Clinical Commentary Review
Skin Barrier and Immune Dysregulation in Atopic
Dermatitis: An Evolving Story with Important Clinical
Implications
Tali Czarnowicki, MDa,b, James G. Krueger, MD, PhDa,b, and Emma Guttman-Yassky, MD, PhDa,c New York, NY
Atopic dermatitis is the most common chronic inflammatory
skin disease. Its pathogenesis combines barrier defects, immune
dysregulation, and increased skin infections; however, the
relative contribution of each of these components is yet to be
determined. Uninvolved atopic dermatitis skin also displays
broad immune and barrier abnormalities, which highlights a role
for proactive treatment strategy. The residual disease genomic
profile that accompanies clinical resolution provides further
support for proactive treatment approaches. Although intrinsic
and extrinsic atopic dermatitis subtypes share a common clinical
phenotype, they show some important differences in their Th22/
Th17 cytokine profile, which opens the door for personalized
specific therapeutics for each disease category. Ó 2014
American Academy of Allergy, Asthma & Immunology (J Allergy
Clin Immunol Pract 2014;-:---)
Key words: Atopic dermatitis; Microbiome; Immune dysregula-
tion; Skin barrier; Proactive treatment; Residual disease genomic
profile; Intrinsic atopic dermatitis; Extrinsic atopic dermatitis
ATOPIC DERMATITIS PATHOGENESIS AND
GENETIC STRUCTURAL COMPONENTS OF THE
EPIDERMAL BARRIER
Atopic dermatitis (AD) is the most common chronic inflam-
matory skin disease. Its prevalence has significantly increased in
recent years, and it now affects approximately 3% of adults (5%-
7% in Asia)1 and up to 25% of children.2 Disease pathogenesis,
which combines both environmental and genetic factors, is still
debated, with 2 alternate pathogenic hypotheses. The “outside-
in,” hypothesis suggests that epidermal-barrier dysfunction is the
primary insult and a prerequisite to immune activation; whereas,
the “inside-out” hypothesis indicates that AD is primarily a
cytokine-driven disease with a reactive epidermal hyperplasia.
a
The Laboratory for Investigative Dermatology, The Rockefeller University,
New York, NY
b
Center for Clinical and Translational Science, The Rockefeller University,
New York, NY
c
Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York,
NY
No funding was received for this work.
Conflicts of interest: The authors declare that they have no relevant conflicts.
Received for publication February 11, 2014; revised manuscript received and
accepted for publication March 20, 2014.
Corresponding author: Emma Guttman-Yassky, MD, PhD, Department of Derma-
tology, Icahn School of Medicine at Mount Sinai Medical Center, 5 E 98th St,
New York, NY 10029. E-mail: eguttman@rockefeller.edu.
2213-2198/$36.00
Ó 2014 American Academy of Allergy, Asthma & Immunology
http://dx.doi.org/10.1016/j.jaip.2014.03.006
Although originally perceived as 2 competitive mechanisms,
there is accumulating evidence that supports their integrated role
in disease development, but their relative contribution to the AD
phenotype is still debated.2-10
The role and significance of barrier integrity in AD has been
increasingly recognized.11 Disrupted epidermal terminal differ-
entiation and reduced lipids have all been implicated as part of
the barrier defects.3,4 The epidermal differentiation complex
(EDC) locus12,13 on chromosome 1q21 is a cluster of more than
60 genes that encode for major proteins involved in terminal
differentiation and formation of the cornified envelope.7,14
Among these genes are serine protease inhibitor, Kazal type
5(SPINK5), loricrin (LOR), involucrin, and filaggrin (FLG) as
well as small proline-rich proteins and late cornified envelope
proteins.4,15 Proteins encoded by this complex have a significant
functional overlap in maintaining the cornified envelope integ-
rity.16 Among them, Filaggrin (filament-aggregating protein)/
FLG, a key protein involved in cornification and hydration
(breakdown products act as osmolytes),17 is the most commonly
associated genetic component with a risk of AD development,
severity, and increased propensity toward other atopic condi-
tions.7 Its deficiency has been postulated to increase pH (which
causes serine protease activation and modification of microbial
colonization)18 and impair skin integrity, hydration, protease
activity, and antimicrobial peptide (AMP) function. Multiple
FLG mutations have been identified, with loss-of-function (null)
mutations being the most abundant (mainly R510X and
2282del4).19-21 FLG mutations are found in 10% to 50% of AD
cases but also in 9% of the non-AD population, and 40% of the
null-alleles carriers never develop AD.20,22,23 Patients with FLG
mutations also may outgrow their disease or have extended re-
missions.22 Furthermore, in a genomic comparison among AD,
psoriasis, and normal skin, we demonstrated that multiple
cornification genes (beyond FLG) are downregulated in AD,
with delayed coordinated expression of their proteins,24 which
possibly implies a secondary barrier abnormality in response to a
primary immune activation.
ALTERED MICROBIOME CONTRIBUTES TO
BARRIER DEFECT IN AD
Microbiome is a term coined by Lederberg in 2001 and defined
as “the ecological community of commensal, symbiotic, and
pathogenic microorganisms that literally share our body space.”25 A
5-year National Institutes of Health project started in 2009,26 the
Human Microbiome Project aims at characterizing the microbiome
in health and in different skin diseases, including evaluation of
cutaneous microbiome in AD.27 This project will expand our un-
derstanding regarding the effect of the microbiome on disease
1
2 CZARNOWICKI ET AL
Abbreviations used
AD- Atopic dermatitis
AL- Atopic lesional
AMP- Antimicrobial peptide
ANL- Atopic nonlesional
CCL20- Chemokine, CC motif, ligand 20/macrophage
inflammatory protein 3
CXCL5- Chemokine, CXC motif, ligand 5/epithelial-derived
neutrophil-activating peptide 78
DC- Dendritic cell
EDC- Epidermal differentiation complex
FLG- Filaggrin
LOR- Loricrin
NB- Narrow band
RDGP- Residual disease genomic profile
S100A- S100-Calcium binding protein
SCORAD- Scoring of atopic dermatitis index
STAT- Signal transducer and activator of transcription
TCI- Topical calcineurin inhibitor
TCS- Topical corticosteroid
TEWL- Transepidermal water loss
TSLP- Thymic stromal lymphopoietin
development and its correlation with the immune and barrier
defects. One of the most troubling features of AD skin is the
susceptibility to localized and disseminated skin infections.5,18
Ninety percent of patients with AD are colonized and/or infected
with Staphylococcus aureus (S aureus), with emerging methicillin-
resistant S aureus strains imposing a therapeutic challenge.28-30
As opposed to psoriasis and healthy skin, high levels of S aureus
are found on AD nonlesional skin as well,31 which stresses the
significance of treating AD nonlesional skin. Several variables
have been suggested to account for the high susceptibility to
infections in patients with AD. The Th2 cytokines, IL-4 and IL-
13,32 have a permissive effect on microbial invasion, epidermal
barrier,33 cell-mediated immunity, lowering AMPs (b-defensins;
human b defensins and cathelicidins; human cationic antimi-
crobial protein18/LL-37) production.28,34 An association be-
tween AMPs and the skin barrier has been found, with the
correlation of increased transepidermal water loss (TEWL) with
high levels of human b defensin-2.35,36 Recently, IL-4 and IL-13
also have been reported to increase Staphylococcal a toxin induced
keratinocyte death through signal transducer and activator of
transcription (STAT) 6 signaling.37
The S aureus superantigens staphylococcal enterotoxin B and
toxic shock syndrome toxin 1 promote lymphocyte IL-31 pro-
duction in patients with AD.38 IL-31, in turn, has been shown to
