Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease with an

increasing prevalence (up to 20% in children and 5% in adults) and

presents a major public health problem in industrialised countries.1,2

Characteristic features of AD include pruritus and chronic or chronically

relapsing dermatitis, usually beginning at infant age. AD is a genetic

complex disease and is often, but not always, accompanied by other

atopic disorders such as allergic rhino-conjunctivitis or allergic bronchial

asthma. These diseases may appear simultaneously or develop in

succession during the course of disease. AD is characteristic for early

childhood, while pollen allergy and allergic asthma predominate in

adolescence. This characteristic, age-dependent sequence has been

postulated as the atopic march.3 The cutaneous manifestations of

atopy often represent the beginning of this atopic carrier while

asthmatic diseases usually mark its full expression. Therapeutic strategies

should be directed towards the delay or avoidance of this development

by early intervention against skin inflammation, which may prevent

subsequent sensitisation.

Definition, Clinical Symptoms and Complications

Since the recent consensus nomenclature by the World Allergy

Organization (WAO),4 the term atopy should only be applied in

combination with documented allergen-specific immunoglobulin E (IgE)

antibodies in serum or with a positive skin-prick test. Thus, the term AD

should be reserved for an eczematous condition with the typical clinical

signs and associated to IgE-mediated sensitisation. Consequently, atopic

dermatitis/eczema (7080%; formerly extrinsic AD) should be

distinguished from non-atopic eczema (2030%; formerly intrinsic AD).

However it should be noticed that, based on recent epidemiological

studies, non-atopic eczema is, at least in children, not a stable condition

but should be considered as a transient phase during which sensitisation

may be facilitated leading to AD stricto sensu. Therefore, whether an

eczema is atopic or non-atopic can only be answered after a period of

several months of course, once sensitisation has been definitely excluded

or confirmed.

Non-atopic and atopic dermatitis are not clinically different. Both develop

on dry skin and may in some instances resemble a mild form of ichthyosis.

Intense pruritus is also the hallmark of both forms. The clinical spectrum

is wide and can vary depending on the age of the patients and the degree

of involvement, i.e. acute (oozing, crusted vesicles or papules on

erythematous plaques), sub-acute (mainly excoriated plaques) and

chronic (lichenified and excoriated plaques) lesions. With respect to age,

first signs of inflammation typically occur during the third month of life

and infants present facial and patchy or, less commonly, generalised

dermatitis, usually accompanied by the typical milk crust or milk scurf.

In childhood, sites of predilection of dermatitis are flexural areas, dorsum

of the feet and hands with lichenification. For unknown reasons, in more

than 60% of cases AD may enter into complete remission during puberty.

In adults, localised inflammation with lichenification of the flexural areas

is the most common pattern. Predilection sites are the face, neck, scalp,

upper chest, large joint flexures, and backs of the hands. Even if the

inflammation has resolved, dry skin continues to be a persistent problem,

especially in winter months.

The most important complications of AD are due to secondary

staphylococcal and viral infections. These infections are due to a defect in

the local innate immunity, i.e. defective production of antimicrobial

peptides (AMPs, see below). Patients with AD are at increased risk of

widespread herpes simplex virus infection (eczema herpeticum).5,6 The

course of this complication may be severe with high fever and

widespread eruptions.

Histology of both forms of dermatitis is highly similar to that of allergic

contact dermatitis and has no fundamental impact on the diagnosis of

AD. However, it is important to note that clinically normal appearing skin

of AD patients contains a sparse peri-vascular T-cell infiltrate, suggesting

minimal inflammation.7 This residual inflammation is considered the

background for further flares.

