DOI: 10.1111/j.1365-3164.2011.00967.
Current evidence of skin barrier dysfunction in human
and canine atopic dermatitis
Rosanna Marsella*, Thierry Olivry† and
Didier-Noel Carlotti‡ for the International Task
Force on Canine Atopic Dermatitis
*Department of Small Animal Clinical Sciences, College of Veterinary
Medicine, University of Florida, Gainesville, FL, USA
†Department of Clinical Sciences, College of Veterinary Medicine,
North Carolina State University, Raleigh, NC, USA
‡Aquivet Clinique VétérinaireService de DermatologieParc d’Activités
MermozAvenue de la ForêtF, Eysines, Bordeaux
Correspondence: Rosanna Marsella, Department of Small Animal
Clinical Sciences, College of Veterinary Medicine, University of
Florida, Gainesville, FL, USA. E-mail: marsella@ufl.edu
Sources of Funding
This study is self-funded.
Conflict of Interest
No conflicts of interest have been declared.
Abstract
Atopic dermatitis (AD) is a multifaceted disease
resulting from a complex interaction between envi-
ronmental and genetic factors. Both of these factors
can shape skin barrier function and the immunologi-
cal response of predisposed patients. There is
increasing evidence that an impaired skin barrier
plays a role in both human and canine AD. Although
many primary skin barrier defects had already been
documented in the past in humans, the recent identi-
fication of the filaggrin mutations and the fact that
such mutations are now considered the most impor-
tant risk factor for development of AD have further
emphasized the relevance of epidermal dysfunction
in human AD. Much less is known in veterinary medi-
cine, but evidence is rapidly building to support a role
for skin barrier dysfunction in canine AD. Canine AD
shares many clinical and immunological similarities
with its human counterpart. The similar distribution
of clinical lesions and the importance of the epicuta-
neous route of allergen exposure provided the
incentive to investigate the role of skin barrier impair-
ments in canine AD. The purpose of this comparative
review is to present the current evidence of barrier
dysfunction in both human and canine AD.
Accepted 27 January 2011
Introduction
Atopic dermatitis (AD) is a multifaceted disease resulting
from a complex interaction between environmental and
genetic factors. Both of these factors can shape skin
ª 2011 The Authors. Veterinary Dermatology
ª 2011 ESVD and ACVD, Veterinary Dermatology, 22, 239–248.
barrier function and the immunological response of
predisposed patients. There is increasing evidence that
an impaired skin barrier plays a role in both human and
canine AD. Although many primary skin barrier defects
had already been documented in the past in humans, the
recent identification of the filaggrin mutations and the
fact that such mutations are now considered the most
important risk factor for development of AD have fur-
ther emphasized the relevance of epidermal dysfunction
in human AD.1,2 It is currently proposed that geneti-
cally inherited mutations affecting barrier function in
conjunction with acquired environmental stressors lead
to increased allergen penetration. This promotes a
T-helper 2 (Th2) shift that further aggravates the skin bar-
rier.3 Bacterial colonization further worsens the skin bar-
rier (bacterial ceramidases, for example, can contribute to
ceramide deficiency in atopic skin)4 creating a self-perpet-
uating cycle of inflammation, pruritus and additional sensi-
tizations.3
Much less is known in veterinary medicine, but evi-
dence is rapidly building to support a role for skin barrier
dysfunction in canine AD. Canine AD shares many clinical
and immunological similarities with its human counter-
part.5 The similar distribution of clinical lesions6 and the
importance of the epicutaneous route of allergen expo-
sure7–9 provided the incentive to investigate the role of
skin barrier impairments in canine AD. The purpose of this
comparative review is to present the current evidence of
barrier dysfunction in both human and canine AD.
Human medicine: human atopic dermatitis
Methods to assess barrier function
Barrier function can be assessed in a variety of ways.10,11
The integrity of the skin barrier can be assessed objec-
tively in a noninvasive way by measuring transepidermal
water loss (TEWL).12,13 Skin barrier function as assessed
by TEWL is intrinsically compromised in children with AD
but not in children with other allergic conditions.14 The
magnitude of increase in TEWL correlates with AD sever-
ity.14,15 The TEWL is higher in AD patients16–19 than in
healthy control subjects, even in clinically unaffected
areas.20 In humans, TEWL varies between anatomical
sites,21–23 and it is affected by a variety of factors, such
as the age of the patient,22,24,25 but it is not linked to
particular genetic mutations.26 Measurement of TEWL,
moreover, allows assessment of otherwise unnoticed
damage to the epidermal water barrier in nonlesional skin.
Interestingly, TEWL has been reported to be higher in
patients with extrinsic AD than in patients with the intrin-
sic form (patients with AD in whom allergen-specific IgE
is not detectable).27 Patients with the intrinsic form have
239
Marsella et al.
been documented to retain a normal barrier function and
sensory reactivity to external pruritic stimuli.27 The advan-
tages and disadvantages of various TEWL-measuring
devices (i.e. evaporimeters) have been investigated.28 In
open-chamber devices, the probe consists of a cylindrical
open chamber with two sensors mounted in the diffusion
chamber to measure the humidity and the temperature.
