SECTION C: OVERVIEW OF INFLAMMATORY SKIN DISEASES

THE LATEST FINDINGS IN CELLULAR BIOLOGY

Atopic dermatitis
William Abramovits, MD
Dallas, Texas
Atopic dermatitis (AD) is commonly associated with immunoglobulin E (IgE) antibodyerelated
mechanisms, which are the focus of this article. The vast majority of patients with AD exhibit
hyperproduction of IgE, particularly during disease onset or are. IgE-dependent late-phase reactions
may inuence the chronic inammatory response in AD. Clearly, genetics plays a major role in determining
who develops AD. However, the recent increase in AD prevalence suggests that a complex interaction
between environmental factors and susceptibility genes results in clinical expression of the disorder. These
immunologic triggers differ among individuals and include various foods, airborne allergens, irritants and
contactants, hormones, stress, climate, and microorganisms. Although much about AD remains to be
elucidated, our current understanding of its pathophysiology has provided clinicians with the ability to
construct more rational therapeutic interventions, including multiple-agent regimens that provide both
immediate relief and effective long-term management. Future advances will come from identication of the
genes causing this disease and further elucidation of the immunoregulatory mechanisms involved in the
pathogenesis of AD. ( J Am Acad Dermatol 2005;53:S86-93.)
A
topic dermatitis (AD) is a common inam-
matory skin disorder that is both uncomfort-
able and distressing to patients as a result of
its associated intense pruritus and unsightly lesions.
When severe, AD can be extremely disabling, caus-
ing major psychological problems, and, in the case of
a young child, be overwhelming to the entire family.
1
AD commonly associated with immunoglobulin E
(IgE) antibodyerelated mechanisms is the focus of
this review, which addresses the genetics and path-
ophysiology of this disorder.
AD is a genotypic diathesis in which minor skin
stimulation is perceived as an itch that, when
scratched or rubbed, elicits a heightened immune
response. The heightened immune response leads
to the development of eczema, which is the clinical
syndrome of eczematous dermatitisa group of
inflammatory skin conditions characterized by
pruritus; pale, erythematous, and violaceous hues;
vesiculation; erosion; scaling; exudation; crusting;
lichenification; and excoriations.
2
Treatments for
AD include topical agents, phototherapy, systemic
medications, and general or preventive measures,
which are described in greater detail elsewhere in
this supplement.
EPIDEMIOLOGY
The prevalence of AD is on the rise; in the United
States, the lifetime prevalence in children born after
1980 is 15% to 20%,
3,4
a 3- to 4-fold increase
compared with the 5% reported in school-aged
Abbreviations used:
AD: atopic dermatitis
APC: antigen-presenting cell
ECP: eosinophil cationic protein
FceRI: high-affinity receptor for IgE
GM-CSF: granulocyte-macrophage colony-
stimulating factor
IDEC: inflammatory dendritic epidermal
cell
IFN-a -b, -g: interferon alfa, beta, gamma
IgE: immunoglobulin E
IL-1 -2, etc: interleukin 1, 2, etc
LC: Langerhans cell
mRNA: messenger RNA
PDC: plasmacytoid dendritic cell
SC: stratum corneum
T
H
0, T
H
1, T
H
2: T helper cell types 0, 1, 2
TNF: tumor necrosis factor
From the Texas Dermatology Associates, PA; Baylor University
Medical Center; and University of Texas Southwestern School of
Medicine.
This article is part of a supplement supported by Connetics Corp,
Palo Alto, California.
Disclosure: Dr Abramovits has received research support and/or is
a consultant and lecturer for Fujisawa Healthcare, Novartis
Pharmaceuticals Corp, Ferndale Laboratories, Abbott Labora-
tories, Connetics Corp, Amgen, Biogen Idec, Centocor, Genen-
tech, and Galderma.
Reprint requests: William Abramovits, MD, Texas Dermatology
Research Associates, 5310 Harvest Hill Rd, Suite 260, Dallas,
TX 75230. E-mail: waresearch@texasderm.com.
0190-9622/$30.00
2005 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2005.04.034
S86
children in the 1950s.
3
AD occurs slightly more
frequently in females than males by a ratio of about
1.5:1.
5
The majority of cases, at least 60%, arise within
the first year of life
6
; the remainder appear in two
peaks: age 2 to 12 years and from puberty into
adulthood.
AD occurs more frequently in temperate and
colder, dryer regions rather than in humid, tropical
areas. Factors that may contribute to increased inci-
dence include urban settings with increased expo-
sure to harmful environmental stimuli from industry,
smaller family size, infection with Staphylococcus
aureus, and late age of the mother at the time of
birth.
4,7-10
SIGNS, SYMPTOMS, AND COURSE
Many of the skin features associated with AD, in-
cluding excoriation, lichenication, and susceptibil-
ity tosecondary infections, are the result of scratching
or rubbing to relieve intense itching. This activity
then triggers ares, produces papular eruptions, and
helps spread the disease to other skin regions, result-
ing in chronically involved areas. Table I lists major
and minor diagnostic criteria for AD.
Lesion distribution
Lesions are distributed in a characteristic age-
related pattern. In infants, the face, particularly the
cheeks, are primarily affected, with general sparing
of the nose and paranasal area.
11
Lesions are highly
pruritic, red, scaly, and crusted, sometimes present-
ing as weeping patches,
6
that result in substantial
sleep disruption.