reduce FLG expression and mediate proinflammatory cytokines
secretion.39 IL-22 via STAT3 increases epidermal antimicrobial
defense40-42 but decreases terminal differentiation genes.43 IL-17
holds an important role in regulatory innate immunity. It is
involved in b-defensins upregulation44 and in neutrophil
recruitment.45 As previously demonstrated,46 Th17/IL-23 acti-
vation is reduced in chronic AD compared with psoriasis. IL-17
induces AMP keratinocyte gene expression, thus its relative
deficiency in AD skin might contribute to the propensity toward
skin infections. Further support to the IL-17 anti-infection role is
provided by a recent publication that showed that Th17 harbors
an antiviral capacity, which is conveyed through IL-29 produc-
tion in patients with psoriasis.47
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S aureus is involved on several levels in the pathogenesis of AD;
It induces toxin-specific IgE secretion and basophilic activation,48
mechanically disrupts epidermal integrity through protease ac-
tivity,49 inhibits terminal differentiation markers (KRT1,
KRT10, LOR, and FLG) through IL-6 secretion50 and directly
activates eosinophils,51 thus further compromising barrier integ-
rity and function. Superantigen-producing S aureus colonization is
correlated with serum IL-4 levels,52 and staphylococcal exotoxins
are strong inducers of IL-22 and IL-31 in AD (compared with
psoriasis and healthy controls),38,53 which all support a S aureus
role in inducing and maintaining chronic skin inflammation in
AD. A myriad of antistaphylococcal strategies have been tried so
far. Among them are bleach baths, oral antibiotics, topical iodine,
triclocarban 1.5%, fluticasone ointments with and without anti-
biotics, and fabrics with antibacterial properties.54 Although these
strategies reduce bacterial loads, there is the problem that the skin
is rapidly recolonized by S aurues.55
Interestingly, barrier-directed treatments as well as anti-in-
flammatory medications (topical calcineurin inhibitors [TCI]
and topical corticosteroids [TCS]) reduce the bacterial load and
improve barrier function,56-59 which suggests that neutralizing
this component will recover the compromised innate immunity
in AD.60 Novel therapeutics directed at improving the bacterial
overload include ceragenins (synthetic antimicrobial com-
pounds), oral vitamin D, vaccines, and toxin-neutralizing agents
(directed mainly staphylococcal enterotoxin B and toxic shock
syndrome toxin 1), but yet the standard of care to reduce bac-
terial overload includes barrier repair by hydration and topical
anti-inflammatory formulas.5,61-65 There is a high need to
identify more-effective treatments for Staphylococcal colonization
because a Cochrane database systematic review concludes that
results vary but global degree of improvement in symptoms and
or signs after available treatments was only average.54
The microbiome individually affects the development and
profile of the adaptive immune system and has an “imprint” on
many of its aspects.66 However, it has yet to be determined how
S aureus colonization differentially drives cytokines polarization
in different age groups and how its eradication will redirect these
pathways and affect barrier integrity in AD. Better microbiome
characterization by the Human Microbiome Project and parallel
studies as well as application of different eradication protocols
will help to better address these questions.
THE COMPLEX DIALOG BETWEEN THE IMMUNE
DYSREGULATION AND THE EPIDERMAL BARRIER
DEFECT IN AD: CHICKEN OR THE EGG?
The interplay between skin barrier and immune dysregulation
in AD is complicated, and cytokine imbalance has a major
impact on keratinocyte differentiation and other barrier features.
AD is characterized by overexpression of the Th2 cytokines IL-4
and IL-13 as well as the Th22 cytokine, IL-22. As we recently
showed,9 acute initiation of AD is associated with overexpression
of Th2 and Th22 cytokines genes, with intensification of these
axes toward chronic disease, and the appearance of a significant
Th1 component. Th17 also has some contribution in acute AD
onset. During the acute disease phase, Th2 cytokines, notably
IL-4, IL-5, IL-13, and IL-31, are detected in atopic lesional (AL)
but also in atopic nonlesional (ANL) skin. The Th22 pathway
genes IL-22 and S100-calcium binding proteins (S100A) 7-9
were also shown to be elevated in AL skin. Conversely, an
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impaired barrier causes increased IL-1 levels, which promote an
innate immune response that leads to cutaneous inflammation.67
In recent years, FLG skin expression has been shown to be
modulated in AD by the Th2 and Th22 cytokine milieu. Th2
(IL-4, IL-13, and IL-31) and Th22 (IL-22) cytokines compro-
mise the epidermal barrier by several mechanisms. They down-
regulate the expression of the EDC genes, thus suppressing major
terminal differentiation proteins, such as FLG, LOR, and invo-
lucrin,9,39,68-71 regardless of the FLG genotype,7 and FLG
expression is restored under anti-inflammatory regimens with
either TCI or TCS.58 Thus, the genetic defects are not the sole
contributor to the low expression of FLG. Other adverse effects
of exogenous IL-4 on the skin barrier include inhibition of
desmoglein 3 expression and reduction of ceramide synthe-
sis.72,73 FLG mutations have been associated with pH alkaliza-
tion, which leads to serine protease activation.74 Deficiency in
FLG breakdown products, either genetically predisposed or via
Th2 induction, modulates the skin microbiome and renders
patients with AD more susceptible to skin infections.7
IL-22 plays a central role in skin homeostasis.75 It induces
STAT3 activation in keratinocytes and has proinflammatory
activities. IL-22 upregulates the proinflammatory molecules
S100A7, S100A8, and S100A9, as well as matrix metal-
loproteinase-3/stromelysin-1, the platelet-derived growth factor
A, and CXCL5 (chemokine, CXC motif, ligand 5/epithelial-
derived neutrophil-activating peptide 78) (neutrophil attractant).
IL-22 also inhibits keratinocytes differentiation, enhances kera-
tinocyte migration, and induces epidermal hyperplasia.76
Another link between barrier defect and Th2 polarization is
provided by thymic stromal lymphopoietin (TSLP), an IL-
7elike cytokine, which was designated in the past as the “master
switch for allergic inflammation.”77 The compromised epithelial
barrier serves as a semipermeable border for penetrating allergens,
which, in turn, increase TSLP keratinocyte production and
adaptive Th2 response by TSLP-activated dendritic cells (DC),
mediated by the downstream mediator OX40L.3,18,70,78,79 The
disrupted barrier exposes antigen that presents cells to capture
more allergens and thus promotes allergic sensitization.80
Epicutaneous application of the house dust mite on ANL skin
provokes a positive eczematous reaction in up to 40% to 50% of
atopy patch tests.81 It has recently been shown by Landheer et al82
that an house dust mite positive patch test in ANL skin resulted in
increased TSLP expression that was comparable with AL skin
levels. This observation shows that disease mediators are readily
recruited to ANL skin upon induction of sensitization. IL-25,
another epithelial cellederived cytokine, and a member of the IL-
17 family, induces TSLP-DCeactivated Th2 memory cells,83 is
associated with Th2-mediated immunity and its messenger RNA
expression is elevated in AD lesional skin.83-85 When comparing
IL-25 levels in lesional AD, psoriasis and allergic contact dermatitis
skin showed high levels in both ANL and AL AD skin, in contrast
to only lesional skin in psoriasis and allergic contact dermatitis.
The same study also showed that IL-25 reduced FLG synthesis.