The open-chamber devices are based on the diffusion
principle, in which the water vapour pressure gradient is
indirectly measured by two pairs of combined thermistors
and hygrosensors, present at two different heights inside
a hollow cylinder. The water pressure measured in the
chamber is used to calculate the evaporated water over a
constant skin area. The probe head is placed horizontally
on the skin at a constant pressure, and its small size
minimizes the influence of air turbulence inside the probe.
The measuring usually takes between 30 and 40 s. Criti-
cisms of this traditional open system are related to
effects of ambient and body-induced airflows near the
probe, probe size, the limitation of measurement sites
and application ⁄ probe angles. Other important factors to
consider during TEWL measurements with an open-
chamber method are air convection, room temperature
and ambient humidity. Another consideration is that vola-
tile agents, other than water, might affect the readings
(e.g. when measurements are made immediately after
application of moisturizers).
Closed-chamber devices use a closed, unventilated
chamber system, which is not affected by ambient or
body-induced airflows. Closed-chamber conditions are
created upon skin contact with a surface area of 1 cm
diameter, and the measuring time is between 8 and 10 s.
It has been proposed that closed-chamber devices
allowed measurements at any angle, had short reading
times and were insensitive to external air currents. A
recent study reported that both open- and closed-cham-
ber devices are able to estimate water loss rates accu-
rately when held in a vertical position.28 Even though
closed-chamber evaporimeters might be easier to use
than open-chamber devices, their tendency to become
saturated in conditions of high water loss are a disadvan-
tage when assessing TEWL dynamically.28 Open- and
closed-chamber TEWL readings, furthermore, correlate
well.29 The TEWL values of healthy volunteers were mea-
sured simultaneously with three closed- and open-cham-
ber devices in the same room according to the guidelines
of the standardization group of the European Society of
Contact Dermatitis, and there was no statistically signifi-
cant difference between the mean forearm TEWL values
measured by all three instruments. The authors con-
cluded that the TEWL values measured by all instruments
were constant, with small standard deviations.30
As TEWL measurements appear to be variable, it has
been suggested that continuous assessment of the epi-
dermal water barrier by multiple TEWL measurements
over longer periods of time would decrease the risk of
mistakes and increase accuracy.31
Skin capacitance is another parameter used to assess
the skin barrier function. Electrical skin capacitance mea-
sures the hydration of the stratum corneum and provides
an estimate of cutaneous capacity to retain moisture.
Capacitance has been shown to affect the balance of
240
epidermal cell proliferation and differentiation. Higher skin
hydration values indicate greater cutaneous water capaci-
tance.32
Chemical and enzymatic abnormalities in the atopic
epidermis
Lipids
The stratum corneum, composed of flattened keratino-
cytes and lipids, is crucial for the protective functions of
the skin. Lipids in this layer are composed primarily of
free fatty acids, cholesterol and ceramides. Ceramides, in
particular, are the dominant lipids, constituting approxi-
mately 50% of the human stratum corneum lipids,33 and
play a crucial role in skin barrier function.34,35 Ceramides
are also the the most heterogeneous of the epidermal
lipids and include 11 different molecules.36 Ceramides
are generated from a sphingoid base and a fatty acid.
Sphingoid bases include, but are not limited to, sphingo-
sin, dihydro-sphingosin and phyto-sphingosin. Over the
last few years, critical enzymes in ceramide biosynthesis,
including ceramide synthases and ceramide hydroxy-
lase ⁄ desaturase, have been identified.37 Ceramide syn-
thesis is upregulated in the basal cell layer. Ceramides are
then rapidly converted into glucosyl-ceramides and
sphingomyelins that are then packed into the lamellar
bodies. Once the content of these organelles is released
at the interface between the stratum granulosum and
stratum corneum, ceramides are regenerated by hydroly-
sis by b-glucocerebrosidase and sphingomyelinase Thus,
ceramide levels in the stratum corneum are regulated by
a balance between synthetic enzymes (e.g. b-glucocere-
brosidase and sphingomyelinase) and ceramidases
(which are responsible for their degradation). Ceramidas-
es may be endogenous or exogenous (e.g. from bacte-
ria).4
Impaired skin barrier function in human AD has been
linked to a variety of epidermal abnormalities, although it
is unclear whether they are primary, secondary or both.
The stratum corneum of atopic skin is characterized bio-
chemically by a reduction in the amounts of ceramides,
especially ceramide-1, sebum lipids and water-soluble
amino acids,38 although one study reported normal levels
of ceramides in uninvolved atopic skin.39 In atopic individ-
uals, decreased epidermal sphingomyelinase activity is
found in both nonlesional and, more significantly, lesional
skin, correlating with reduced stratum corneum ceramide
content and disturbed barrier function.40 This is associ-
ated with impaired expression of cornified envelope
proteins and keratins important for skin barrier function.
Another mechanism for decreased ceramides in atopic
skin is the decreased biosynthesis of free glucosylcera-
mides and ceramides.38
Some studies have proposed that ceramide deficiency
is linked to a novel sphingolipid-metabolizing enzyme,
termed sphingomyelin glucosylceramide deacylase,41–43
which hydrolyses sphingomyelin or glucosylceramide,
decreasing their availability for synthesis of ceramides.
