in the formation
IL-10. In addition to producing increased proliferation of comedones.
of keratinocytes, these neurotransmitters stimulate T Acne and seborrhoeic dermatitis may be caused
cells and vasodilation. by a neurogenic stimulation of sebaceous secretion.
The Koebner phenomenon occurs when scratching Sensory nerves release neuropeptides (neurotensin, so-
causes the release of neurotransmitters. matostatin, substance P, NGF, hormone melanocyte, and
PPAR-) stimulant- and the peptide derived from the
Hyperhidrosis (excessive sweating) (30, 31) propiomelanocortina, all of which stimulate sebaceous
gland sebocytes, increasing secretion. The activated
Sweating is a multifunctional response that aids lo- sebocytes also secrete cytokines (IL1- IL-6, TNF-,
comotion, thermal regulation, self-protection and the INF- and PPAR-) that produce inflammation.
communication of the psychological state. The primary Seborrhoea or excessive sebaceous secretion and
stimulus is heat. Secondary stimuli may include emo- seborrhoeic dermatitis may increase sebum production
tions and certain foods (seasoning and spices). through a neurogenic mechanism similar to acne.
Normal sweating is caused by the activation of the
CNS and an effector or peripheral system. The amyg-
Rosacea and red face syndrome (flushing) (34, 35)
dala, cingulate cortex, and medulla participate via ef-
ferent fibres that descend the spinal cord and connect The nervous system can instigate vasomotor reactions.
to preganglionic sympathetic neurons in the nucleus Shock may result in vasoconstriction, causing facial
intermediolateralis. In the brain, there is a temperature pallor. Psychological reactions can cause vasodilation
controller, located in the pre-optic area of the anterior which is clinically manifested as blushing, facial red-
hypothalamus, which has termoreceptors with neurons ness, erythrosis or persistent or chronic blushing that
sensitive to temperature changes. When these receptors can lead to rosacea.
are activated, a signal passes through the spinal cord Vasodilatation can be produced by neuropeptides
and connects to preganglionic 12 and 13 sympathetic (released by the sensory nerves), nitric oxide (released
neurons, which release acetylcholine that stimulates by nerve C-fibres) and acetylcholine and vasoactive
the sweat glands through gland eccrine-capillary in- intestinal peptide (released by the cholinergic fibres).
teraction. Vasodilation induced skin diseases of psychological
Excessive sweating can be located in the feet, the origin include vasomotor rosacea, vasomotor instabi-
sacral region, axillae, trunk, face and scalp. When it lity, and facial erythrodysaesthesia. A rosacea inductor

Acta Derm Venereol Suppl 217


46 J. F. Honeyman

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