12
In older children, lesions erupt
primarily in flexural areas as exudating papules in
the acute stage and thickened plaques with lichen-
ification in the chronic stage.
6,11
Adults with AD also
experience lichenification in flexural regions as well
as involvement of the hands, wrists, ankles, feet, and
face, particularly the forehead and around the eyes.
Xerosis is a common characteristic of all stages,
especially in the winter months, and results from
enhanced transepidermal water loss.
Association with other atopic diseases
AD commonly occurs in concert with other atopic
diseases, most frequently as part of the atopic triad
of childhood diseasesallergic dermatitis, asthma,
and allergic rhinitis (or rhinoconjunctivitis).
13
Several
studies have reported that AD in infants or young
children frequently improves with time, but is asso-
ciated with increased risk of asthma and allergic
rhinitis.
14,15
In fact, AD in the first 3 months of life
is predictive of allergic airway disease at 5 years
of age.
16
Patients with severe dermatitis and mild
asthma have an elevated risk of developing severe
or pronounced late asthmatic response when ex-
posed to allergens.
17
This supports the concept
of overlap in the pathophysiology of these atopic
diseases.
In a retrospective analysis of private insurance
and Medicaid claims data from 1997 and 1998,
18
among the most likely related comorbidities of AD,
the most frequently occurring were allergic rhinitis
(seen in 7% and 6% of patients with AD/eczema in
the private insurer and Medicaid populations, re-
spectively), asthma (5%, 14%), nonsuppurative otitis
media and eustachian tube disorders (5%, 5%), and
disorders of the conjunctiva (4%, 7%). Additionally,
the prevalence of patients with AD/eczema who had
claims for such comorbidities was higher than that in
the control populations.
GENETICS
The increased incidence of allergic dermatitis in
children is associated with the prevalence of atopic
disease in their parents; approximately 27% of
children whose parents are not atopic develop
AD versus 38% and 50%, respectively, of children
with one or two affected parents.
19
A parental history
of atopic respiratory disease increases the risk
Table I. Clinical features of AD*
Essential features
n Pruritus
n Facial and extensor eczema in infants and younger
children
n Flexural eczema in older children and adults
n Chronic or relapsing dermatitis
Frequently associated features
n Personal or family history of atopic disease
n Xerosis
n Cutaneous infections
n Nonspecific dermatitis of hands or feet
n Raised serum IgE concentrations
n Positive immediate-type allergy skin tests
n Early age at onset
Other features
n Ichthyosis, palmar hyperlinearity, keratosis pilaris
n Pityriasis alba
n Nipple eczema
n White dermatographism and delayed blanch response
n Anterior subcapsular cataracts, keratoconus
n Dennie-Morgan infraorbital folds, orbital darkening
n Facial erythema or pallor
Adapted from Leung DYM, Bieber T. Lancet. 2003;361:151-60, and
reprinted with permission from Elsevier.
*Other skin disorders that can mimic AD should be excluded.
J AM ACAD DERMATOL
VOLUME 53, NUMBER 1
Abramovits S87
significantly more for IgE-associated than non-IgE-
associated AD. This suggests that heredity is proba-
bly the most important causal component in the
development of AD.
Studies of twins support this; in two early genetic-
epidemiologic studies in population-based twin
samples, the pairwise concordance rate was 0.72 to
0.86 for monozygotic twins and 0.21 to 0.23 for
dizygotic twins.
20,21
However, inheritance of AD does not t a simple
Mendelian pattern,
22
probably because of the num-
ber of contributory genes involved, which can vary
among affected persons. Even within particular AD
subtypes, the genotype exhibits some variation be-
tween patients. Various chromosomal regions have
been associated with AD in different gene linkage
studies (Table II
23-29
). Many of these regions contain
candidate genes coding for proteins that play im-
portant roles in the pathogenesis of AD.
PATHOGENESIS
The pathogenesis of AD is not completely under-
stood, although several cell types (eg, T lympho-
cytes, Langerhans cells, eosinophils, keratinocytes)
and factors (eg, cytokines and immunoglobulins,
particularly IgE) have been implicated. This review
focuses primarily on IgE-associated allergic AD.
Lymphocytes
According to a concept known as the hygiene
hypothesis, exposure to infection during early
childhood protects a child against atopic disease by
inducing or stimulating maturation of type 1 T-helper
(T
H
1) cells, that is, CD4
1
T-helper lymphocytes (T
H
0
cells) differentiate into T
H
1 cells rather than T
H
2
cells.
4
In individuals genetically predisposed to AD,
this exposure may be insufficient to counter a gen-
eral susceptibility to imbalance of T
H
2 versus T
H
1
immune responses. However, some researchers
believe that reduced numbers of infections during
early childhood resulting from decreased exposure
to infections, greater use of antibiotics, and other
aspects of a modern, more urban lifestyle, may lead
to enhanced T
H
2 allergic responses, thus accounting
for the recent increase in prevalence of AD.
11
Several factors are involved in the differentiation
of precursor T
H
0 lymphocytes into either T
H
2 or T
H
1
cells (Fig 1), including the cytokine environment at
the time of interaction between T
H
0 cells and anti-
gen-presenting cells (APCs), as well as costimulatory
signals. T
H
1 lymphocytes produce interleukin 2
(IL-2), interferon gamma (IFN-g), and tumor necrosis
factor (TNF); activate macrophages; and promote
delayed hypersensitivity reactions.