Beyond the potential role of IL-25 in AD, these observations
further demonstrate the abnormal phenotype of ANL skin in
AD.86 When considered together, evolving data provide many
links between the immune and barrier abnormalities, which sug-
gest mechanisms by which immune activation promotes barrier
defects, which, in turn, augments the propensity for atopy. This
concept is reinforced by the fact that correcting the barrier also
ameliorates the inflammatory infiltrates.74
CZARNOWICKI ET AL 3
NONLESIONAL AD SKIN IS CHARACTERIZED BY
IMMUNE DYSREGULATION AND DEFECTIVE
BARRIER
Unlike psoriasis, in which the nonlesional phenotype is close
to normal skin,87 visibly normal skin in AD is abnormal and
harbors broad barrier and immune defects.88 These include
decreased hydration, increased TEWL, and impaired lipids.89-91
Increased T-cell infiltrates also have been demonstrated in ANL
compared with healthy skin.92 In a comprehensive genomic and
histologic study93 that compared chronic AL, ANL, and normal
skin phenotypes, we demonstrated increased epidermal thickness
as well as increases in T-cell and myeloid DC infiltrates in
ANL skin. ANL and AL skin also were shown to share an
abnormal barrier phenotype, including very low expression levels
of many EDC and terminal differentiation genes compared with
normal skin. Indeed, effective AD treatments, including narrow
band (NB) UV-B94 and cyclosporine-A95 were reported not
only to improve the AL but also the ANL phenotype. Interest-
ingly, in patients with higher scoring of atopic dermatitis
index (SCORAD), increases in inflammatory markers also were
detected in ANL skin, possibly due to the influence of systemic
cytokine activation.
The alternate explanations to the ANL abnormal phenotypes
are that initiation of immune activation and an increase in
circulating cytokines alter terminal differentiation in ANL skin
or, alternately, that it results from fixed genetic defects in
epidermal and immune functioneregulating genes. These al-
ternatives are not mutually exclusive, so disease pathogenesis
also can be explained by an integrated model in which barrier
and immune defects cooperate to create a chronic disease
phenotype.
Both AL and ANL skin are characterized by xerosis. Decreases
in skin ceramides, pH alterations, chymase overexpression, and
FLG mutations have all been suggested as potential causes of
xerosis.2 As previously mentioned, the ANL skin may appear
clinically normal; however, it harbors impaired barrier function
(with increased TEWL),91 varied inflammatory infiltrates, high-
affinity IgE receptor upregulation on Langerhans cells96-99 and
reduced lipids compared with normal skin.100 There are con-
flicting reports regarding the differential expression of FLG and
LOR across AL and ANL skin in AD. In 2007, Howell et al69
showed that FLG expression is increased in ANL skin compared
with AL skin, where it is inhibited by IL-4 and IL-13. Kim
et al70 showed that, compared with non-AD skin, in AD unin-
volved and, more prominently, in involved skin, LOR and
involucrin were downregulated. They showed that IL-4 and IL-
13 significantly inhibit the induction of these 2 genes via STAT6
activation.
Our group showed that epidermal terminal differentiation
gene products, such as FLG and LOR are reduced in both AL
and ANL skin compared with normal skin and that further
downregulation does not occur within AL skin,93 which leads to
the concept that disease exacerbations are not accompanied by
further compromise of this aspect of the skin barrier. Interest-
ingly, despite similar reductions in differentiation genes in ANL
and AL skin, the expression of the S100s (S100A7, S100A8, and
S100A9), which are part of the EDC but also act as proin-
flammatory molecules, is highly increased from ANL to AL
skin.9 This effect might be partially explained by the inductive
effect of IL-22 and IL-17 on the S100 proteins.71,76
4 CZARNOWICKI ET AL
DISCREPANCY BETWEEN CLINICAL AND
IMMUNOBIOLOGIC FEATURES OF ANL SKIN IN AD
AND THE RATIONALE FOR “PROACTIVE
TREATMENT”
Long-term treatment of AD should be targeted at optimization
of the barrier dysfunctions and the immune aberrations. The
traditional long-term topical treatment approach in AD consisted
of “reactive” applications of emollients and anti-inflammatory
topical compounds, mainly TCS or TCI upon flares.101 These
treatments may only lead to short and transient symptomatic re-
missions. Furthermore, reactive treatments are often started late
because compliance studies show that patients with AD who
experience a flare start treating their lesions with anti-inflamma-
tory medications with 6 to 7 days of delay.34 In recent years, a
“proactive” therapeutic strategy has emerged and was corrobo-
rated in several studies. According to this treatment rationale,
“stabilization” of acute flares is followed by a maintenance
regimen; AL skin is intensively treated with topical anti-inflam-
matory products to reach an apparent clinical resolution, followed
by long-term, low-dose intermittent applications of anti-inflam-
matory topical treatments to previously affected skin, combined
with a daily application of emollients to the entire skin surface.102
This approach supports the notion that AD treatment should
continue even after apparent clearance of the lesions due to the
abnormal nature of ANL skin. One of the clinical trials that
showed the superiority of this treatment strategy in a randomized,
double-blind study showed that the addition of fluticasone pro-
pionate twice weekly to maintenance emollients significantly
reduced the risk of AD relapse.103 Further support to the ad-
vantageous properties of the proactive approach is provided by
Hanifin et al104 and by Wollenberg et al,105 who report that
proactive twice-weekly year-long application of TCS and TCI,
respectively, is more effective than its “reactive” application in
reducing AD exacerbations. Proactive treatment also decreases
serum IgE levels in patients with severe AD.106
In conclusion, the traditional management of AD is mostly
reactive; however, analysis of accumulating data suggests that, to
achieve long-term remissions, reduce flare-up frequency, and
control subclinical inflammation, the proactive approach should
be adopted, with early and preventive intervention, followed by
long-term (3-12 months, depending on severity) maintenance
treatments.34 A future therapeutic strategy aimed at individualized
treatments might be in developing new disease severity assessment
tools, which will not only be based on the clinical disease extent
(and subjective symptoms) but also on molecular and cellular
parameters, which is particularly important because it is hard to
quantify erythema and lichenification, and different parameters
may react differently to treatment, and there are fixed parameters
(genetic) that are constant. The comprehensive disease severity
assessment tools will be helpful to accurately define disease
remission and determine therapeutic and follow-up periods.
INTRINSIC AND EXTRINSIC AD: NEW INSIGHTS
AND THERAPEUTIC IMPLICATIONS
Historically, the term “atopic dermatitis” was coined to
associate AD and high IgE levels with other “atopic” or allergic
diseases (ie, asthma and allergic rhinitis). The IgE model was
supported by several observations.107-110 These include a high
expression of FceRI on both Langerhans cells and inflammatory
epidermal DCs in AD,18 and serum IgE autoreactivity against
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keratinocytes that correlated with disease severity and IgE
levels.111 Furthermore, IgE production by B cells was shown to
be enhanced by IL-4 and IL-13, and to be inhibited by IFN-
g.112,113 All of these observations have built the “IgE-model” as
the major component in AD pathogenesis. AD is divided into
“intrinsic” (normal serum-IgE levels) and “extrinsic” (IgE asso-
ciated; high serum-IgE levels) forms with a distribution of 20%
and 80%, respectively.114 Intrinsic AD, despite lacking elevated
IgE, shares similar clinical and histologic phenotypes, and is
characterized by delayed onset, female predominance,115 absence
of other atopic diseases, negative skin prick test to environmental
and food allergens, and undetectable levels of allergen-specific
IgEs.110 Because IgE was perceived as a fundamental component
in the pathogenesis of AD, it raised a question whether these
intrinsic and extrinsic variants are part of 1 disease on different
sides of a spectrum or 2 separate entities.116
To evaluate the differences and similarities between these 2
subtypes117 and when trying to assess differences beyond IgE
levels, we compared cellular and molecular characteristics between
42 patients with extrinsic AD and 9 patients with intrinsic AD.
Several measurements were common to both forms, including
epidermal hyperplasia, increased T cells, DCs, and Langerhans
cells infiltrates, and high activation of the S100 epidermal re-
sponses (potentially in response to IL-17 and IL-22) and Th2
cytokine production. However, significant differences were
observed between the groups. Overall, intrinsic disease showed
higher immune activation, which was particularly significant for
Th17 (IL-17, IL-12/IL-23p40, CCL20 [chemokine, CC motif,
ligand 20/macrophage inflammatory protein 3-], and elafin) and
Th22 (IL-22) axes. Positive correlations were found between IgE
levels and SCORAD values only in extrinsic AD, which suggests
the potential role of IgE in inflammation amplification.