The enzymatic characteristics of the sphingomyelin
glucosylceramide deacylase are completely distinct from
ceramidase as well as the other known deacylases.41,42
Sphingomyelin glucosylceramide deacylase activity is
ª 2011 The Authors. Veterinary Dermatology
ª 2011 ESVD and ACVD, Veterinary Dermatology, 22, 239–248.

enhanced more than fivefold in lesional stratum corneum,
more than threefold in uninvolved stratum corneum and
approximately threefold in the involved epidermis from
patients with AD compared with healthy control sub-
jects.41,42 This increased enzymatic activity appears to be
specific to AD and is not detected in patients with contact
dermatitis, who have the same enzymatic activity as
healthy control subjects.41 It is interesting to note that, in
peripheral blood lymphocytes of AD patients, there is no
increase in activity compared with healthy control sub-
jects, indicating that the high expression of sphingomye-
lin deacylase is highly associated with the skin of AD
patients.44 In one study, a lack of phosphatidylcholine–
sphingomyelin transacylase activity was also proposed as
an underlying defect in human AD, although the number
of samples evaluated in that study was too small to draw
final conclusions.45
In summary, lipid deficiency, especially of ceramides,
in the skin of atopic patients is considered an important
component of the disease. Furthermore, treatments
aimed at correcting such deficiencies, by topical applica-
tion of lipid preparations, have been reported to amelio-
rate clinical signs.46,47
Proteins
Proteins important in the epidermal differentiation ⁄ cornifi-
cation process have also been reported to be decreased
in patients with AD. Filaggrin is undoubtedly the most dis-
cussed protein at the moment. An early study reported
decreased expression of filaggrin in the skin of atopic
patients in both lesional and clinically unaffected skin.48
The more recent report of loss-of-function mutations in
the gene encoding for filaggrin (FLG)49 has triggered
large-scale investigation of the genetic mutations in FLG
in a variety of populations.50–52 Of all the genes previously
investigated as candidates for the development of AD,
FLG is currently considered the most important, and
FLG mutations are thought to be a major risk factor for
AD.53–55 It is accepted that FLG mutations predispose to
allergic sensitizations and to the development of early-
onset, extrinsic disease that persists into adulthood.56–59
It is, however, important to note that decreased filaggrin
expression does not necessarily imply a genetic mutation,
because filaggrin can be reduced by Th2 cytokines.60
Decreased expression in the skin of some patients may
therefore be a secondary phenomenon or may result
from epigenetic modifications. Nevertheless, decreased
filaggrin expression may still be clinically relevant in atopic
individuals lacking the FLG mutations. It is estimated that
only 18–48% of all eczema patients have FLG muta-
tions,61 and that 40% of individuals with the FLG null
alleles have never had signs of eczema.62 These consid-
erations highlight the fact that that the link between FLG
mutations and AD is not a simple and direct one and that
AD is the result of a complex interaction between genetic
and environmental factors.63
Interestingly, flaky tail (Flgft) mice, essentially deficient
in filaggrin, have been used to investigate the role of
filaggrin in AD. In specific pathogen-free conditions, the
majority of Flgft mice develop clinical and histological
eczematous skin lesions similar to human AD with
outside-to-inside skin barrier dysfunction, suggesting that
ª 2011 The Authors. Veterinary Dermatology
ª 2011 ESVD and ACVD, Veterinary Dermatology, 22, 239–248.
Skin barrier dysfunction in atopic dermatitis
the Flgft mouse genotype has potential as an animal
model of AD corresponding to FLG mutation in human
AD.64
Epidermal proteases and protease inhibitors
Skin barrier function in AD is impaired by a variety of
mechanisms. Besides mutations in the genes encoding
for proteins, there is also evidence of mutations in the
genes encoding for proteases and protease inhibitors.
This could lead to increased desquamation and an
impaired skin barrier. Desquamation is determined by a
cocktail of proteases (e.g. serine, cysteine and aspartic
proteases) regulated by protease inhibitors.65
Human tissue kallikreins (KLKs) are a family of 15 tryp-
sin- or chymotrypsin-like secreted serine proteases
(KLK1–KLK15) important for desquamation.66 Many KLKs
have been identified in normal stratum corneum and
sweat, including KLK7 (also called stratum corneum chy-
motryptic enzyme, SCCE) and KLK5 (also called stratum
corneum tryptic enzyme, SCTE). A mutation in the gene
encoding for KLK7 ⁄ SCCE has been described in some
human patients with AD. This mutation leads to a change
in activity and increased desquamation, particularly at
alkaline pH.67 This genetic associationwas not confirmed
in other studies, however, and there are no additive
effects of mutations on phenotype.26 In the stratum
corneum of AD patients, all kallikreins, except KLK11, have
been reported to be significantly elevated.68 Alterations of
the levels of KLKs in the stratum corneum of atopic
patients are more pronounced than those in the serum.66
In a recent study investigating stratum corneum thick-
ness and proteases, it was found that lesional atopic skin
had a significantly thinner stratum corneum and that ser-
ine protease activity [stratum corneum tryptase-like
enzyme (45-fold), plasmin (30-fold), urokinase (7.1-fold),
trypsin-like KLKs (5.8-fold) and chymotrypsin-like KLKs
(3.9-fold)] were increased in atopic skin when compared
with healthy control subjects.69 The increased serine pro-
tease activities were found in acute eczematous AD,
especially in deeper layers of the stratum corneum.67
These elevations in protease activities were associated
with impaired barrier function, irritation and reduced skin
capacitance (a measurement of the stratum corneum
hydration). Elevations of some serine proteases (e.g. plas-
min and urokinase) are, however, not specific for AD, but
can be found in other circumstances in which the skin
barrier is disrupted.70 Protease activity was also found to
correlate with clinical staging of AD (i.e. clinical scores)
and tended to normalize as the disease regressed.71
Whether increased proteases are the cause or simply a
marker of disease activity remains unknown. Cells within
the inflammatory infiltrate (e.g. mast cells) can produce
proteases (e.g. chymase, a chymotrypsin-like serine pro-
teinase),72 which can further contribute to the disruption
of the skin barrier. This makes it difficult to separate
cause from effect.