30,31
Conversely,
T
H
2 lymphocytes produce IL-4, IL-5, IL-6, IL-10, and
IL-13, which signal B lymphocytes to produce IgE,
activate mast cells and eosinophils, and promote
type 1 hypersensitivity reactions.
30-33
Cytokines pro-
duced by T
H
2 lymphocytes also stimulate the prolif-
eration and differentiation of B lymphocytes and
suppress T
H
1 cell activities.
Although the T
H
1/T
H
2 paradigm model, with T
H
2
responses predominating in AD, has made a major
contribution to our understanding of immunologic
processes,
34
the actual mechanisms involved may be
more complex. Patients with AD exhibit a biphasic
helper T-cell pattern in which T
H
2 immune re-
sponses appear early in the acute stage, but switch
to a more T
H
1-like profile as chronic lesions
emerge.
35
Compared with normal skin, both acute
and chronic AD lesions contain significantly more
cells expressing messenger RNA (mRNA) for IL-4,
IL-5, and IL-13, but the expression of IFN-g is similar
to that seen in normal skin.
36,37
However, compared
with acute lesions, chronic lesions are associated
with significantly fewer IL-4 and IL-13 mRNA-
expressing cells, significantly more IL-5 and IL-12
Table II. Summary of major linkage studies for AD
Chromosomal site Candidate gene Study, year
3q21 Costimulatory molecules involved
in T-lymphocyte activation
(CD80 and CD86)
Lee et al,
23
2000
5q31-33 Interleukin 4 Kawashima et al,
24
1998
Forrest et al,
25
1998
11q13 b subunit of the high-affinity
receptor for IgE (FceRIb)
Folster-Holst et al,
26
1998
13q12-14 None identified Beyer et al,
27
2000
14q11.2 Mast cell chymase Mao et al,
28
1996
1q21, 17q25, 20p Dermal inflammatory genes? Cookson et al,
29
2001
Reprinted with permission from MacLean JA, Eidelman FJ. Arch Dermatol 2001;137:1474-6.
J AM ACAD DERMATOL
JULY 2005
S88 Abramovits
mRNA-expressing cells, and significantly more
antieeosinophil cationic protein (ECP) antibody
eosinophils. These data suggest that maintenance
of chronic inflammation in AD lesions is associated
with predominance of IL-5 and IL-12 expression and
eosinophil infiltration.
Cytokine IL-12 may be pivotal in the switch from
T
H
2 predominance during the acute phase to greater
T
H
1 involvement during the chronic or maintenance
phase (Fig 1).
38
In this view, T
H
2-type cytokines
predominate during the acute phasein part be-
cause of a relative increase in IL-4 levels and no
change or decreases in IFN-g levelsand stimulate
eosinophils, which produce IL-12. In turn, IL-12
activates T
H
1 and T
H
0 cells and promotes increased
production of IFN-g, which inhibits T
H
2 responses
and helps to maintain the AD lesion over an ex-
tended period.
38
In AD, the localization of allergic disease to
the skin is likely to be regulated by the expression
of a skin-homing receptor on memory effector
T lymphocytes.
35
This receptor, or cell-adhesion
molecule, which has been termed cutaneous
lymphocyte-associated antigen, interacts with vas-
cular endothelial cell surface antigens to direct circu-
lating T lymphocytes to the reactive skin site. An
increased number of activated cutaneous lympho-
cyte-associated antigen T lymphocytes have been
reported in the blood of patients with AD.
Immunoglobulins
The vast majority of patients with AD exhibit
hyperproduction of IgE, particularly during disease
onset or are, possibly the result of enhanced pro-
duction of T
H
2-type cytokines during the acute
phase of the disease.
Acute lesions are associated with increases in IL-4,
which induces the T
H
0-to-T
H
2 differentiation pro-
cess, and results in declining or unchanged levels of
IFN-g. IL-4 also has been shown to inhibit IFN-g
synthesis and stimulate B lymphocytes to synthesize
IgE.
39
This latter effect depends on cognate inter-
action between the T-cell receptoreCD3 complex
on T lymphocytes and major histocompatibility com-
plex antigen on B lymphocytes. The IL-4erelated
inhibition of IFN-g synthesis is likely to be important
for IgE synthesis as well, since IFN-g has been shown
to inhibit IL-4 regulation of IgE synthesis. This
inhibition extends elsewhere; peripheral blood
mononuclear cells have a decreased capacity to
produce IFN-g.
11
After crosslinking with an allergen, IgE plays a key
role in type I hypersensitivity reactions by inducing
mast cells and basophils to release various bioactive
mediators, including histamine.
33
Allergen-specific
IgE activates mast cells and basophils by interacting
with a high-affinity receptor for IgE (FceRI) located
on these cells. It has been suggested that the pruri-
tus and erythema that are present after exposure to
Fig 1. Differentiation of T-helper (Th) lymphocytes. Depending on which cytokines are
present at the time of antigen presentation, the Th0 lymphocyte is driven toward a Th1 or Th2
type. Th1 cells produce interleukin (IL)-2 and interferon gamma (IFN-g) and are effector cells of
cell-mediated immunity (CMI) and delayed-type hypersensitivity (DTH). Th2 cells produce IL-4,
IL-5, and IL-13 and induce IgE production by Bcells and activation of mast cells and eosinophils.
