Study of Psychoneuroimmunology in Atopic Dermatitis

Cita Rosita Sigit Prakoeswa

, Bayu Bijaksana Rumondor

, Menul Ayu Umborowati

, Sylvia

Anggraeni

, Anang Endaryanto

Allergy Immunology Division, Dermatology Venereology Department, Faculty of Medicine, Universitas Airlangga - Dr.

Soetomo General Hospital, Surabaya, Indonesia.

Medical Student, Faculty of Medicine, Universitas Airlangga - Dr. Soetomo General Hospital, Surabaya, Indonesia.

Allergy Immunology Division, Child Health Department, Faculty of Medicine, Universitas Airlangga - Dr. Soetomo

General Hospital, Surabaya, Indonesia.

Keywords: psychoneuroimmunology, atopic dermatitis, stress, hypothalamus-pituitary-adrenal.

Abstract: Psychoneuroimmunology is an inter disciplinary field that specifically examines the biochemical cross talk

between brain, behavior and the immune system and between allergy immunology concept and

psychosocial factors. The increase of allergic manifestation may be associated with environmental factors

such as stress. A growing number of studies have suggested an altered hypothalamus-pituitary- adrenal

(HPA) axis function to stress in allergy. It is speculated that a dysfunctional HPA axis in response to stress

may facilitate and/or consolidate immunological aberrations and thus, may increase the risk for allergic

sensitization and exacerbation especially under stressful conditions. It has been established via clinical and

physiological means that psychological stress is a significant contributor to allergy course through its direct

and indirect effects on immune response, cutaneous neuropeptide expression, and skin barrier function.

1 INTRODUCTION

Psychoneuroimmunology is an interdisciplinary

field of study which focuses in the biochemical

interactions between the brain, social behavior and

the immune system (Suarez et al., 2012), especially

the correlation between immunologic disorders and

psychosocial factors (Chida et al., 2008; Nordlind,

2008). Hypersensitivity reactions are identified by

overabundant production of immunoglobulin E

(IgE), one of which is atopic dermatitis (AD)

(Buske-Kirschbaum, 2009).

Allergen presentation by dendritic cells initiates

the late phase response via activation of T-helper

(Th) cells which in turn secretes large amounts of

interleukin (IL)-4, IL-5 and IL-13. This reflects a

Th-2 dominant response which plays a big role in

allergic inflammations. IL-4 and IL-13 stimulates

the synthesis of IgE and also induces B cells to

switch from other Ig isotypes into IgE. This is

followed with an increase of Vascular Cells

Adhesion Molecule 1 (VCAM-1) expressions, and

the recruitment and invasion of eosinophils to

inflamed sites. IL-5 induces eosinophils to secrete

Eosinophyl Cationic Protein (ECO) which

contributes to the degradation of cells. The role of

immunologic dysfunction in the pathomechanism of

allergic diseases including AD has been proven in

several previous studies, however most of them

remained not well understood (Buske-Kirschbaum,

2009; Dave et al., 2011).

One popular hypothesis which potentially

explains the increased prevalence of AD is that its

immunopathology is affected by several factors i.e.:

lifestyle, nutritional status and intake, pollution and

also psychosocial stress.

This study aimed to discuss the role

psychoneuroimmunlogy in the pathogenesis of

allergy, including the potential impact of hyper or

hypo responsiveness of hypothalamus-pituitary-

adrenal (HPA) axis towards the onset and chronicity

of allergic diseases in dermatology, in this case,

atopic dermatitis. Other factors which contributes to

the dysfunction of HPA axis in allergy, including

stress management therapy which targets neuro-

immune systems for comprehensive allergic

management is also discussed in this study.

Prakoeswa, C., Rumondor, B., Umborowati, M., Anggraeni, S. and Endaryanto, A.

Study of Psychoneuroimmunology in Atopic Dermatitis.