Pathophysiology

Genetics

AD is a paradigmatic genetically complex disease involving gene-gene

and gene-environment interactions and much progress in understanding

its pathogenesis has been achieved in recent years.8 Genetic linkage

studies have identified several chromosomal regions linked to the

epidermal barrier function (Chr. 1q21), and genetic variants causing the

development of AD but mainly linked to candidate genes of the immune

system (such as cytokines and chemokines and their receptors) have been

additionally detected. Most importantly, it has been shown that two loss-

13 T O U C H B R I E F I N G S 2 0 0 7

Atopic Dermatitis

a report by

Thomas Bieber

Professor of Dermatology and Allergy, University of Bonn

Atopic Dermatitis Clinical and Pathophysiological Aspects

Thomas Bieber is Chair and Director of the Department of Dermatology and Allergy at theRheinische Friedrich-Wilhelms-University in Bonn, Germany. Besides clinical dermatology and

allergy, his scientific focus is in the immunobiology of dendritic cells, their role in allergic diseasesand tolerance mechanisms, as well as genetic aspects of these conditions. He is member or

honorary member of several national and international societies and of the German academy ofsciences Leopoldina, and is author or co-author of more than 350 papers and book chapters. Heis associate editor and member of several editorial boards of national and international journals,including Allergy and the Journal of Allergy and Clinical Immunology. He has received many awards such

as the Karl-Hansen-Award of the German Society for Allergology and Immunology (DGAI), thePharmacia international research award and the Gold Medal of the Foundation for AllergyResearch in Europe and was recipient of the distinguished Heisenberg Fellowship from the

German Research Council (DFG). Professor Bieber started his studies in medicine and biology in1976 at the University Louis Pasteur in Strasbourg, France. He trained in dermatology and allergy

at the departments of Strasbourg (1982-1985) and then Munich, Germany.

Email: [email protected]

Bieber_edit.qxp 18/4/07 12:27 pm Page 13

14 E U R O P E A N D E R M A T O L O G Y R E V I E W 2 0 0 7

Atopic Dermatitis

of-function mutations of the profilaggrin/filaggrin gene (FLG) (R510X and

2282del4), a key protein in terminal differentiation of the epidermis,

seem to be important risk factors for AD and AD in combination with

asthma.9 These variants seem to be more associated with the true AD

form.10 It is expected that other yet-to-be-defined genetic variants from

epidermal structures such as those localised in the epidermal differential

complex (EDC) on Chr. 1q21 may also play a role in these phenomena.

These genetic findings provide important support for the well-known

dryness and impairment of the epidermal barrier observed in AD patients

(increased transepidermal water loss) and could also deliver further clues

as to the natural history of the disease, i.e. the transition of a non-atopic

eczema to an atopic eczema due to a facilitated penetration of and

sensitisation to aeroallergens during chronic inflammation. However, two

paradoxical situations remain to be clarified:

some chromosomal regions found for AD correspond to gene loci

found in patients with psoriasis, although AD and psoriasis are

clinically almost mutually excluding; and

the chromosomal regions do not correspond to those previously

reported for other atopic diseases such as allergic asthma.11

Immunological Mechanisms

Innate as well as adaptive immune systems play a major role in the

pathophysiological puzzle of AD. The former are able to promptly

react to almost all kinds of microbial colonisation and attacks,12 while

they are also involved in the initiation of the more specific but slower

mechanisms of the adaptive immune response. Epithelial cells of the

skin and cells residing at the interface between our environment and

our organism are equipped with highly conserved recognition

structures the so-called pattern recognition receptors (PRRs) such as

the Toll-like receptors (TLRs). These TLRs can bind a variety of

microbial structures due to highly conserved microbial surface

molecules the so-called pathogen-associated molecular pattern

(PAMP). The binding of microbial products to the cell surface of

epithelial cells leads to cell activation, ultimately resulting in the

production of newly described molecules with antimicrobial activities:

the antimicrobial peptides (AMPs). In human skin the major AMPs are

cathelicidin (LL37) and human beta defensin (HBD) 1, 2 and 3. It has

been shown that the strong colonisation of AD with Staphylococcus

aureus (which can trigger/enhance inflammation in an allergen-

independent way by the secretion of superantigens/enterotoxins) and

the higher risk of developing widespread viral infections (eczema

herpeticum) are due to a downregulation of AMPs secondary to the

particular inflammatory micro-milieu.13-15

AD is characterised by multiple alterations of the adaptive immune

system. A predominant systemic T-helper type 2 (Th2) dysbalance with

increased IgE levels and eosinophilia are the hallmarks in this condition,

while only eosinophilia is seen in non-atopic eczema.16 Interestingly, a

Th2 profile is only detected in early/acute lesions of AD while chronic

lesions rather have a Th1/Th0 pattern. Thus, chronic AD is not a classical

Th2 disease but rather a biphasic (Th2 followed by Th1) disease. Another

unsolved question is the role of reported Th1-mediated apoptosis since

apoptotic cells are more observed in acute lesions with Th2 profile and

not in chronic lesions.

The role of T-cells with regulatory activities (Treg) in AD has been

addressed recently. Treg form a complex family of cells with distinct

surface markers but all expressing the nuclear factor Foxp3, which is

mutated in immune dysregulation, polyendocrinopathy, enteropathy,

X-linked (IPEX) syndrome. Interestingly, staphylococcal superantigens

subvert the function of regulatory T-cells and may thereby augment skin

inflammation.17,18

Much interest has been focused recently on the role of chemokines in the

recruitment of inflammatory cells in the skin.19 Thus, MCP-4/CCL13,

RANTES/CCL5, MIP-4/CCL18, TARC/CCL17, PARC/CCL18, MDC/CCL22,

eotaxin/CCL11 and I-309/CCL1 have been shown to be involved in the

development of acute and chronic skin inflammation, as well as in the

amplification of allergic reactions to bacteria or allergens. Their exact

value in pathogenesis is, however, still not resolved.

The role of dendritic cells (DC) in AD has been extensively discussed

elsewhere.20 While myeloid (mDC, e.g. Langerhans cells (LC) and

inflammatory dendritic epidermal cells (IDEC)) have been found in large

amounts in lesional skin of AD, plasmacytoid dendritic cells (pDC) are

almost absent, which is in contrast to other inflammatory skin diseases

such as allergic contact dermatitis or lupus erythematosus. LC and IDEC

both express the high-affinity receptor for IgE (FcRI) in lesional skin but

not in normal skin, suggesting a complex regulatory mechanism related

to atopic status. While LC are present in normal skin, IDEC are detected

mainly in inflamed skin. LC and IDEC play a central role in the uptake and

presentation of antigens or allergens to Th1/Th2 cells and most probably

also to regulatory T-cells. Interestingly, FcRI expression is detected on LC

from normal skin during active flares of other atopic diseases such as

allergic asthma or rhinitis, while FcRI+ IDEC are confined to lesional skin.

The role of LC in the initiation of the inflammatory reaction in AD is still

unclear since they are active in priming nave T-cells into T-cells of Th2

type but produce only few amounts of pro-inflammatory cytokines. This

is in contrast to IDEC, which lead to a switch to Th1 response and secrete

high amounts of pro-inflammatory signals that contribute to the

amplification of allergic immune response. The model of atopy patch test

has shown that high numbers of IDEC invade the epidermis 72 hours

after allergen challenge while alterations of the phenotype of LC and

IDEC occur, including the upregulation of FcRI.

pDC play a major role in antiviral defence mechanisms by secreting type

1 interferons (IFN), i.e. IFN- and -. The absence of pDC in the skin ofAD patients might contribute to their susceptibility towards viral skin

infections such as herpes simplex-induced eczema herpeticum. In

contrast to LC and IDEC, pDC seem to constitutively express FceRI (even

in non-atopics)21 but is further upregulated in AD patients. Activation of

this receptor leads to an altered surface expression of major

The former is able to promptly react

to almost all kinds of microbial

colonisation and attacks, while it is

also involved in the initiation of the

more specific but slower mechanisms

of the adaptive immune response.