(Adapted and reprinted with permission from Friedmann PS. Hosp Med 2002;63:653-6.)
J AM ACAD DERMATOL
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Abramovits S89
allergens may be related to substances released
by mast cells bearing allergen-specific IgE.
40
IgE-
dependent late-phase reactions may influence the
chronic inflammatory response in AD.
40
IgE autoreactivity also may be involved in the
pathogenesis of AD.
41
Most patients with AD have
circulating IgE antibodies that are directed against
endogenous proteins; this situationmayhelptomain-
tain allergic inflammation after exposure to an aller-
gen trigger.
Langerhans cells and other APCs
Skin lesions from patients with AD contain in-
creased levels of CD1a
1
epidermal Langerhans cells
(LCs), which belong to the dendritic cell family of
APCs. LCs express the high-affinity IgE receptor
FceRI on their surface and likely play an important
role in allergen presentation to T
H
1 and T
H
2 lym-
phocytes in AD, an event that appears to require not
only the presence of cell-bound IgE but also the
initial internalization of FceRI.
42,43
The resulting
activation of T
H
2 lymphocytes promotes IgE expres-
sion, which in turn may lead to the development of
a positive feedback mechanism that amplifies the
response to any antigen/allergen.
40
AD lesions also contain another population of
CD1a
1
dendritic epidermal cells, called inflamma-
tory dendritic epidermal cells (IDECs), that are not
found in normal skin and are distinct from classic
LCs.
44
Like LCs, IDECs express FceRI on their surface
and likely play an important role in allergen presen-
tation to T
H
2 and T
H
1 lymphocytes in AD. FceRI
expression may be even greater in IDECs than in
classic LCs. However, IDECs differ fromLCs inseveral
ways. IDECs lack intracellular tennis racketeshaped
Birbeck granules, organelles whose function is un-
known but may be to serve as loading compartments
or reservoirs (or both) for antigens before LC matu-
ration.
44-46
In addition, IDECs express the CD206
mannose receptor and possess pits and vesicles on
their surface in close proximity to large endosome-
like structures, all relating to endocytotic uptake of
bacterial components.
47
IDECs also appear to ex-
press large amounts of the costimulatory molecules
CD80 and CD86, which are necessary for T-cell
activation and proliferation, and release high levels
of proinflammatory cytokines (eg, IL-12, IL-18, and
IFN-g), which serve to amplify AD-associated inflam-
matory reactions; they may be responsible for the
switch from a T
H
2 response to a T
H
1 response that is
observed in the chronic phase of AD.
45,48
In contrast,
LCs may be responsible for the release of chemotactic
signaling molecules that serve to stimulate the mi-
gratory capacity of IDECs and naive T cells.
48
Compared with levels in normal and nonlesioned
skin, expression of FceRI is highly up-regulated on
CD1a
1
cells from patients with AD, and expression
is significantly correlated with serum IgE levels.
44
Increased numbers of CD1a
1
APCs and up-regulated
expression of FceRI should increase the capacity
for antigen/allergen capture and presentation of
antigen/allergen to CD4
1
T lymphocytes.
40
IgE-bearing CD1a
1
APCs that have captured
antigen/allergen may also activate memory T
H
2
lymphocytes in atopic skin and may also expand
the pool of systemic T
H
2 lymphocytes by migrating
to the lymph nodes and stimulating T
H
0 cells.
35
LCs
in patients with AD also may participate in the
recruitment of CD4
1
T lymphocytes to the lesion
site by stimulating enhanced production of IL-16.
49,50
Interestingly, a third type of APC, called plasma-
cytoid dendritic cells (PDCs), has also been identi-
ed, and these cells have been shown to produce
large amounts of IFN-a and IFN-b.
51
Although high
numbers of IDECs are found in lesions of AD
patients, few PDCs are evident in these lesions,
possibly accounting for why AD patients demon-
strate a predisposition to viral infections (eg, eczema
herpeticum). High levels of PDCs and low levels of
IDECs are also found in skin samples from persons
with systemic lupus erythematosus.
51
Eosinophils and monocytes/macrophages
Skin inltration by eosinophils and macrophages,
and the consequent production of IL-12, appears to
be important in the chronic inammatory response
associated with AD lesions.
52
Eosinophilia is also
common in patients with AD, as are elevated levels
of ECP in the matrix and core of secondary eosino-
phil granules. ECP is a toxic protein that may play a
role in propagation of the allergic inflammatory
process and modulation of the immune response;
increased levels have been associated with disease
activity. Eosinophils from patients with AD appear
to be primed or in a state of preactivation and
demonstrate increased migratory responsiveness to
various chemotaxins.
30,53
Exposure to IL-5, IL-3, and
granulocyte-macrophage colony-stimulating factor
(GM-CSF) from T
H
2 lymphocytes and mast cells,
and exposure to TNF-a from Langerhans cells, are
probably responsible for the heightened attraction of
eosinophils to the skin reaction site.
30
GM-CSF is a
very potent eosinophil chemotactic factor.
30
Patients with AD show delayed eosinophil apo-
ptosis; this dysregulated apoptosis of eosinophils
and other cells may contribute to the emergence and
persistence of AD lesions.