Proteases are regulated by protease inhibitors. A partic-
ularly important, pH-dependent protease inhibitor is
lymphoepithelial Kazal-type 5 serine protease inhibitor
(LEKTI), which is encoded by the serine protease inhibitor
Kazal-type 5 (SPINK5) gene.73 The most convincing
evidence for a role of excessive serine protease activity in
241
Marsella et al.
AD comes from Netherton syndrome, a disease associ-
ated with loss-of-function mutations in SPINK5 and
decreased LEKTI. Patients with this condition have
severe AD and high IgE. Their stratum corneum is extre-
mely thin, resulting in severe skin barrier defects. A signif-
icant association with atopy, AD and Netherton syndrome
has been reported.74 The pathogenic role of serine prote-
ase inhibitor LEKTI in AD has been recently questioned
owing to contradictory results from the analyses of an
association between genetic polymorphisms of SPINK5
and AD. The association of AD with SPINK5 polymor-
phisms and AD has been reported by some studies75,76
but not confirmed by other authors.26 A recent study
reported that expression of LEKTI was significantly
decreased in atopic patients compared with healthy vol-
unteers.77 Due to reduced protease inhibition, trypsin-like
hydrolytic activity in AD was slightly increased, although
not significantly.74 The authors of the study concluded
that functional analyses in addition to genetic investiga-
tions are necessary to gain further and more detailed
insights into the role of LEKTI in AD.
Ultrastructural evaluation
It has long been known that water permeability of the
stratum corneum is regulated primarily by the lamellar
arrangement of lipid bilayers between the corneocytes.78
The process of postsecretory extracellular development
of the lamellar body has been investigated in detail in
healthy skin in electron microscopy studies.79 These
investigations found that there are differences between
inner and outer parts of the stratum corneum, in terms of
both lipid lamellae and corneodesmosomes.77 Differ-
ences have been reported in the relative volume of lamel-
lar bodies in the upper layers of the stratum corneum
between atopic patients and healthy control subjects.80
Lamellar bodies remain undelivered within the cells of the
uppermost stratum granulosum cell layer of humans with
AD (26% in atopics versus 8% in control subjects,
P < 0.01). The authors concluded that a pathological fail-
ure to extrude lamellar bodies in AD may be at least partly
responsible for the lipid abnormalities and skin barrier
impairments observed in affected patients. Additionally,
lipid lamellae appear misshapen and decreased in number
when compared with healthy control subjects.78 No addi-
tional studies have specifically evaluated this proposed
defect of extrusion.