Th17/IL-23 pathway upregulation is important in psoriasis
pathogenesis118,119; however, its role in AD is controver-
sial,120,121 and it is overall accepted that this pathway is less
dominant in AD compared with psoriasis.46 Results of our study
suggest a role for Th17 in intrinsic disease, supported by
increased IL-17 expression in the intrinsic AD transcriptome and
a positive correlation between Th17-associated chemokine
CCL20 (messenger RNA) and disease severity (SCORAD). Pa-
tients with intrinsic AD were shown to have predominantly Th1/
Th17 responses to metals (nickel and cobalt).122 Thus, perhaps
the intrinsic AD phenotype promotes a Th1/Th17 immune
environment reflected in patch test results, or, alternatively, these
metals are associated with induction of AD in an intrinsic setting.
Similarly to our skin data, Kabashima-Kubo et al113 did not find
significant differences in Th2 (IL-4, IL-5) cytokines in blood.
However, other reports123,124 in blood showed increased IFN-g
in intrinsic disease and a Th2 bias in extrinsic AD. Hence, higher
circulating levels of Th2 cytokines might promote IgE class
switching, which is the basis of allergic inflammation in extrinsic
AD. IL-22 and IL-17 levels in blood and in lesional and non-
lesional AD and psoriasis skin are summarized in Table I.
Besides immune differences, there also is barrier variation be-
tween the 2 forms. An improved barrier profile accompanies the
intrinsic form due to a higher Th17 profile (IL-17 induces AMPs
keratinocyte gene expression)46 and a lower frequency of FLG
mutations.113,125 Mori et al115 compared the surface hydration
(capacitance) and TEWL between extrinsic and intrinsic disease,
and showed that extrinsic ANL skin has lower hydration and
increased TEWL compared with intrinsic disease. It is yet to be
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TABLE I. Blood and skin IL-17 and IL-22 levels in AD variants and
psoriasis
Intrinsic AD Extrinsic AD Psoriasis Normal
IL-17 blood* [ [ [[[ D
IL-17 skin†
Nonlesional \ \ [ D
Lesional [[ [ [[[
IL-22 blood [[z [[z [ D
IL-22 skinx
\ \ \
Nonlesional D
Lesional [[[ [[ [
The number of arrows indicate the magnitude of the values. The unfilled arrow
indicates a trace elevation in the cytokine level. The filled arrows are higher values
ranging from 1e3 (where 3 is the highest).
*Measurements of IL-17A have been done in psoriasis and normal controls by using
the Singulex assay, the only US Food and Drug Administration approved assay for
IL-17; comparable IL-17A measurements in AD have not been published; small
increases in the frequency of circulating Th17 T cells have been measured in both
intrinsic and extrinsic AD, but larger increases in this cell population have been
detected in patients with psoriasis (from Refs 113,118,133-135).
†From Refs 9,117.
zAvailable publications show elevated IL-22 in AD but not comparing intrinsic vs
extrinsic disease forms.
xFrom Refs 9,117,120.
determined if these barrier features of intrinsic AD translate into a
lower frequency of skin infections and an altered microbiome.
Similar Th2 cytokine activation in skin in both subtypes117
weakens the concept of a cutaneous Th2 milieu in extrinsic
disease as an inducer of IgE switching.126,127 The high levels of T
regulatory cells (FOXP3þ) in intrinsic AL skin found in our
study is an alternative mechanism to explain the lower IgE levels
found in patients with intrinsic disease. However, the regulatory
mechanisms in blood versus skin might be different. Although
Adkis et al127 showed increased expression of activation markers
(HLA-DR and CD25) on CD4þ and CD8þ cells in both
intrinsic and extrinsic disease forms, a comparison of a broader
panel of activation markers between central and effector memory
T cells has not been performed, and potential differences of
activation levels might account for difference regulatory activity
of IgE in intrinsic disease.
These findings have important therapeutic implications. Anal-
ysis of our data implies that T cells are a unifying pathogenic factor
that should be addressed by targeted agents. High Th2 activation
in all patients could be addressed by anti-Th2 therapeutic ap-
proaches in both intrinsic and extrinsic AD. The higher IL-23/
Th17 in intrinsic disease might lead to selective targeting of this
axis in patients with intrinsic disease, which has important rele-
vance because there are ongoing and upcoming clinical trials with
anti-p40 (ustekinumab [Stelara]; Centocor Ortho Biotech Inc,
Horsham, Pa) (clinicaltrials.gov identifier NCT01806662), anti-
IL-22 (ILV-094; clinicaltrials.gov identifier NCT01941537), and
several Th2-axis targeted therapies, including anti-IL-4R alpha
mAb (Dupilumab [REGN668/SAR231893]; clinicatrial.gov
identifier NCT01979016), and anti-IL-31 (BMS-981164;
clinicatrial.gov identifier NCT01614756) that will try to address
efficacy across AD and its subtypes.
RESIDUAL GENOMIC SIGNATURE: IMPLICATIONS
FOR ASSESSING SUCCESSFUL TREATMENT IN AD
An AD clinical course is characterized by remissions and ex-
acerbations in which the plaques tend to retain their original
CZARNOWICKI ET AL 5
distribution and recur at the same anatomic sites, which suggests
that residual molecular and/or cellular alterations predispose
these areas to further breakouts.128 To understand the residual
skin alterations after successful therapy, which led to resolved
clinical disease, we tracked the residual disease genomic profile
(RDGP), defined as the differentially expressed genes, that
showed less than 75% improvement. The study included 11
patients with moderate-severe AD after a successful 12 weeks of
thrice weekly NBeUV-B treatment. Several immune genes,
pathogenically linked to AD (S100A7, S100A8) as well as
important cellular infiltrates (CD11cþ myeloid DCs and FceRIþ
inflammatory epidermal DCs) showed less than 75% improve-
ment despite clinical resolution. Interestingly, ANL skin profile
also was improved under NBeUV-B treatment compared with
normal skin. Given the fact that NBeUV-B has known effects
on keratinocytes and is not specifically targeting the immune
system, it will be important to conduct similar studies by using
targeted therapeutics that are currently in clinical trials for AD.
Future studies that compare RDGP across different broad and
targeted immune treatments are needed to gain a full under-
standing of the set of genes that is disease specific versus treat-
ment specific.
This report has several important implications. It sheds light
on the basis for the sinusoidal character of AD and helps to
explain the recurrent nature of this disease. These observations
also have fundamental implications for the therapeutic approach;
the RDGP needs to be considered after clinical disease resolu-
tion. For example, addressing lipid-associated RDGPs by use of
systemic peroxisome proliferator-activated receptor (PPAR)-g
agonists (eg, rosiglitazone), which has recently been linked to
several inflammation-associated genes and, in a clinical series
report, was shown to positively affect AD in several pathways.129
FUTURE THERAPIES AND CRITICAL MISSING
INFORMATION
Despite extensive research conducted on AD, many aspects of
disease development, pathogenesis, the mechanisms of disease
initiation and progression, and optimal treatment are still elusive.
The onset of AD in childhood is coupled to active differentiation
of memory B cells and T cells from naive precursors. The
sequence of T-cell activation, B-cell activation, IgE class
switching, and differentiation of skin-homing and/or resident
effector memory T cells must still be determined. Whether AD is
an inside-out or outside-in disease, the common denominator is
large-cell infiltrates and T-cell activation. The nature of the
disease as a T-celledriven one is further supported by the ad-
vantageous effects of cyclosporine treatment, regardless of FLG
mutation.130 Much more characterization of child-onset AD is
needed to better address the interplay and the relationship of
barrier versus immune features of AD. Our current collaboration
in defining the unique skin and blood biomarkers of pediatric
AD (clinicaltrials.gov identifier NCT01782703) will help to
better define the pediatric disease profile compared with adult
disease features and will delineate developmental mechanisms.