54,55
The cytokine IL-5 is
probably responsible for this enhanced viability.
56
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JULY 2005
S90 Abramovits
Monocytes, the predominant cell type in chronic
AD lesions, also exhibit reduced apoptosis resulting
in increased survival
57
and probably contribute to
the chronic inflammatory responses of skin lesions.
This apoptotic effect appears to be related to in-
creased production of GM-CSF by monocytes in AD.
IL-10 also may play an important role in the regula-
tion of monocyte survival and macrophage devel-
opment by inhibiting GM-CSFerelated antiapoptotic
effects early in lesion development.
58
Keratinocytes
Keratinocytes are integral to the structure of the
stratum corneum (SC) as a result of their differenti-
ation into corneocytes and subsequent production of
ceramides.
59-61
They also appear to act as primary
inducers and targets of immunological responses
occurring in the skin.
59
In AD, the activity of kera-
tinocytes in both areas is altered.
62
For example, the SCthe permeability barrier
between the body and the external environment
is impaired, as manifested by increased transepider-
mal water loss anddiminishedwater-binding capacity,
thus causing the associated dryness and intense
pruritus of AD.
63
This defect stems from reduced
levels of ceramides caused by an overexpression of
the enzyme that hydrolyzes the ceramide precursor
sphingomyelin.
62,64
The products of this hydrolysis
are free fatty acid and sphingosyl phosphoryl cho-
line, an up-regulator of plasminogen activator and an
inducer of keratinocyte proliferation. In addition, the
decrease in ceramide generation may result in en-
hanced levels of protein kinase C,
65
which in turn
leads to excessive up-regulation of activator protein-
1 and, ultimately, hyperproduction of GM-CSF by
keratinocytes.
66
High levels of GM-CSF are a central
feature of AD as this cytokine contributes to the
initiation and maintenance of the chronic inflamma-
tory process through the induction of LC generation
and maturation and the enhancement of the antigen-
presenting capacity of LCs and dendritic cells and
macrophage survival.
66,67
GM-CSF also induces hy-
perproliferation and apoptosis of keratinocytes.
67
In addition, scratching precipitated by pruritus
causes trauma and further insult to the already
compromised SC and induces keratinocytes to
release a variety of proinammatory cytokines.
41
These include IL-1, TNF-a, IL-4, and certain chemo-
kines (CC chemokines, so named for the spacing of
conserved cysteines) that are critical for the induc-
tion of adhesion molecules, as well as the directing of
lymphocytes, macrophages, and eosinophils to cu-
taneous sites of inflammation.
68
Keratinocytes also
produce IL-1a and IL-1 receptor antagonist,
69
potent
mediators of inflammation, as well as thymic stromal
lymphopoietin, an IL-7-like cytokine that may be key
in T
H
2 polarization.
62
The defective SC barrier also allows entry of
S aureus and other microbes. This, together with the
increased binding affinity of AD skin for S aureus
(probably the result of underlying inflammation),
leads to the increased colonization of S aureus
frequently reported in patients with AD.
70,71
In-
vasion by S aureus can have serious consequences
for keratinocytes as the microbe releases several
immunomodulatory proteins, including cytolytic a
toxin (promotes fatal keratinocyte damage) and
superantigenic toxin (induces keratinocytes to ex-
press proinflammatory and cytotoxic cytokines, no-
tably TNF-a and b-hemolysin, which interferes with
ceramide metabolism).
62
These toxins and other pro-
tein products may prevent keratinocytes from pro-
ducing the antimicrobial peptides b-defensins and
cathelicidins at levels sufficient to kill S aureus.
71,72
The inhibitory effects of IL-4 and IL-13 on keratino-
cytes may also contribute to decreased production
of these peptides.
Some evidence exists that keratinocytes also act
as nonprofessional APCs by reactivating memory
T cells and participating in T-cell education as they
express TNF-a, IL-1, GM-CSF, IL-10, chemokines,
and several costimulatory molecules, such as major
histocompatibility complex class II, CD54 (intercel-
lular adhesion molecule 1), CD40, and CD58 (lym-
phocyte function-associated antigen-3).
62
CONCLUSION
Clearly, genetics plays a major role in determin-
ing who develops AD. However, the recent increase
in the prevalence of AD suggests that a complex in-
teraction between environmental factors and sus-
ceptibility genes results in clinical expression of the
disorder. These immunologic triggers differ among
individuals and include various foods, airborne al-
lergens, irritantsandcontactants, hormones, stress, cli-
mate, and microorganisms.
AD is most commonly associated with IgE-related
mechanisms, and the vast majority of patients with
ADexhibit hyperproduction of IgE. Although ADhas
been characterized as a T
H
2-type disorder within
the T
H
1/T
H
2 paradigm, research has revealed that a
biphasic response model may account more accurately
for the underlying immunologic mechanisms; pa-
tients initially exhibit T
H
2-like immune responses
early in the acute stage and switch to a more T
H
1-like
profile as chronic lesions emerge. Although much
about AD remains to be elucidated, our current un-
derstanding of its pathophysiology has provided
clinicians with the ability to construct more rationale
therapeutic interventions, including multiple-agent
J AM ACAD DERMATOL
VOLUME 53, NUMBER 1
Abramovits S91
regimens that provide both immediate relief and
effective long-term management.