DOI: 10.5220/0008160304850488

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 485-488

ISBN: 978-989-758-494-7

485

2 CASE

A 11-year-old female came to the dermatology and

venerology outpatient clinic in Dr. Soetomo teaching

hospital with clinically severe eczema along with

allergic history towards house dust mites, animal fur

and certain food. Laboratory results show a total IgE

value of 937 (Normal value: <100), with specific

IgE positivity towards eggs, poultry, shrimp, crabs,

house dust mites, and bird feather as well as cat and

dog fur. After a series of thorough anamnesis and

examinations, this patient was diagnosed with severe

atopic eczema, allergic rhinitis and chronic

intermittent cough. Comprehensive patient

management was done including skin care and

topical as well as oral corticosteroid for eczema,

symptomatic medication for allergic rhinitis, and

immunotherapy.

Patient went through these regiment for a year.

For the first few months, food elimination program

almost always fails where the patient fails to avoid

food which causes allergic reactions. The impact

could be directly seen along with worsening of

eczema. Clinical improvement of eczema eventually

was seen after 9 months of treatment due to the

patient's gradually increased compliance towards the

food elimination program.

Patient went through a series of immunotherapy

every week for the first 14 appointments, followed

by every 3 weeks for the next. Respiratory tract

conditions including sneezing, nose itching, show

clinical improvement after the 10th administration.

Another positive impact was that oral corticosteroid

was needed less frequently after 4th immunotherapy.

This researcher found an interesting fact that all the

clinical improvements regarding eczema and

respiratory tract complaints are somehow related to

the patients father's presence.

Figure 1: Graph demonstrating evaluated aspects of this patient's disease progression throughout the year,

illustrated by different lines. (Endaryanto, 2015).

3 DISCUSSION

In the earlier decades of life, atopy is characterised

by hyperresponsiveness of HPA axis to stress

(Buske-Kirschbaum, 2009; Ball et al., 2006). The

dysfunction of HPA axis mechanism in newborns

which eventually leads to allergy is yet well

understood. However, some studies have shown that

it is influenced by genetic factors and the prosess of

fetal programming. (De Weerth et al., 2005; Wüst et

al., 2006). During stress psychological, the increase

of endogenous cortisol which triggers dominant

response from th2 will further increase the risk of

allergic sensitisation and (accelerate) the onset of

RCD 2018 - The 23rd Regional Conference of Dermatology 2018

486

allergies. Cortisole stimulates IL-4 which will later

induce the production of IgE and B-cells. (Barnes,

2001). During the course of time, hyperresponsive

HPA axis will switch to hyporesponsiveness. The

factors which causes this phenomenon is not fully

understood, but it is thought to be affected by

chronic inflammation which induces continuous

secretion of proinflammatory cytokines or by

(chronic/prolonged) stress due to the allergy itself or

due to social problems. In chronic allergy in

children, lack of cortisol adequate secretion response

in stressful conditions causes lack of inflammatory

response control such as the regulation of pro-

inflammatory cytokines, the adhesion of leucocytes

and the activation of eosinophils. Hence, in

children, stress also can be a risk factor of

exacerbation and chronic progression of allergies

due to its impact which causes HPA axis

dysfunction.

The central nervous system response to

phychologic stress (Suarez et al., 2012). The HPA

axis responses to phsychologic stress by increasing

the secretion of corticotropin releasing hormone

(CRH) and adrenocorticotropic hormone (ACTH)

(Glaser, 2005). which then triggers the secretion of

pituitary prolactin (PRL) which inhibits lymphocyte

proliferation induced by stress (Foitzik et al., 2009).

CRH and ATCH also stimulates norepinephrine

(NE) and the release of cortisol from adrenal cortex

which in turn stimulates and regulates other immune

responses while sending a negative feedback to the

hypothalamus and hypophysis. This is followed by

an increased release of serotonin (5HT) in the brain

stem as well as P-Substance (SP), gastrin-releasing

peptide (GRP) and calcitonin gene related peptide

(CGRP) in the dorsal ganglia (Norlind et al., 2008;

Roosterman et al., 2006; Slominski et al., 2005).

In the dermis, immune cells release cytokines,

chemokines and neuropeptides which modulates the

inflammatory responses, triggers the sensation of

pain and itchiness and also transmits sensory stimuli

through dorsal ganglia and spinal tract to spesific

areas in the central nervous system. Cutaneous mast

cells are known to be well related to SP, CGRP,

pituitary adenylate cyclase activating protein

(PACAP) and opioid releasing neurons; and is

responsive towards said neuromediators. As a

response to stress, cutaneous mast cells stimulate

several inflammatory mediators, hence inducing

local production of neurohormones and

neuropeptides (Suarez et al., 2007).