Pathogenically, open questions remain. What is the relative
role of IgE in AD? Does Th17 axis have an inhibitory effect on
the antibody-switched IgE production? Do increasing levels of
IgE in extrinsic disease amplify cutaneous inflammation? Vari-
able outcomes have been reported for omalizumab (humanized
IgG1 mAb)131 treatment in AD despite its effectiveness in
6 CZARNOWICKI ET AL
allergic asthma. Selective drug administration to patients with
IgE autoreactivity might lead to better outcomes, which improve
both immune dysregulation and the barrier defect caused by
keratinocyte targeting of these autoantibodies. Nevertheless, the
autoimmune profile of AD is still a therapeutic target, and
double-filtration plasmapheresis was effective in treating recalci-
trant AD.132 Interestingly, this treatment affected other immu-
noglobulin levels parallel to clinical improvement, which raises a
question regarding a potential role for other immunoglobulins in
AD pathogenesis and especially in intrinsic AD in which IgE
levels are not a factor.
Intrinsic and extrinsic subtypes open new pathogenic and
therapeutic investigation horizons. Does different immune acti-
vation in intrinsic versus extrinsic AD provide an opportunity to
select therapies on the basis of specific cytokine patterns? For
example, intrinsic AD is characterized by increased Th17 acti-
vation along with increased products of IL-23, which might serve
as a target for therapeutic intervention. A phase II ongoing
double-blind pilot study of anti-p40 (ustekinumab [Stelara];
clinicaltrials.gov identifier: NCT01806662; Centocor Ortho
Biotech Inc, Horsham, Pa) administration for chronic AD is now
being held in our institution, and stratification analysis of results
according to intrinsic and extrinsic forms will help to evaluate the
benefit of this treatment for intrinsic disease and the therapeutic
significance of Th17 dominance in this subtype. Another area of
interest will be to compare the RDGP profile between intrinsic
and extrinsic disease subjected to the same therapeutic inter-
vention. In conclusion, AD is the most common inflammatory
skin disease. Its pathogenic as well as developmental aspects are
complex. Ongoing studies with highly specific immune antago-
nists will shed light on disease mechanisms, and these agents hold
promise for better long-term disease treatments.
REFERENCES
1. Thappa DM, Malathi M. Is there something called adult onset atopic dermatitis
in India? Indian J Dermatol Venereol Leprol 2013;79:145-7.
2. Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483-94.
3. Elias PM, Hatano Y, Williams ML. Basis for the barrier abnormality in atopic
dermatitis: outside-inside-outside pathogenic mechanisms. J Allergy Clin
Immunol 2008;121:1337-43.
4. Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of
atopic dermatitis and psoriasis—part I: clinical and pathologic concepts.
J Allergy Clin Immunol 2011;127:1110-8.
5. Boguniewicz M, Leung DYM. Recent insights into atopic dermatitis and
implications for management of infectious complications. J Allergy Clin
Immunol 2010;125:4-13.
6. Elias PM, Steinhoff M. “Outside-to-inside” (and now back to “outside”)
pathogenic mechanisms in atopic dermatitis. J Invest Dermatol 2008;128:
1067-70.
7. McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin
disease. J Allergy Clin Immunol 2013;131:280-91.
8. Bieber T, Novak N. Pathogenesis of atopic dermatitis: new developments. Curr
Allergy Asthma Rep 2009;9:291-4.
9. Gittler JK, Shemer A, Suarez-Farinas M, Fuentes-Duculan J, Gulewicz KJ,
Wang CQF, et al. Progressive activation of T(H)2/T(H)22 cytokines and se-
lective epidermal proteins characterizes acute and chronic atopic dermatitis.
J Allergy Clin Immunol 2012;130:1344-54.
10. Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and other
eczemas. J Invest Dermatol 2009;129:320-2.
11. Taieb A, Hanifin J, Cooper K, Bos JD, Imokawa G, David TJ, et al. Pro-
ceedings of the 4th Georg Rajka International Symposium on Atopic
Dermatitis, Arcachon, France, September 15-17, 2005. J Allergy Clin Immunol
2006;117:378-90.
12. Mischke D, Korge BP, Marenholz I, Volz A, Ziegler A. Genes encoding
structural proteins of epidermal cornification and S100 calcium-binding pro-
teins form a gene complex (“epidermal differentiation complex”) on human
chromosome 1q21. J Invest Dermatol 1996;106:989-92.
J ALLERGY CLIN IMMUNOL PRACT
MONTH 2014
13. Volz A, Korge BP, Compton JG, Ziegler A, Steinert PM, Mischke D. Physical
mapping of a functional cluster of epidermal differentiation genes on
chromosome-1q21. Genomics 1993;18:92-9.
14. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death
in the skin. Nat Rev Mol Cell Biol 2005;6:328-40.
15. Barnes KC. An update on the genetics of atopic dermatitis: scratching the
surface in 2009. J Allergy Clin Immunol 2010;125:16-29.e1-11. quiz 30-1.
16. O’Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic
dermatitis. J Allergy Clin Immunol 2008;122:689-93.
17. Rawlings AV, Harding CR. Moisturization and skin barrier function. Dermatol
Ther 2004;17(Suppl 1):43-8.
18. Boguniewicz M, Leung DYM. Atopic dermatitis: a disease of altered skin
barrier and immune dysregulation. Immunol Rev 2011;242:233-46.
19. Brown SJ, Relton CL, Liao HH, Zhao YW, Sandilands A, Wilson IJ, et al.
Filaggrin null mutations and childhood atopic eczema: a population-based
case-control study. J Allergy Clin Immunol 2008;121:940-6.
20. Palmer CNA, Irvine AD, Terron-Kwiatkowski A, Zhao YW, Liao HH, Lee SP,
et al. Common loss-of-function variants of the epidermal barrier protein filaggrin
are a major predisposing factor for atopic dermatitis. Nat Genet 2006;38:441-6.
21. Baurecht H, Irvine AD, Novak N, Illig T, Buhler B, Ring J, et al. Toward a
major risk factor for atopic eczema: Meta-analysis of filaggrin polymorphism
data. J Allergy Clin Immunol 2007;120:1406-12.
22. Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, et al. The
burden of disease associated with filaggrin mutations: a population-based,
longitudinal birth cohort study. J Allergy Clin Immunol 2008;121:872-877.e9.
23. Leung DYM. Our evolving understanding of the functional role of filaggrin in
atopic dermatitis. J Allergy Clin Immunol 2009;124:494-5.
24. Guttman-Yassky E, Suarez-Farinas M, Chiricozzi A, Nograles KE, Shemer A,
Fuentes-Duculan J, et al. Broad defects in epidermal cornification in atopic
dermatitis identified through genomic analysis. J Allergy Clin Immunol 2009;
124:1235-44.
25. Lederberg J, McCray AT. ‘Ome sweet ‘omics: a genealogical treasury of
words. Scientist 2001;15:8-9.
26. NIH HMP Group Working Group, Peterson J, Garges S, Giovanni M,
McInnes P, Wang L, et al. The NIH Human Microbiome Project. Genome Res
2009;19:2317-23.
27. Kong HH, Segre JA. Skin microbiome: looking back to move forward. J Invest
Dermatol 2012;132:933-9.
28. 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.
29. Agner T. Staphylococcal-mediated worsening of atopic dermatitis: many
players involved. Br J Dermatol 2010;163:1147.