2
Future advances
will come from identification of the genes causing this
disease and further elucidation of the immunoregula-
tory mechanisms involved in the pathogenesis of AD.
REFERENCES
1. Barnetson RS, Rogers M. Childhood atopic eczema. BMJ
2002;324:1376-9.
2. Abramovits W, Goldstein AM, Stevenson LC. Changing para-
digms in dermatology: topical immunomodulators within a
permutational paradigm for the treatment of atopic and
eczematous dermatitis. Clin Dermatol 2003;21:383-91.
3. Lewis-Jones S. Atopic dermatitis in childhood. Hosp Med
2001;62:136-43.
4. Larsen FS, Hanifin JM. Epidemiology of atopic dermatitis.
Immunol Allergy Clin North Am 2002;22:1-24.
5. Kuster W, Petersen M, Christophers E, Goos M, Sterry W.
A family study of atopic dermatitis. Clinical and genetic
characteristics of 188 patients and 2,151 family members.
Arch Dermatol Res 1990;282:98-102.
6. Rudikoff D, Lebwohl M. Atopic dermatitis. Lancet 1998;
351:1715-21.
7. von Mutius E. The environmental predictors of allergic disease.
J Allergy Clin Immunol 2000;105:9-19.
8. Harris JM, Cullinan P, Williams HC, Mills P, Moffat S, White C,
et al. Environmental associations with eczema in early life. Br J
Dermatol 2001;144:795-802.
9. Olesen AB, Ellingsen AR, Larsen FS, Larson PO, Veien NK,
Thestrup-Pedersen K. Atopic dermatitis may be linked to
whether the child is first- or second-born and/or the age of
the mother. Acta Derm Venereol 1996;76:457-60.
10. Jones SM. Triggers of atopic dermatitis. Immunol Allergy Clin
North Am 2002;22:55-72.
11. Leung DYM, Bieber T. Atopic dermatitis. Lancet 2003;361:
151-60.
12. Dahl RE, Bernhisel-Broadbent J, Scanlon-Holdford S, Sampson
HA, Lupo M. Sleep disturbances in children with atopic
dermatitis. Arch Pediatr Adolesc Med 1995;149:856-60.
13. Stone KD. Atopic diseases of childhood. Curr Opin Pediatr
2002;14:634-46.
14. Gustafsson D, Sjoberg O, Foucard T. Development of allergies
and asthma in infants and young children with atopic der-
matitisa prospective follow-up to 7 years of age. Allergy
2000;55:240-5.
15. Linna O, Kokkonen J, Lahtela P, Tammela O. Ten-year prog-
nosis for generalized infantile eczema. Acta Paediatr 1992;
81:1013-6.
16. Bergman RL, Edenharter G, Bergmann KE, Forster J, Bauer CP,
Wahn V, et al. Atopic dermatitis in early infancy predicts allergic
airway disease at 5 years. Clin Exp Allergy 1998;28:965-70.
17. BrinkmanL, Raaijmakers JA, Bruijnzeel-KoomenCA, KoedermanL,
Lammers JW. Bronchial and skin reactivity in asthmatic patients
with and without atopic dermatitis. Eur Respir J 1997;10:1033-40.
18. Ellis CN, Drake LA, Prendergast MM, Abramovits W,
Boguniewicz M, Daniel CR, et al. Cost of atopic dermatitis
and eczema in the United States. J Am Acad Dermatol 2002;
46:361-70.
19. Bohme M, Wickman M, Lennart NS, Svartengren M, Wahgren
C. Family history and risk of atopic dermatitis in children up to
4 years. Clin Exp Allergy 2003;33:1226-31.
20. Larsen FS, Holm NV, Henningsen K. Atopic dermatitis.
A genetic-epidemiologic study in a population-based twin
sample. J Am Acad Dermatol 1986;15:487-94.
21. Schultz LF. Atopic dermatitis: a genetic epidemiologic study
in a population-based twin sample. J Am Acad Dermatol
1993;28:719-23.
22. Beltrani VS. Clinical features of atopic dermatitis. Immunol
Allergy Clin North Am 2002;22:25-42.
23. Lee Y-A, Wahn U, Kehrt R, Tarani L, Businco L, Gustafsson D,
et al. A major susceptibility locus for atopic dermatitis maps to
chromosome 3q21. Nat Genet 2000;26:470-3.
24. Kawashima T, Noguchi E, Arinami T, Yamakawa-Kobayashi K,
Nakagawa H, Otsuka F, et al. Linkage and association of an
interleukin 4 gene polymorphism with atopic dermatitis in
Japanese families. J Med Genet 1998;35:502-4.
25. Forrest S, Dunn K, Elliott K, Fitzpatrick E, Fullerton J, McCarthy
M, et al. Identifying genes predisposing to atopic eczema.
J Allergy Clin Immunol 1999;104:1066-70.
26. Fo lster-Holst R, Moises HW, Yang L, Fritsch W, Weissenbach J,
Christophers E. Linkage between atopy and the IgE high-
affinity receptor gene at 11q13 in atopic dermatitis families.
Hum Genet 1998;102:236-9.
27. Beyer K, Renate N, Friedhoff L, Bjo rkste n B, Huang S-K, Barnes
KC, et al. Association and linkage of atopic dermatitis with
chromosome 13q12-14 and 5q31-33 markers. J Invest Derma-
tol 2000;115:906-8.