15E U R O P E A N D E R M A T O L O G Y R E V I E W 2 0 0 7

Atopic Dermatitis Clinical and Pathophysiological Aspects

histocompatibility class (MHC) molecules, an enhanced apoptosis of pDC

and a decrease in the secretion of type I interferons.

Atopic Dermatitis An Autoimmune Disease?

The majority of sera from patients with severe AD contain IgE antibodies

directed against human proteins. Some of these IgE-reactive

autoantigens have been identified by cloning from human cDNA

expression libraries obtained from epithelial cells. A particular

representative is the structure designated Hom s 1, which is a 55kDa

cytoplasmic protein in skin keratinocytes. Interestingly, most of these

autoantigens are intracellular proteins, suggesting that release of these

autoallergens from damaged tissues (by scratching) could trigger IgE- or

T-cell-mediated responses. Thus, while IgE immune responses are

initiated by environmental allergens, allergic inflammation can be

maintained by human endogenous antigens in patients with severe AD.22

FcRI-expressing DC could be instrumental in these mechanisms.

Non-atopic and Atopic Dermatitis in the Context of the

Natural History of Atopic Dermatitis

As mentioned above, the new definition of AD requires the presence

of IgE-mediated sensitisation. However, this would mean that non-

atopic dermatitis and AD represent two different diseases. Since dry

skin is an important clinical sign of both conditions and is considered

as a cardinal sign in atopic individuals as well, there is a great need for

new concepts that council these diverging ideas. Based on the most

recent genetic and immunological findings, a new picture emerges in

which the natural history of AD seems to be divided in three phases:

(i) an initial phase representing non-atopic dermatitis occurring in early

infancy when sensitisation has not yet taken place. This is then

followed in 6080% of cases by (ii) a sensitisation to food and/or

environmental allergens with the development of the true atopic

dermatitis (according to the new definition). In this form, it is

speculated that FcRI+ DC play a major role in control of the

inflammation. Consequently, these AD patients will have benefit from

prevention measurements. (iii) Finally, most probably due to

scratching, tissue damage and molecular mimicry, IgE sensitisation to

self proteins is observed in about 25% of AD patients. Whether these

specific IgE have a pathophysiological role or are only to be considered

as an epiphenomenon remains to be clarified. According to this

concept, sensitisation may be influenced by the intensity of skin

inflammation, which would be in line with the concept of atopic

march. Furthermore, attempts to effectively control skin inflammation

as early as possible would putatively help to reduce the degree of

subsequent sensitisation.

Future Perspectives

We are currently experiencing a new and fascinating phase in the

modern research of AD. Combining data from epidemiology, genetics,

skin physiology and immunology and allergy provides new areas of

research that will certainly provide us with new perspectives and new

concepts in the pathophysiology and management of this disease. The

role of innate immunity, which has been underestimated over the years,

is now the subject of numerous projects and functional genetics will help

us to better understand the consequences of so many genetic variants in

candidate genes. This will hopefully lead to the development of new

biologics but also new antagonist molecules based on small molecular-

weight compounds, steroid analogues and many others that are or will

be in the pipeline in the next few years. Finally, beside these new

pharmacological approaches, one of the most important aspects remains

the strategy to intervene very early in the course of these young children

by controlling skin inflammation at the earliest timepoint. This may help

us to better control the emergence of sensitisation and to provide a rapid

and hopefully definitive cure for the disease. Physicians would be able to

provide a convincing disease-modifying strategy for AD patients.

1. Leung DY, Bieber T, Atopic dermatitis, Lancet,2003;361(9352):15160.

2. Akdis CA, Akdis M, Bieber T, et al., Diagnosis and treatment ofatopic dermatitis in children and adults: European Academy ofAllergology and Clinical Immunology/American Academy ofAllergy, Asthma and Immunology/PRACTALL Consensus Report,Allergy, 2006;61(8):96987.