30. Higaki S, Morohashi M, Yamagishi T, Hasegawa Y. Comparative study of
staphylococci from the skin of atopic dermatitis patients and from healthy
subjects. Int J Dermatol 1999;38:265-9.
31. Cho SH, Strickland I, Boguniewicz M, Leung DYM. Fibronectin and fibrin-
ogen contribute to the enhanced binding of Staphylococcus aureus to atopic
skin. J Allergy Clin Immunol 2001;108:269-74.
32. 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.
33. Howell MD, Fairchild HR, Kim BE, Bin LH, Boguniewicz M, Redzic JS, et al.
Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation.
J Invest Dermatol 2008;128:2248-58.
34. Bieber T. Atopic dermatitis. Ann Dermatol 2010;22:125-37.
35. Jensen JM, Pfeiffer S, Akaki T, Schroder JM, Kleine M, Neumann C, et al.
Barrier function, epidermal differentiation, and human beta-defensin 2
expression in tinea corporis. J Invest Dermatol 2007;127:1720-7.
36. Clausen ML, Jungersted JM, Andersen PS, Slotved HC, Krogfelt KA,
Agner T. Human beta-defensin-2 as a marker for disease severity and skin
barrier properties in atopic dermatitis. Br J Dermatol 2013;169:587-93.
37. Brauweiler AM, Goleva E, Leung DY. Th2 Cytokines Increase Staphylo-
coccus aureus alpha toxin induced keratinocyte death through the Signal
Transducer and Activator of Transcription 6 (STAT6). J Invest Dermatol (27
January 2014) doi:10.1038/jid.2014.43. Epub ahead of print.
38. Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L, et al. IL-31:
a new link between T cells and pruritus in atopic skin inflammation. J Allergy
Clin Immunol 2006;117:411-7.
39. Cornelissen C, Marquardt Y, Czaja K, Wenzel J, Frank J, Luscher-Firzlaff J,
et al. IL-31 regulates differentiation and filaggrin expression in human orga-
notypic skin models. J Allergy Clin Immunol 2012;129:426-33. 33.e1-8.
40. Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 increases
the innate immunity of tissues. Immunity 2004;21:241-54.
J ALLERGY CLIN IMMUNOL PRACT
VOLUME -, NUMBER -
41. Sa SM, Valdez PA, Wu JF, Jung K, Zhong F, Hall L, et al. The effects of IL-20
subfamily cytokines on reconstituted human epidermis suggest potential roles
in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
J Immunol 2007;178:2229-40.
42. Witte E, Witte K, Warszawska K, Sabat R, Wolk K. Interleukin-22: a cytokine
produced by T, NK and NKT cell subsets, with importance in the innate immune
defense and tissue protection. Cytokine Growth Factor Rev 2010;21:365-79.
43. Wolk K, Witte E, Wallace E, Docke WD, Kunz S, Asadullah K, et al. IL-22
regulates the expression of genes responsible for antimicrobial defense, cellular
differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J
Immunol 2006;36:1309-23.
44. Kao CY, Chen Y, Thai P, Wachi S, Huang F, Kim C, et al. IL-17 markedly up-
regulates beta-defensin-2 expression in human airway epithelium via JAK and
NF-kappaB signaling pathways. J Immunol 2004;173:3482-91.
45. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, Ley K. Phagocytosis of
apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity
2005;22:285-94.
46. Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Zaba LC, Cardinale I,
Nograles KE, et al. Low expression of the IL-23/Th17 pathway in atopic
dermatitis compared to psoriasis. J Immunol 2008;181:7420-7.
47. Wolk K, Witte K, Witte E, Raftery M, Kokolakis G, Philipp S, et al. IL-29 is
produced by T(H)17 cells and mediates the cutaneous antiviral competence in
psoriasis. Sci Transl Med 2013;5:204ra129.
48. Bunikowski R, Mielke MEA, Skarabis H, Worm M, Anagnostopoulos I,
Kolde G, et al. Evidence for a disease-promoting effect of Staphylococcus
aureus-derived exotoxins in atopic dermatitis. J Allergy Clin Immunol 2000;
105:814-9.
49. Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M, et al.
Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 2009;
129:1892-908.
50. Son ED, Kim HJ, Park T, Shin K, Bae IH, Lim KM, et al. Staphylococcus
aureus inhibits terminal differentiation of normal human keratinocytes by
stimulating interleukin-6 secretion. J Dermatol Sci 2014;74:64-71.
51. Hosoki K, Nakamura A, Nagao M, Hiraguchi Y, Tanida H, Tokuda R, et al.
Staphylococcus aureus directly activates eosinophils via platelet-activating
factor receptor. J Leukoc Biol 2012;92:333-41.
52. Nada HA, Gomaa NI, Elakhras A, Wasfy R, Baker RA. Skin colonization by
superantigen-producing Staphylococcus aureus in Egyptian patients with
atopic dermatitis and its relation to disease severity and serum interleukin-4
level. Int J Infect Dis 2012;16:e29-33.
53. Niebuhr M, Scharonow H, Gathmann M, Mamerow D, Werfel T. Staphylo-
coccal exotoxins are strong inducers of IL-22: a potential role in atopic
dermatitis. J Allergy Clin Immunol 2010;126:1176-11783.e4.
54. Bath-Hextall FJ, Birnie AJ, Ravenscroft JC, Williams HC. Interventions to
reduce Staphylococcus aureus in the management of atopic eczema: an
updated Cochrane review. Br J Dermatol 2010;163:12-26.
55. Boguniewicz M, Sampson H, Leung SB, Harbeck R, Leung DYM. Effects of
cefuroxime axetil on Staphylococcus aureus colonization and superantigen
production in atopic dermatitis. J Allergy Clin Immunol 2001;108:651-2.
56. Boguniewicz M, Leung DY. The ABC’s of managing patients with severe
atopic dermatitis. J Allergy Clin Immunol 2013;132:511-512.e5.
57. Schittek B. The antimicrobial skin barrier in patients with atopic dermatitis.
Curr Probl Dermatol 2011;41:54-67.
58. Jensen JM, Pfeiffer S, Witt M, Brautigam M, Neumann C, Weichenthal M,
et al. Different effects of pimecrolimus and betamethasone on the skin barrier
in patients with atopic dermatitis. J Allergy Clin Immunol 2009;123:
1124-33.
59. Hung SH, Lin YT, Chu CY, Lee CC, Liang TC, Yang YH, et al. Staphylo-
coccus colonization in atopic dermatitis treated with fluticasone or tacrolimus
with or without antibiotics. Ann Allergy Asthma Immunol 2007;98:51-6.
60. Howell MD, Boguniewicz M, Pastore S, Novak N, Bieber T, Girolomoni G,
et al. Mechanism of HBD-3 deficiency in atopic dermatitis. Clin Immunol
2006;121:332-8.
61. Boguniewicz M. New strategies for dealing with Staphylococcus aureus
colonization and the emerging methicillin-resistant Staphylococcus aureus
epidemic in atopic dermatitis. Chem Immul Allery 2012;96:113-9.
62. Sidbury R, Sullivan AF, Thadhani RI, Camargo CA. Randomized controlled
trial of vitamin D supplementation for winter-related atopic dermatitis in
Boston: a pilot study. Br J Dermatol 2008;159:245-7.
63. Savage PB, Li CH, Taotafa U, Ding BW, Guan QY. Antibacterial properties of
cationic steroid antibiotics. FEMS Microbiol Lett 2002;217:1-7.
64. Chin JN, Rybak MJ, Cheung CM, Savage PB. Antimicrobial activities of
ceragenins against clinical isolates of resistant Staphylococcus aureus. Anti-
microb Agents Chemother 2007;51:1268-73.