28. Mao XQ, Shirakawa T, Yoshikawa T, Kawai M, Sasaki S,
Enomoto T, et al. Association between genetic variants of
mast-cell chymase and eczema. Lancet 1998;348:581-3.
29. Cookson WO, Ubhi B, Lawrence R, Abecasis GR, Walley AJ,
Cox HE, et al. Genetic linkage of childhood atopic dermatitis
to psoriasis susceptibility loci. Nat Genet 2001;27:372-3.
30. Gimenez JCM. Atopic dermatitis. Allergol Immunol Clin
2000;15:279-95.
31. Knoell KA, Greer KE. Atopic dermatitis. Pediatr Rev 1999;20:
46-52.
32. Friedmann PS. The pathogenesis of atopic eczema. Hosp Med
2002;63:653-6.
33. Jelinek DF. Regulation of B lymphocyte differentiation. Ann
Allergy Asthma Immunol 2000;84:375-85.
34. Asadullah K, Sterry W, Trefzer U. Cytokines: interleukin and
interferon therapy in dermatology. Clin Exp Dermatol 2002;
27:578-84.
35. Leung DYM. Atopic dermatitis: new insights and opportunities
for therapeutic intervention. J Allergy Clin Immunol 2000;
105:860-76.
36. Hamid QA, Boguneiwicz M, Leung DYM. Differential in situ
cytokine gene expression in acute versus chronic atopic
dermatitis. J Clin Invest 1994;94:870-6.
37. Hamid QA, Naseer T, Minshall EM, Song YL, Boguneiwicz M,
Leung DYM. In vivo expression of IL-12 and IL-13 in atopic
dermatitis. J Allergy Clin Immunol 1996;98:225-31.
38. Grewe M, Bruijnzeel-Koomen C, Scho pf E, Thepen T,
Langeveld-Wilschut AG, Ruzicka T, et al. A role for Th1 and
Th2 cells in the immunopathogenesis of atopic dermatitis.
Immunol Today 1998;19:359-61.
39. Vercelli D, Jabara HH, Lauener RP, Geha RS. IL-4 inhibits the
synthesis of IFN-g and induces the synthesis of IgE in human
mixed lymphocyte cultures. J Immunol 1990;144:570-3.
40. Galli E, Cicconi R, Rossi P, Casati A, Brunetti E, Mancino G.
Atopic dermatitis: molecular mechanisms, clinical aspects and
new therapeutical approaches. Curr Mol Med 2003;3:127-38.
41. Leung DYM, Soter NA. Cellular and immunologic mechanisms
in atopic dermatitis. J Am Acad Dermatol 2001;44(Suppl):
S1-12.
42. Mudde GC, van Reijsen FC, Boland GJ, De Gast GC, Bruijnzeel
PLB, Bruijnzeel CAFM. Allergen presentation by Langerhans
cells from patients with atopic dermatitis is mediated by IgE.
Immunology 1990;69:335-41.
J AM ACAD DERMATOL
JULY 2005
S92 Abramovits
43. Ju rgens M, Wollenberg A, Hanau D, de la Salle H, Bieber T.
Activation of human epidermal Langerhans cells by engage-
ment of the high affinity receptor for IgE, FceRI. J Immunol
1995;155:5184-9.
44. Wollenberg A, Kraft S, Hanau D, Bieber T. Immunomorpho-
logical and ultrastructural characterization of Langerhans cells
and a novel, inflammatory dendritic epidermal cell (IDEC)
population in lesional skin of atopic eczema. J Invest Dermatol
1996;106:446-53.
45. Schuller E, Teichmann B, Haberstok J, Moderer M, Nieber T,
Wollenberg A. In situ expression of the costimulatory mole-
cules CD80 and CD86 on Langerhans cells and inflammatory
dendritic epidermal cells (IDEC) in atopic dermatitis. Arch
Dermatol Res 2001;293:448-54.
46. McDermott R, Ziylan U, Spehner D, Bausinger H, Lipsker D,
Mommaas M, et al. Birbeck granules are subdomains of
endosomal recycling compartment in human epidermal Lang-
erhans cells, which form where Langerin accumulates. Mol Biol
Cell 2002;13:317-35.
47. Wollenberg A, Mommaas M, Oppel T, Schottdorf EM,
Gunther S, Moderer M. Expression and function of the
mannose receptor CD206 on epidermal dendritic cells in inflam-
matory skin diseases. J Invest Dermatol 2002;118:327-34.
48. Novak N, Valenta R, Bohle B, Bausinger H, Lipsker D, Mommaas
M, et al. FcepsilonRI engagement of Langerhans cell-like den-
dritic cells and inflammatory dendritic epidermal cell-like den-
dritic cells induces chemotactic signals and different T-cell
phenotypes in vitro. J Allergy Clin Immunol 2004;113:949-57.
49. Reich K, Hugo C, Middel P, Blaschke V, Heine A, Gutgesell C,
et al. Evidence for a role of Langerhans cell-derived IL-16 in
atopic dermatitis. Clin Immunol 2002;109:681-7.
50. Laberge S, Ghaffar O, Boguneiwicz M, Center DM, Leung DYM,
Hamid QA. Association of increased CD41 T-cell infiltration
with increased IL-16 gene expression in atopic dermatitis.
