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Atopic Dermatitis

Atopic Dermatitis Clinical and Pathophysiological Aspects

a report by

Thomas Bieber
Professor of Dermatology and Allergy, University of Bonn

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

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

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

In adults, localised inflammation with lichenification of the flexural areas

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

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

Characteristic features of AD include pruritus and chronic or chronically

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

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

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

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

especially in winter months.

atopic disorders such as allergic rhino-conjunctivitis or allergic bronchial

asthma. These diseases may appear simultaneously or develop in

The most important complications of AD are due to secondary

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

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

childhood, while pollen allergy and allergic asthma predominate in

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

adolescence. This characteristic, age-dependent sequence has been

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

postulated as the atopic march.3 The cutaneous manifestations of

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

atopy often represent the beginning of this atopic carrier while

course of this complication may be severe with high fever and

asthmatic diseases usually mark its full expression. Therapeutic strategies

widespread eruptions.

should be directed towards the delay or avoidance of this development

by early intervention against skin inflammation, which may prevent

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

subsequent sensitisation.

contact dermatitis and has no fundamental impact on the diagnosis of

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

Definition, Clinical Symptoms and Complications

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

Since the recent consensus nomenclature by the World Allergy

minimal inflammation.7 This residual inflammation is considered the

Organization (WAO),

background for further flares.

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

Pathophysiology

should be reserved for an eczematous condition with the typical clinical

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

Genetics

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

AD is a paradigmatic genetically complex disease involving gene-gene

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

and gene-environment interactions and much progress in understanding

However it should be noticed that, based on recent epidemiological

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

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

studies have identified several chromosomal regions linked to the

but should be considered as a transient phase during which sensitisation

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

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

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

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

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

several months of course, once sensitisation has been definitely excluded

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

or confirmed.

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

Thomas Bieber is Chair and Director of the Department of Dermatology and Allergy at the
Rheinische 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 diseases
and 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 of
sciences Leopoldina, and is author or co-author of more than 350 papers and book chapters. He
is 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), the
Pharmacia international research award and the Gold Medal of the Foundation for Allergy
Research 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 in
1976 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.

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

Email: thomas.bieber@ukb.uni-bonn.de

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

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

TOUCH BRIEFINGS 2007

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

AD is characterised by multiple alterations of the adaptive immune

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

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

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

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

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

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

form.

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

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

epidermal structures such as those localised in the epidermal differential

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

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

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

These genetic findings provide important support for the well-known

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

dryness and impairment of the epidermal barrier observed in AD patients

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

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

not in chronic lesions.

10

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

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

sensitisation to aeroallergens during chronic inflammation. However, two

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

paradoxical situations remain to be clarified:

surface markers but all expressing the nuclear factor Foxp3, which is
mutated in immune dysregulation, polyendocrinopathy, enteropathy,

some chromosomal regions found for AD correspond to gene loci

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

found in patients with psoriasis, although AD and psoriasis are

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

clinically almost mutually excluding; and

inflammation.17,18

the chromosomal regions do not correspond to those previously

reported for other atopic diseases such as allergic asthma.11

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,

Immunological Mechanisms

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

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

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

pathophysiological puzzle of AD. The former are able to promptly

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

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

amplification of allergic reactions to bacteria or allergens. Their exact

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

value in pathogenesis is, however, still not resolved.

mechanisms of the adaptive immune response. Epithelial cells of the

skin and cells residing at the interface between our environment and

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

our organism are equipped with highly conserved recognition

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

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

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

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

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

microbial structures due to highly conserved microbial surface

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

molecules the so-called pathogen-associated molecular pattern

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

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

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

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

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

more specific but slower mechanisms

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

of the adaptive immune response.

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

epithelial cells leads to cell activation, ultimately resulting in the

after allergen challenge while alterations of the phenotype of LC and

production of newly described molecules with antimicrobial activities:

IDEC occur, including the upregulation of FcRI.

the antimicrobial peptides (AMPs). In human skin the major AMPs are
cathelicidin (LL37) and human beta defensin (HBD) 1, 2 and 3. It has

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

been shown that the strong colonisation of AD with Staphylococcus

1 interferons (IFN), i.e. IFN- and -. The absence of pDC in the skin of

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

AD patients might contribute to their susceptibility towards viral skin

independent way by the secretion of superantigens/enterotoxins) and

infections such as herpes simplex-induced eczema herpeticum. In

the higher risk of developing widespread viral infections (eczema

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

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

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

particular inflammatory micro-milieu.13-15

this receptor leads to an altered surface expression of major

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Atopic Dermatitis Clinical and Pathophysiological Aspects

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

recent genetic and immunological findings, a new picture emerges in

and a decrease in the secretion of type I interferons.

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

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

Atopic Dermatitis An Autoimmune Disease?

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

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

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

directed against human proteins. Some of these IgE-reactive

environmental allergens with the development of the true atopic

autoantigens have been identified by cloning from human cDNA

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

expression libraries obtained from epithelial cells. A particular

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

Much interest has been focused

as an epiphenomenon remains to be clarified. According to this

recently on the role of chemokines in

concept, sensitisation may be influenced by the intensity of skin

the recruitment of inflammatory cells in

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

march. Furthermore, attempts to effectively control skin inflammation

the skin.

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

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

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

cytoplasmic protein in skin keratinocytes. Interestingly, most of these

skin physiology and immunology and allergy provides new areas of

autoantigens are intracellular proteins, suggesting that release of these

research that will certainly provide us with new perspectives and new

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

concepts in the pathophysiology and management of this disease. The

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

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

initiated by environmental allergens, allergic inflammation can be

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

maintained by human endogenous antigens in patients with severe AD.

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

FcRI-expressing DC could be instrumental in these mechanisms.

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

22

biologics but also new antagonist molecules based on small molecularNon-atopic and Atopic Dermatitis in the Context of the

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

Natural History of Atopic Dermatitis

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

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

pharmacological approaches, one of the most important aspects remains

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

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

atopic dermatitis and AD represent two different diseases. Since dry

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

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

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

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

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

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

provide a convincing disease-modifying strategy for AD patients.

1.
2.

3.
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