CZARNOWICKI ET AL 7
65. Yang X, Buonpane RA, Moza B, Rahman AKMNU, Wang NY,
Schlievert PM, et al. Neutralization of multiple staphylococcal superantigens
by a single-chain protein consisting of affinity-matured, variable domain re-
peats. J Infect Dis 2008;198:344-8.
66. Brown AF, Leech JM, Rogers TR, McLoughlin RM. Colonization: modulation
of host immune response and impact on human vaccine design. Front Immunol
2014;4:507.
67. Dinarello CA. Immunological and inflammatory functions of the interleukin-1
family. Ann Rev Immunol 2009;27:519-50.
68. Sehra S, Yao Y, Howell MD, Nguyen ET, Kansas GS, Leung DY, et al. IL-4
regulates skin homeostasis and the predisposition toward allergic skin
inflammation. J Immunol 2010;184:3186-90.
69. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A,
et al. Cytokine modulation of atopic dermatitis filaggrin skin expression.
J Allergy Clin Immunol 2007;120:150-5.
70. Kim BE, Leung DYM, Boguniewicz M, Howell MD. Loricrin and involucrin
expression is down-regulated by Th2 cytokines through STAT-6. Clin
Immunol 2008;126:332-7.
71. Nograles KE, Zaba LC, Guttman-Yassky E, Fuentes-Duculan J, Suarez-
Farinas M, Cardinale I, et al. Th17 cytokines interleukin (IL)-17 and IL-22
modulate distinct inflammatory and keratinocyte-response pathways. Br J
Dermatol 2008;159:1092-102.
72. Kurahashi R, Hatano Y, Katagiri K. IL-4 suppresses the recovery of cutaneous
permeability barrier functions in vivo. J Invest Dermatol 2008;128:1329-31.
73. Hatano Y, Terashi H, Arakawa S, Katagiri K. Interleukin-4 suppresses the
enhancement of ceramide synthesis and cutaneous permeability barrier func-
tions induced by tumor necrosis factor-alpha and interferon-gamma in human
epidermis. J Invest Dermatol 2005;124:786-92.
74. Elias PM. Therapeutic implications of a barrier-based pathogenesis of atopic
dermatitis. Ann Dermatol 2010;22:245-54.
75. Fujita H. The role of IL-22 and Th22 cells in human skin diseases. J Dermatol
Sci 2013;72:3-8.
76. Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F. IL-22
inhibits epidermal differentiation and induces proinflammatory gene expres-
sion and migration of human keratinocytes. J Immunol 2005;174:3695-702.
77. Liu YJ. Thymic stromal lymphopoietin: master switch for allergic inflamma-
tion. J Exp Med 2006;203:269-73.
78. Ziegler SF, Liu YJ. Thymic stromal lymphopoietin in normal and pathogenic T
cell development and function. Nat Immunol 2006;7:709-14.
79. Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N, et al.
TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell
response through OX40 ligand. J Exp Med 2005;202:1213-23.
80. De Benedetto A, Kubo A, Beck LA. Skin barrier disruption: a requirement for
allergen sensitization? J Invest Dermatol 2012;132:949-63.
81. Darsow U, Laifaoui J, Kerschenlohr K, Wollenberg A, Przybilla B,
Wuthrich B, et al. The prevalence of positive reactions in the atopy patch test
with aeroallergens and food allergens in subjects with atopic eczema: a Eu-
ropean multicenter study. Allergy 2004;59:1318-25.
82. Landheer J, Giovannone B, Mattson JD, Tjabringa S, Bruijnzeel-Koomen CA,
McClanahan T, et al. Epicutaneous application of house dust mite induces
thymic stromal lymphopoietin in nonlesional skin of patients with atopic
dermatitis. J Allergy Clin Immunol 2013;132:1252-4.
83. Wang YH, Angkasekwinai P, Lu N, Voo KS, Arima K, Hanabuchi S, et al. IL-
25 augments type 2 immune responses by enhancing the expansion and
functions of TSLP-DC-activated Th2 memory cells. J Exp Med 2007;204:
1837-47.
84. Owyang AM, Zaph C, Wilson EH, Guild KJ, McClanahan T, Miller HR, et al.
Interleukin 25 regulates type 2 cytokine-dependent immunity and limits
chronic inflammation in the gastrointestinal tract. J Exp Med 2006;203:843-9.
85. Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, et al. IL-25 induces IL-
4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 2001;15:
985-95.
86. Hvid M, Vestergaard C, Kemp K, Christensen GB, Deleuran B, Deleuran M.
IL-25 in atopic dermatitis: a possible link between inflammation and skin
barrier dysfunction? J Invest Dermatol 2011;131:150-7.
87. Gudjonsson JE, Ding J, Li X, Nair RP, Tejasvi T, Qin ZS, et al. Global gene
expression analysis reveals evidence for decreased lipid biosynthesis and
increased innate immunity in uninvolved psoriatic skin. J Invest Dermatol
2009;129:2795-804.
88. Matsumoto M, Sugiura H, Uehara M. Skin barrier function in patients with
completely healed atopic dermatitis. J Dermatol Sci 2000;23:178-82.
89. Jensen JM, Folster-Holst R, Baranowsky A, Schunck M, Winoto-Morbach S,
Neumann C, et al. Impaired sphingomyelinase activity and epidermal differ-
entiation in atopic dermatitis. J Invest Dermatol 2004;122:1423-31.
8 CZARNOWICKI ET AL
90. Di Nardo A, Wertz P, Giannetti A, Seidenari S. Ceramide and cholesterol
composition of the skin of patients with atopic dermatitis. Acta Derm Venereol
1998;78:27-30.
91. Werner Y, Lindberg M. Transepidermal water loss in dry and clinically normal
skin in patients with atopic dermatitis. Acta Derm Venereol 1985;65:102-5.
92. Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene
expression in acute versus chronic atopic dermatitis. J Clin Invest 1994;94:
870-6.
93. Suarez-Farinas M, Tintle SJ, Shemer A, Chiricozzi A, Nograles K, Cardinale I,
et al. Nonlesional atopic dermatitis skin is characterized by broad terminal
differentiation defects and variable immune abnormalities. J Allergy Clin
Immunol 2011;127:954-964.e1-4.
94. Tintle S, Shemer A, Suarez-Farinas M, Fujita H, Gilleaudeau P, Sullivan-
Whalen M, et al. Reversal of atopic dermatitis with narrow-band UVB pho-
totherapy and biomarkers for therapeutic response. J Allergy Clin Immunol
2011;128:583-593.e1-4.
95. Khattri S, Shemer A, Rozenblit M, Suárez-Fariñas M, Dhingra N,
Czarnowicki T, et al. Cyclosporine a in atopic dermatitis modulates activated
inflammatory pathways and reverses epidermal pathology. J Allergy Clin
Immunol 2014. In press.
96. Proksch E, Folster-Holst R, Jensen JM. Skin barrier function, epidermal pro-
liferation and differentiation in eczema. J Dermatol Sci 2006;43:159-69.
97. Wollenberg A, Wen S, Bieber T. Phenotyping of epidermal dendritic cells:
clinical applications of a flow cytometric micromethod. Cytometry 1999;37:
147-55.
98. Semper AE, Heron K, Woollard ACS, Kochan JP, Friedmann PS, Church MK,
et al. Surface expression of Fc epsilon RI on Langerhans’ cells of clinically
uninvolved skin is associated with disease activity in atopic dermatitis, allergic
asthma, and rhinitis. J Allergy Clin Immunol 2003;112:411-9.
99. Wollenberg A, Ehmann LM. Long term treatment concepts and proactive
therapy for atopic eczema. Ann Dermatol 2012;24:253-60.
100. Macheleidt O, Kaiser HW, Sandhoff K. Deficiency of epidermal protein-bound
omega-hydroxyceramides in atopic dermatitis. J Invest Dermatol 2002;119:
166-73.