J Allergy Clin Immunol 1998;102:645-50.
51. Wollenberg A, Wagner M, Gunther S, Towarowski A, Tuma E,
Moderer M, et al. Plasmacytoid dendritic cells: a new cutane-
ous dendritic cell subset with distinct role in inflammatory skin
diseases. J Invest Dermatol 2002;119:1096-102.
52. Kapp A. The role of eosinophils in the pathogenesis of atopic
dermatitiseosinophil granule proteins as markers of disease
activity. Allergy 1993;48:1-5.
53. Bruijnzeel PL, Kuijper PH, Rihs S, Betz S, Warringa RA,
Koenderman L. Eosinophil migration in atopic dermatitis. I:
Increased migratory responses to N-formyl-methionyl-leucyl-
phenylalanine, neutrophil-activating factor, platelet-activat-
ing factor, and platelet factor 4. J Invest Dermatol 1993;
100:137-42.
54. Akdis M, Trautmann A, Klunker S, Blaser K, Akdis CA. Cytokine
network and dysregulated apoptosis in atopic dermatitis. Acta
Odontol Scand 2001;59:178-82.
55. Trautmann A, Akdis M, Blaser K, Akdis CA. Role of dysregulated
apoptosis in atopic dermatitis. Apoptosis 2000;5:425-9.
56. Domae M, Sagara H, Sakaue M, Fukuda T, Kamikawa Y. The
antiallergic drug oxatomide promotes human eosinophil
apoptosis and suppresses IL-5-induced eosinophil survival.
J Allergy Clin Immunol 2003;111:567-72.
57. Bratton DL, Hamid QA, Boguneiwicz M, Doherty DE, Kailey JM,
Leung DYM. Granulocyte macrophage colony-stimulating fac-
tor contributes to enhanced monocyte survival in chronic
atopic dermatitis. J Clin Invest 1995;95:211-8.
58. Hashimoto SI, Komuro I, Yamada M, Akagawa KS. IL-10 inhibits
granulocyte-macrophage colony-stimulating factor-dependent
human monocyte survival at the early stage of the culture and
inhibits the generation of macrophages. J Immunol 2001;
167:3619-25.
59. Chu DH, Haake AR, Holbrook K, Loomis CA. Structure and
development of skin. In: Freedberg IM, Eisen AZ, Wolff K, Austen
K, Goldsmith LA, Katz SI, editors. Fitzpatricks dermatology in
general medicine, Vol 1. 6th ed. New York: McGraw-Hill; 2003.
pp. 58-88.
60. Madison KC, Sando GN, Howard EJ, True CA, Gilbert D,
Swartzendruber DC, et al. Lamellar granule biogenesis: a
role for ceramide glucosyltransferase, lysosomal enzyme
transport, and the Golgi. J Investig Dermatol Symp Proc 1998;
3:80-6.
61. Madison KC, Howard EJ. Ceramides are transported through
the Golgi apparatus in human keratinocytes in vitro. J Invest
Dermatol 1996;106:1030-5.
62. Esche C, de Benedetto A, Beck LA. Keratinocytes in atopic
dermatitis: inflammatory signals. Curr Allergy Asthma Rep
2004;4:276-84.
63. Werner Y. The water content of the stratum corneum in
patients with atopic dermatitis. Measurement with the Corne-
ometer CM 420. Acta Derm Venereol 1986;66:281-4.
64. Hara J, Higuchi K, Okamoto R, Kawashima M, Imokawa G.
High-expression of sphingomyelin deacylase is an impor-
tant determinant of ceramide deficiency leading to barrier
disruption in atopic dermatitis. J Invest Dermatol 2000;
115:406-13.
65. Imokawa G. Lipid abnormalities in atopic dermatitis. J Am
Acad Dermatol 2001;45(Suppl):S29-32.
66. Girolomoni G, Pastore S. The role of keratinocytes in the
pathogenesis of atopic dermatitis. J Am Acad Dermatol 2001;
45(Suppl):S25-8.
67. Breuhahn K, Mann A, Muller G, Wilhelmi A, Schirmacher P,
Enk A, et al. Epidermal overexpression of granulocyte-
macrophage colony-stimulating factor induces both kerati-
nocyte proliferation and apoptosis. Cell Growth Differ 2000;
11:111-21.
68. Robert C, Kupper TS. Inflammatory skin diseases, T cells, and
immune surveillance. N Engl J Med 1999;341:1817-28.
69. Pastore S, Corinti S, La Placa M, Didona B, Girolomoni G.
Interferon-gamma promotes exaggerated cytokine produc-
tion in keratinocytes cultured from patients with atopic
dermatitis. J Allergy Clin Immunol 1998;101:538-44.
70. Cho SH, Strickland I, Tomkinson A, Fehringer AP, Gelfand EW,
Leung DY. Preferential binding of Staphylococcus aureus to
skin sites of Th2-mediated inflammation in a murine model.
J Invest Dermatol 2001;116:658-63.
71. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M,
Ganz T, et al. Endogenous antimicrobial peptides and skin
infections in atopic dermatitis. N Engl J Med 2002;347:
1151-60.
72. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF,
et al. Cytokine milieu of atopic dermatitis, as compared to
psoriasis, skin prevents induction of innate immune response
genes. J Immunol 2003;171:3262-9.
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