3. Spergel JM, Paller AS, Atopic dermatitis and the atopic march, JAllergy Clin Immunol, 2003;112(6 Suppl):S11827.

4. Johansson SG, Bieber T, Dahl R, et al., Revised nomenclaturefor allergy for global use: report of the Nomenclature ReviewCommittee of the World Allergy Organization, October 2003, JAllergy Clin Immunol, 2004;113(5):8326.

5. Wollenberg A, Zoch C, Wetzel S, et al., Predisposing factorsand clinical features of eczema herpeticum: a retrospectiveanalysis of 100 cases, J Am Acad Dermatol,2003;49(2):198205.

6. Peng WM, Jenneck C, Bussmann C, et al., Risk Factors ofAtopic Dermatitis Patients for Eczema Herpeticum, J InvestDermatol, 2006.

7. Mihm MC Jr., Soter NA, Dvorak HF, Austen KF, The structure ofnormal skin and the morphology of atopic eczema, J InvestDermatol, 1976;67(3):30512.

8. Cookson W, The immunogenetics of asthma and eczema: anew focus on the epithelium, Nat Rev Immunol,2004;4(12):97888.

9. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al., Commonloss-of-function variants of the epidermal barrier proteinfilaggrin are a major predisposing factor for atopic dermatitis,Nat Genet, 2006;38(4):4416.

10. Weidinger S, Rodriguez E, Stahl C, et al., Filaggrin MutationsStrongly Predispose to Early-Onset and Extrinsic AtopicDermatitis, J Invest Dermatol, 2006.

11. Bowcock AM, Cookson WO, The genetics of psoriasis, psoriaticarthritis and atopic dermatitis, Hum Mol Genet, 2004;13 SpecNo 1:R4355.

12. Schroder JM, Harder J, Antimicrobial skin peptides and proteins,Cell Mol Life Sci, 2006;63(4):46986.

13. Ong PY, Ohtake T, Brandt C, et al., Endogenous antimicrobialpeptides and skin infections in atopic dermatitis, N Engl J Med,2002;347(15):115160.

14. Howell MD, Jones JF, Kisich KO, et al., Selective killing ofvaccinia virus by LL-37: implications for eczema vaccinatum, JImmunol, 2004;172(3):17637.

15. Howell MD, Gallo RL, Boguniewicz M, et al., Cytokine milieu ofatopic dermatitis skin subverts the innate immune response to

vaccinia virus, Immunity, 2006;24(3):3418.16. Novak N, Bieber T, Allergic and nonallergic forms of atopic

diseases, J Allergy Clin Immunol, 2003;112(2):25262.17. Ou LS, Goleva E, Hall C, Leung DY, T regulatory cells in atopic

dermatitis and subversion of their activity by superantigens, JAllergy Clin Immunol, 2004;113(4):75663.

18. Cardona ID, Goleva E, Ou LS, Leung DY, Staphylococcalenterotoxin B inhibits regulatory T cells by inducingglucocorticoid-induced TNF receptor-related protein ligand onmonocytes, J Allergy Clin Immunol, 2006;117(3):68895.

19. Homey B, Steinhoff M, Ruzicka T, Leung DY, Cytokines andchemokines orchestrate atopic skin inflammation, J Allergy ClinImmunol, 2006;118(1):17889.

20. Novak N, Bieber T, The role of dendritic cell subtypes in thepathophysiology of atopic dermatitis, J Am Acad Dermatol,2005;53(2 Suppl 2):S1716.

21. Novak N, Allam JP, Hagemann, T et al., Characterization ofFcepsilonRI-bearing CD123 blood dendritic cell antigen-2plasmacytoid dendritic cells in atopic dermatitis, J Allergy ClinImmunol, 2004;114(2):36470.

22. Mittermann I, Aichberger KJ, Bunder R, et al., Autoimmunityand atopic dermatitis, Curr Opin Allergy Clin Immunol,2004;4(5):36771.

Much interest has been focused

recently on the role of chemokines in

the recruitment of inflammatory cells in

the skin.


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Atopic Dermatitis