Prolonged psychological stress may damage the

natural barrier of the skin and increase levels of

endogenous glucocorticoid which will also attribute

to the alteration of homeostasis and integrity, also

microbial defense of the skin itself. These are mainly

caused by the inhibition of epidermal lipid synthesis

which is mediated by glucocorticoid. Therefore,

replacement of this epidermal lipid is a promising

therapy for people who has stress related allergic

skin disorder. However, no randomised trial study

comparing the efficacy of topical therapy for

patients with stress related atopic dermatitis and

patients with non-stress related atopic dermatitis

(Walker & Papadopuolos, 2005; Suarez et al., 2007;

Steinhoff & Steinhoff, 2009).

There’s a continuous pattern where psychologic

stress causes itch in atopic dermatitis, and the itch

will in turn further cause psychologic stress and this

will continue on. Hence, psychopharmacology will

be useful in breaking this chain. The correlation

which was found between anxiety score in AD

patients who experiences pruritus and NPY and

NGF explains that anxiety causes pruritus via

increase of expression of these neuropeptides.

Therefore stress management and reduction is an

necessary approach in treating pruritus in AD

patients.

Patient with stress related AD also experiences

an increase in serotonin-sensitive mast cells.

Serotonin agonists and SSRIs improves the skin

condition and reliefs the patient from pruritus

through a poorly understood mechanism. Anti-

pruritic effect of SSRI is thought to be due to a

certain mechanism in the central nervous system.

Tandosiprone Citrate (TC), an anxiolitic serotonin

agonist, may be used in stress managements which

are related to worsening AD conditions supported by

other studies using mice models. The administration

of bupropion may show clinical improvements

through its role as anti-inflammatory agents which

lowers TNF and as inhibitor of neurotransmitter

reuptake (Steinhoff & Steinhoff, 2009; Suarez et al.,

2012).

Itchiness caused by psychologic stress is also

thought to be related to substance P (SP). The

increase of psychological stress condition causes

elevated levels of plasma SP which is then related to

the worsening of AD. Adding oral olopatadine to the

regular topical regiment helps relief itchiness and SP

plasma levels. Therefore it is thought that

olopatadine has a potential use of controlling or

reducing the level of SP caused by stress, which is

beneficial towards reducing pruritus in AD. Mice

model studies show clinical improvement after

administration of NK1R antagonists. NK1 receptors

is known to be affiliated to SP, which makes it a

Study of Psychoneuroimmunology in Atopic Dermatitis

487

possible approach for pharmacological

inverventions.

SP levels tend to remain the same, even after

remission of AD, which suggests that SP-ergic

mechanisms does not play a big role in acute clinical

changes in AD (Suarez et al., 2012; Steinhoff &

Steinhoff, 2009). The central or peripheral

mechanisms related to pruritus management is still

poorly understood. Therefore further researches

regarding these matter, including the roles of

neuropeptides as pruritogenic substances in AD

should be done. The decision for

psychoneuroalergologic management approaches in

dermatology for cases such as AD should be

supported by enough clinical evidence. A meta-

analytic review regarding psychologic stress and

atopic dermatitis proves that there is a two way

relation. These findings should receive

comprehensive efforts involving psychologic

interventions in AD management standards.

4 CONCLUSION

The mechanism underlying psychoneuroalergology

in dermatology i.e. the correlation of allergy and

psychologic stress is not fully understood. However,

new perspectives and concepts have been unveiled

from the Psychoneuroimmunology point of view.

Clinically and physiologically, psychologic stress is

shown to have direct and indirect influence towards

immune response, expression of skin neuropeptide

and skin barrier function. Several researches have

shown huge potentials in identifying new therapeutic

approaches by modulating neuroimmune systems.

Hopefully this will further improve AD management

hence reducing chronicity and recurrence rates,

lowering the burden of the disease and improving

the patient's life quality.

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