101. Darsow U, Lubbe J, Taieb A, Seidenari S, Wollenberg A, Calza AM, et al.
Position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad
Dermatol Venereol 2005;19:286-95.
102. Wollenberg A, Bieber T. Proactive therapy of atopic dermatitis: an emerging
concept. Allergy 2009;64:276-8.
103. Berth-Jones J, Damstra RJ, Golsch S, Livden JK, Van Hooteghem O,
Allegra F, et al. Twice weekly fluticasone propionate added to emollient
maintenance treatment to reduce risk of relapse in atopic dermatitis: rando-
mised, double blind, parallel group study. BMJ 2003;326:1367.
104. Hanifin J, Gupta AK, Rajagopalan R. Intermittent dosing of fluticasone pro-
pionate cream for reducing the risk of relapse in atopic dermatitis patients. Br J
Dermatol 2002;147:528-37.
105. Wollenberg A, Reitamo S, Atzori F, Lahfa M, Ruzicka T, Healy E, et al.
Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus oint-
ment. Allergy 2008;63:742-50.
106. Fukuie T, Nomura I, Horimukai K, Manki A, Masuko I, Futamura M, et al.
Proactive treatment appears to decrease serum immunoglobulin-E levels in
patients with severe atopic dermatitis. Br J Dermatol 2010;163:1127-9.
107. Bieber T, Dannenberg B, Prinz JC, Rieber EP, Stolz W, Braun-Falco O, et al.
Occurrence of IgE-bearing epidermal Langerhans cells in atopic eczema: a
study of the time course of the lesions and with regard to the IgE serum level.
J Invest Dermatol 1989;93:215-9.
108. Bieber T, de la Salle H, Wollenberg A, Hakimi J, Chizzonite R, Ring J, et al.
Human epidermal Langerhans cells express the high affinity receptor for
immunoglobulin E (Fc epsilon RI). J Exp Med 1992;175:1285-90.
109. Novak N, Bieber T. The skin as a target for allergic diseases. Allergy 2000;55:
103-7.
110. Schmid P, Simon D, Simon HU, Akdis CA, Wuthrich B. Epidemiology,
clinical features, and immunology of the “intrinsic” (non-IgE-mediated) type
of atopic dermatitis (constitutional dermatitis). Allergy 2001;56:841-9.
111. Altrichter S, Kriehuber E, Moser J, Valenta R, Kopp T, Stingl G. Serum IgE
autoantibodies target keratinocytes in patients with atopic dermatitis. J Invest
Dermatol 2008;128:2232-9.
112. Gould HJ, Sutton BJ, Beavil AJ, Beavil RL, McCloskey N, Coker HA, et al.
The biology of IGE and the basis of allergic disease. Annu Rev Immunol 2003;
21:579-628.
113. Kabashima-Kubo R, Nakamura M, Sakabe J, Sugita K, Hino R, Mori T, et al.
A group of atopic dermatitis without IgE elevation or barrier impairment shows
J ALLERGY CLIN IMMUNOL PRACT
MONTH 2014
a high Th1 frequency: possible immunological state of the intrinsic type.
J Dermatol Sci 2012;67:37-43.
114. Wuthrich B, Schmid-Grendelmeier P. The atopic eczema/dermatitis syndrome:
epidemiology, natural course, and immunology of the IgE-associated
(“extrinsic”) and the nonallergic (“intrinsic”) AEDS. J Investig Allergol Clin
Immunol 2003;13:1-5.
115. Mori T, Ishida K, Mukumoto S, Yamada Y, Imokawa G, Kabashima K, et al.
Comparison of skin barrier function and sensory nerve electric current
perception threshold between IgE-high extrinsic and IgE-normal intrinsic types
of atopic dermatitis. Br J Dermatol 2010;162:83-90.
116. Brenninkmeijer EEA, Spuls PI, Legierse CM, Lindeboom R, Smitt JHS,
Bos JD. Clinical differences between atopic and atopiform dermatitis. J Am
Acad Dermatol 2008;58:407-14.
117. Suarez-Farinas M, Dhingra N, Gittler J, Shemer A, Cardinale I, Strong CD,
et al. Intrinsic atopic dermatitis shows similar T(H)2 and higher T(H)17 im-
mune activation compared with extrinsic atopic dermatitis. J Allergy Clin
Immunol 2013;132:361-70.
118. Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, Haider AS,
et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T
cells. J Invest Dermatol 2008;128:1207-11.
119. Kryczek I, Bruce AT, Gudjonsson JE, Johnston A, Aphale A, Vatan L, et al.
Induction of IL-17þ T cell trafficking and development by IFN-gamma:
mechanism and pathological relevance in psoriasis. J Immunol 2008;181:
4733-41.
120. Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T,
et al. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic
dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin
Immunol 2009;123:1244-1252.e2.
121. Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y. Possible path-
ogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol 2008;128:
2625-30.
122. Yamaguchi H, Kabashima-Kubo R, Bito T, Sakabe J, Shimauchi T, Ito T, et al.
High frequencies of positive nickel/cobalt patch tests and high sweat nickel
concentration in patients with intrinsic atopic dermatitis. J Dermatol Sci 2013;
72:240-5.
123. Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J Dermatol Sci
2010;58:1-7.
124. Miraglia del Giudice M, Decimo F, Leonardi S, Maioello N, Amelio R,
Capasso A, et al. Immune dysregulation in atopic dermatitis. Allergy Asthma
Proc 2006;27:451-5.
125. Weidinger S, Rodriguez E, Stahl C, Wagenpfeil S, Klopp N, Illig T, et al.
Filaggrin mutations strongly predispose to early-onset and extrinsic atopic
dermatitis. J Invest Dermatol 2007;127:724-6.
126. Akdis CA, Akdis M. Immunological differences between intrinsic and
extrinsic types of atopic dermatitis. Clin Exp Allergy 2003;33:1618-21.
127. Akdis M, Akdis CA, Weigl L, Disch R, Blaser K. Skin-homing, CLA(þ)
memory T cells are activated in atopic dermatitis and regulate IgE by an IL-13-
dominated cytokine pattern: IgG4 counter-regulation by CLA(-) memory T
cells. J Immunol 1997;159:4611-9.
128. Suarez-Farinas M, Gittler JK, Shemer A, Cardinale I, Krueger JG, Guttman-
Yassky E. Residual genomic signature of atopic dermatitis despite clinical
resolution with narrow-band UVB. J Allergy Clin Immunol 2013;131:577-9.
129. Behshad R, Cooper KD, Korman NJ. A retrospective case series review of the
peroxisome proliferator-activated receptor ligand rosiglitazone in the treatment
of atopic dermatitis. Arch Dermatol 2008;144:84-8.
130. Haw S, Shin MK, Haw CR. The efficacy and safety of long-term oral cyclo-
sporine treatment for patients with atopic dermatitis. Ann Dermatol 2010;22:
9-15.
131. Babu KS, Polosa R, Morjaria JB. Anti-IgE: emerging opportunities for
Omalizumab. Expert Opin Biol Ther 2013;13:765-77.
132. Kim JY, Park JS, Park JC, Kim ME, Nahm DH. Double-filtration plasma-
pheresis for the treatment of patients with recalcitrant atopic dermatitis. Ther
Apher Dial 2013;17:631-7.
133. Blauvelt A. T-helper 17 cells in psoriatic plaques and additional genetic links
between IL-23 and psoriasis. J Invest Dermatol 2008;128:1064-7.
134. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17,
Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 2010;130:
1373-83.
135. Suarez-Farinas M, Li K, Fuentes-Duculan J, Hayden K, Brodmerkel C,
Krueger JG. Expanding the psoriasis disease profile: interrogation of the skin
and serum of patients with moderate-to-severe psoriasis. J Invest Dermatol
2012;132:2552-64.