Veterinary medicine: canine atopic
dermatitis
Methods to assess the barrier function
The validity and reliability of TEWL measurements in dogs
remains controversial. There are few studies that have
attempted to validate either open-81 or closed-chamber82
devices to measure TEWL in healthy dogs. For example,
one study evaluated the correlation between skin barrier
function and TEWL in healthy dogs using a closed-
chamber technique.83 This showed that increases in
TEWL correlated with the frequency of tape stripping and
inversely correlated with the thickness of the stratum
corneum, reflecting impaired barrier function. In contrast,
other reports provide evidence of very high day-to-day
242
variation and do not recommend the use of TEWL mea-
surements made with either open84 or closed appara-
tus.85 As suggested recently,85 the high variability of site-
to-site, day-to-day and dog-to-dog TEWL measurements
makes this technique largely unsuitable for measurement
of changes associated with disease state or clinical trials
testing interventions aimed at improving skin barrier func-
tion in dogs. A recent study evaluated TEWL and skin
capacitance before and after anaesthesia in 14 body
regions.86 The TEWL was highest for the footpad and
head and lowest for the inguinal region. Following anaes-
thesia, TEWL and skin hydration were significantly lower
on the head, upper back and footpad, and upper back and
elbow, respectively, while skin pH was unaffected by this
procedure. The authors concluded that while measure-
ment of pH would seem to be valid anywhere on the body
in anaesthetized dogs, regional factors should be consid-
ered when interpreting TEWL and skin hydration values
and when treating regional skin diseases in veterinary
practice. The variability in TEWL measurements is much
larger than that reported in human medicine in
recent studies comparing open- and closed-chamber
devices.27,29 This may be partly attributable to the
presence of hair and movement of the subject during
measurements.79 A recent study indicated that clipping
methods and anatomical site selection should be stan-
dardized in order to minimize the experimental variation in
TEWL measurement in dogs even when closed-chamber
devices are used.87 This study also reported that among
the clipped sites, the upper back was the most appropri-
ate site for TEWL measurement 48 h after clipping,
whereas among the unclipped sites, the ear was the
most appropriate. The TEWL values from those anatomi-
cal sites had the least fluctuation and were less affected
by movement.84
Studies on TEWL in dogs with AD are limited. One
study evaluating TEWL using an open-chamber method
in a colony of atopic beagles found that atopic dogs had
significantly higher TEWL than healthy beagles, particu-
larly at the sites predisposed to development of AD, even
if they appeared clinically unaffected.88 These findings
were especially marked in young dogs. Taking into
consideration the technical limitations described above,
these results indicate that an impaired skin barrier might
exist in experimental canine AD, even in atopic skin that
appears clinically unaffected. Whether this is due to a
primary defect or is secondary to subclinical inflammation
is unknown at this time. A similar increase of TEWL in
dogs with AD compared with healthy dogs was also
found in patients with spontaneous disease using a
closed-chamber technique.80 In that study, increases in
TEWL were correlated with reduced proportions of
ceramides in lesional and nonlesional skin.80
Chemical and enzymatic abnormalities in canine
atopic epidermis
Lipids
Preliminary evidence shows that ceramides are
decreased in the skin of dogs with AD, and that this
defect might possibly contribute to impairment of the skin
barrier. In a recent study, intercellular lipids were
ª 2011 The Authors. Veterinary Dermatology
ª 2011 ESVD and ACVD, Veterinary Dermatology, 22, 239–248.

extracted from the stratum corneum of the inguinal area
of both atopic and healthy dogs and quantified by
thin-layer chromatography.80 It was found that levels of
ceramides in lesional and clinically unaffected skin of
atopic dogs were significantly lower than in healthy dogs,
but there were no differences in cholesterol and free fatty
acids.80 In another, more recent study, the stratum corne-
um ceramide contents of samples from clinically unaf-
fected canine atopic skin were found to have decreased
percentages of ceramides 1 and 9, and increased per-
centages of cholesterol compared with samples from no-
natopic dogs.89 Unfortunately, the total amount of skin
lipids was not determined, and whether or not there is a
true deficiency of ceramides 1 and ⁄ or 9 in atopic dogs is
unclear.
Proteins
Limited information exists on the expression of proteins,
such as filaggrin, in atopic and healthy canine skin. A pilot
study investigated expression of filaggrin in the skin of
various animal species, including the dog.90 Immuno-
staining of healthy canine skin with a polyclonal antihu-
man filaggrin antiserum established that filaggrin was
expressed in keratohyalin granules in the cytoplasm of
the stratum granulosum, as in other species.90 A preli-
minary study in an experimental model of atopic beagles
using another polyclonal antibody directed against human
filaggrin showed an abnormal pattern and decreased
immunostaining for skin filaggrin in atopic dogs when
compared with healthy beagles.91 This antiserum recog-
nized intracellular granular antigenic epitopes in both the
stratum granulosum and the lower epidermal layers, sug-
gesting that proteins other than filaggrins (perhaps kera-
tins) were also identified. A more recent study evaluated
the same colony of atopic beagles and age- and breed-
matched healthy control dogs using a polyclonal antibody
specific for canine filaggrin.92 Skin biopsies were taken
before and after allergen challenge, and filaggrin mRNA
was quantified using quantitative real-time PCR. Indirect
immunofluorescence was also used to localize filaggrin
protein expression. It was found that filaggrin fluores-
cence was distributed homogeneously in the stratum
granulosum and the lower layers of the stratum corneum
of healthy dogs, while in atopic dogs a patchy pattern
was visible after house dust mite allergen challenge, sug-
gesting that the changes might be secondary to atopic
inflammation. In another recent study, immunofluores-
cence microscopy was performed in healthy and atopic
dogs with naturally occurring disease using an antibody
raised against the canine filaggrin C-terminus and a com-
mercial antibody directed against the N-terminal segment
of human filaggrin.93 Four distinctive filaggrin expression
patterns were identified in nonlesional skin. It was found
that 10 of 18 dogs with AD exhibited an identical pattern
for both antibodies with comparable (category I, three of
18) or reduced expression (category II, seven of 18) com-
pared with that of control dogs. In contrast, four of 18
dogs displayed aberrant large vesicles revealed by the
C-terminal but not the N-terminal antibody (category III),
while four of 18 showed a control-like N-terminal expres-
sion but lacked the C-terminal protein (category IV). The
missing C-terminal filaggrin in category IV strongly points
ª 2011 The Authors. Veterinary Dermatology
ª 2011 ESVD and ACVD, Veterinary Dermatology, 22, 239–248.
Skin barrier dysfunction in atopic dermatitis
towards mutations resulting in a truncated filaggrin in
four of 18 (22%) of all atopic dogs analysed. The authors
concluded that, in dogs with filaggrin-deficient AD, the
disease is a suitable model to study the barrier dysfunc-
tion typical of the human disease. Finally, a recent study
evaluating possible filaggrin mutations in West Highland
white terriers excluded a major causative role for the Flg
orthologue in AD in this breed.94 The authors did not,
however, exclude the possibility of Flg mutations with
small effect sizes. A lack of linkage of AD in West
Highland white terriers with the FLG has also been
excluded in West Highland white terriers of US lines (C.
Salzman, T. Olivry, D. Nielsen and N. Olby, unpublished
observations).
Proteases and protease inhibitors
Very limited information is currently available on the
role of proteases and their inhibitors in the canine dis-
ease. A recent study investigating gene transcription in
biopsies from dogs with AD reported that significant dif-
ferences existed in mRNA expression between normal
and atopic dogs for SPINK5, mast cell protease I, dipept-
idyl-peptidase-4, phosphatidylinositol-3,4,5-trisphosphate-
5-phosphatase-2 and sphingosine-1-phosphate lyase-1.95
Whether these differences reflect a primary defect or
changes secondary to skin inflammation is not known. A
recent study has demonstrated that it is highly unlikely
that KLK7 is a candidate gene for AD development in
boxer and West Highland white terriers.96
Ultrastructural evaluation
Preliminary studies of the epidermis suggest that ultra-
structural differences exist between atopic and healthy
dogs. The first report came from a pilot study in dogs
with spontaneous AD, which described abnormal lipid
lamellae in atopic dogs.97 This study documented signifi-
cantly reduced thickness and continuity of epidermal
lipid lamellae in atopic compared with healthy dogs.97
Similar observations were made recently in a small num-
ber of dogs with naturally occurring AD.98 A further eval-
uation in an experimental model of atopic beagles
reported irregular and highly disorganized lipid lamellae
in the atopic beagles when compared compared with
healthy control dogs.99 In atopic specimens, lamellar
bodies were detected inside corneocytes, similar to
what is observed in human patients. These findings
were also reported in clinically unaffected atopic skin.
Exposure to allergen and development of clinically
evident lesions was ultrastructurally associated with
copious release of irregularly organized amorphous lipid
material in the intercellular spaces of the lower stratum
corneum and widening of the intercellular spaces in the
stratum corneum.99
Where do we go from here? Implications
for research and practice
Although investigations of alterations to the skin barrier in
atopic dogs are still in their infancy, there is increasing,
albeit preliminary, evidence to suggest that they play a
role, be it primary or secondary to underlying inflamma-
tion. More research is clearly warranted. Investigation of
243
Marsella et al.
differences in lipid composition with particular emphasis
on the evaluation of ceramides is also warranted, as preli-
minary studies indicated that major differences in lipids
can exist between breeds and at different ages (e.g. cho-
lesterol content appears to be variable with age, and wax
diesters increase with age).100
It is tempting to speculate that some of the cutaneous
abnormalities in atopic dogs could be corrected by oral
administration or topical application of lipid preparations,
as in human medicine.45,46,101,102 The role of nutrition in
skin health has long been recognized,103,104 and it is
known that oral supplementation with essential fatty
acids increases skin essential fatty acids, reduces TEWL
and improves skin barrier function.105 The recent study
by Piekutowska et al.98 showed that topical application of
a lipid preparation in atopic dogs may be beneficial.
Repeated topical applications to clinically unaffected skin
of dogs with AD led to a significant increase in lipid lamel-
lae in the deepest part of the stratum corneum and to the
release of lipid material at the junction between the stra-
tum granulosum and stratum corneum; however, the clin-
ical benefit, if any, was not reported. A recent study in
Japan using a topical preparation containing ceramides
showed that some atopic dogs responded very well to
this form of therapy, while others did not respond or
worsened during treatment.106 Clinical benefit was evi-
dent around 4–6 weeks, but did not reach a maximum
until 8–12 weeks in some cases.106 It is unclear whether
a change in lipid ultrastructure, and any potential clinical
benefit, can occur at sites distant from the point of appli-
cation.
At present, studies are still needed to evaluate whether
correction of ultrastructural abnormalities results in appre-
ciable clinical benefit, as it is unknown whether clinical
signs in canine AD correlate with the severity of the skin
impairment, whether assessed by TEWL or electron
microscopy.
This area of research is important and potentially
promising. Therapy to improve the skin barrier could
combine both topical and systemic therapy (e.g. oral
essential fatty acids). Thorough studies are necessary to
avoid using inappropriately formulated products that
could further aggravate an already impaired barrier. It is
important that clinical trials document both the degree
of clinical improvement and improvements to skin barrier
function. While the documentation of chemical or ultra-
structural changes in epidermal lipids is important to
validate a proof of concept for the relevance of barrier-
targeting interventions, it is ultimately the demonstration
of meaningful clinical improvement in well-conducted
trials that will confirm whether or not the approach of
correcting a barrier dysfunction, if present, is valid. In
order to help sort out whether skin barrier impairment is
primary or secondary to even subclinical inflammation, it
could also be interesting to test barrier function in atopic
dogs before and after treatments such as cyclosporine.
Logic would suggest that if the impairment is primary, a
complete improvement should not be seen after treat-
ment, because the defect would be permanent and of
genetic origin. A partial improvement might be expected,
however, as atopic inflammation might have aggravated
a primary defect.
244
If future studies confirm that impaired skin barrier func-
tion in canine AD leads to increased allergen penetration
and increased risk for allergic sensitization, it is tempting
to speculate that proactive restoration of the skin barrier
could alter the course of the disease and minimize the
development of an allergic response. This ‘preventative’
approach could change the way we manage dogs predis-
posed to AD.
References
1. Cork MJ, Danby SG, Vasilopoulos Y et al. Epidermal barrier dys-
function in atopic dermatitis. Journal of Investigative Dermatol-
ogy 2009; 129: 1892–908.
2. Sehra S, Tuana FM, Holbreich M et al. Scratching the surface:
towards understanding the pathogenesis of atopic dermatitis.
Critical Reviews in Immunology 2008; 28: 15–43.
3. Elias PM, Schmuth M. Abnormal skin barrier in the etiopatho-
genesis of atopic dermatitis. Current Opinion in Allergy and Clini-
cal Immunology 2009; 9: 437–46.
4. Ohnishi Y, Okino N, Ito M et al. Ceramidase activity in bacterial
skin flora as a possible cause of ceramide deficiency in atopic
dermatitis. Clinical and Diagnostic Laboratory Immunology 1999;
6: 101–4.
5. Marsella R, Olivry T. Animal models of atopic dermatitis. Clinics
in Dermatology 2003; 21: 122–33.
6. Griffin CE, DeBoer DJ. The ACVD task force on canine atopic
dermatitis (XIV): clinical manifestations of canine atopic dermati-
tis. Veterinary Immunology and Immunopathology 2001; 81:
255–69.
7. Marsella R, Nicklin C, Lopez J. Studies on the role of routes of
allergen exposure in high IgE-producing beagle dogs sensitized
to house dust mites. Veterinary Dermatology 2006; 17: 306–12.
8. Olivry T, Deangelo KB, Dunston SM et al. Patch testing of
experimentally sensitized beagle dogs: development of a model
for skin lesions of atopic dermatitis. Veterinary Dermatology
2006; 17: 95–102.
9. Marsella R, Olivry T, Maeda S. Cellular and cytokine kinetics
after epicutaneous allergen challenge (atopy patch testing) with
house dust mites in high-IgE beagles. Veterinary Dermatology
2006; 17: 111–20.
10. Lodén M. Biophysical properties of dry atopic and normal skin
with special reference to effects of skin care products. Acta
Dermato-Venereologica. Supplementum (Stockholm) 1995; 192:
1–48.
11. Triebskorn A. Methods for measuring the symptoms of ‘‘dry
skin’’. Zeitschrift für Hautkrankheiten 1988; 63(Suppl. 3): 16–9.
12. Oestmann E, Lavrijsen AP, Hermans J, Ponec M. Skin barrier
function in healthy volunteers as assessed by transepidermal
water loss and vascular response to hexyl nicotinate: intra- and
inter-individual variability. British Journal of Dermatology 1993;
128: 130–6.
13. Pinnagoda J, Tupker RA, Agner T et al. Guidelines for transepi-
dermal water loss (TEWL) measurement. A report from the
standardization group of the European society of contact derma-
titis. Contact Dermatitis 1990; 22: 164–78.
14. Gupta J, Grube E, Ericksen MB et al. Intrinsically defective skin
barrier function in children with atopic dermatitis correlates with
disease severity. Journal of Allergy and Clinical Immunology
2008; 121: 725–30.
15. Hon KL, Wong KY, Leung TF et al. Comparison of skin hydra-
tion evaluation sites and correlations among skin hydration,
transepidermal water loss, SCORAD index, Nottingham
Eczema Severity Score, and quality of life in patients with
atopic dermatitis. American Journal of Clinical Dermatology
2008; 9: 45–50.
16. Loden M, Olsson H, Axell T et al. Friction, capacitance and
transepidermal water loss (TEWL) in dry atopic and normal skin.
British Journal of Dermatology 1992; 126: 137–41.
ª 2011 The Authors. Veterinary Dermatology
ª 2011 ESVD and ACVD, Veterinary Dermatology, 22, 239–248.

17. Lee C-H, Chuang H-Y, Shih C-C et al. Transepidermal water loss,
serum IgE and b-endorphin as important and independent bio-
logical markers for development of itch intensity in atopic
dermatitis. British Journal of Dermatology 2006; 154: 1100–7.
18. Seidnari S, Giusti G. Objective assessment of the skin of chil-
dren affected by atopic dermatitis: a study of pH, capacitance
and TEWL in eczematous and clinically normal skin. Acta Der-
mato-Venereologica 1995; 75: 429–33.
19. Boralevi F, Hubiche T, Leaute-Labrze C et al. Epicutaneous aero-
allergen sensitization in atopic dermatitis infants – determining
the role of epidermal barrier impairments. Allergy 2008; 63: 205–
10.
20. Werner Y, Lindberg M. Transepidermal water loss in dry and
clinically normal skin in patients with atopic dermatitis. Acta Der-
mato-Venereologica 1985; 65: 102–5.
21. Kim DW, Park JY, Na GY et al. Correlation of clinical features
and skin barrier function in adolescent and adult patients with
atopic dermatitis. International Journal of Dermatology 2006; 45:
698–701.
22. Nicander I, Nyrn M, Emtestam L et al. Baseline electrical imped-
ance measurements at various skin sites – related to age and
sex. Skin Research and Technology 1997; 3: 252–8.
23. Yosipovitch G, Maayan-Metzger A, Merlob P et al. Skin barrier
properties in different body areas in neonates. Pediatrics 2000;
106: 105–8.
24. Nikolovski J, Stamatas GN, Kollias N et al. Barrier function and
water-holding and transport properties of infant stratum corne-
um are different from adult and continue to develop through the
first year of life. Journal of Investigative Dermatology 2008; 128:
1728–36.
25. Wilhelm KP, Cua AB, Maibach HI. Skin aging. Effect of transepi-
dermal water loss, stratum corneum hydration, skin surface pH
and casual sebum content. Archives of Dermatology 1991; 127:
1806–9.
26. Hubiche T, Ged C, Benard A et al. Analysis of SPINK 5, KLK 7
and FLG genotypes in a French atopic dermatitis cohort. Acta
Dermato-Venereologica 2007; 87: 499–505.
27. Mori T, Ishida K, Mukumoto S et al. Comparison of skin barrier
function and sensory nerve electric current perception thresh-
old between IgE-high extrinsic and IgE-normal intrinsic types of
atopic dermatitis. British Journal of Dermatology 2010; 162:
83–90.
28. Cohen JC, Hartman DG, Garofalo MJ et al. Comparison of
closed chamber and open chamber evaporimetry. Skin Research
and Technology 2009; 15: 51–4.
29. Imhof RE, De Jesus ME, Xiao P et al. Closed-chamber transepi-
dermal water loss measurement: microclimate, calibration and
performance. International Journal of Cosmetic Science 2009;
31: 97–118.
30. Shah JH, Zhai H, Maibach HI. Comparative evaporimetry in man.
Skin Research and Technology 2005; 11: 205–8.
31. Laudańska H, Reduta T, Szmitkowska D. Evaluation of skin
barrier function in allergic contact dermatitis and atopic dermati-
tis using method of the continuous TEWL measurement. Rocz-
niki Akademii Medycznej w Białymstoku 2003; 48: 123–7.
32. Jemec GB, Serup J. Epidermal hydration and skin mechanics.
The relationship between electrical capacitance and the
mechanical properties of human skin in vivo. Acta Dermato-
Venereologica 1990; 70: 245–7.
33. Masukawa Y, Narita H, Sato H et al. Comprehensive quantifica-
tion of ceramide species in human stratum corneum. Journal of
Lipid Research 2009; 50: 1708–19.
34. Choi MJ, Maibach HI. Role of ceramides in barrier function of
healthy and diseased skin. American Journal of Clinical Derma-
tology 2005; 6: 215–23.
35. Coderch L, López O, de la Maza A et al. Ceramides and skin
function. American Journal of Clinical Dermatology 2003; 4:
107–29.
36. Masukawa Y, Narita H, Shimizu E et al. Characterization of over-
all ceramide species in human stratum corneum. Journal of Lipid
Research 2008; 49: 1466–76.
ª 2011 The Authors. Veterinary Dermatology
ª 2011 ESVD and ACVD, Veterinary Dermatology, 22, 239–248.
Skin barrier dysfunction in atopic dermatitis
37. Mizutani Y, Mitsutake S, Tsuji K et al. Ceramide biosynthesis in
keratinocyte and its role in skin function. Biochimie 2009; 91:
784–90.
38. Macheleidt O, Kaiser HW, Sandhoff K. Deficiency of epidermal
protein-bound x-hydroxyceramides in atopic dermatitis. Journal
of Investigative Dermatology 2002; 119: 166–73.
39. Farwanah H, Raith K, Neubert RH et al. Ceramide profiles of the
uninvolved skin in atopic dermatitis and psoriasis are compara-
ble to those of healthy skin. Archives of Dermatologic Research
2005; 296: 514–21.
40. Jensen JM, Fölster-Holst R, Baranowsky A et al. Impaired
sphingomyelinase activity and epidermal differentiation in atopic
dermatitis. Journal of Investigative Dermatology 2004; 122:
1423–31.
41. Imokawa G. A possible mechanism underlying the ceramide
deficiency in atopic dermatitis: expression of a deacylase
enzyme that cleaves the N-acyl linkage of sphingomyelin and
glucosylceramide. Journal of Dermatological Science 2009; 55:
1–9.
42. Hara J, Higuchi K, Okamoto R et al. High-expression of sphingo-
myelin deacylase is an important determinant of ceramide defi-
ciency leading to barrier disruption in atopic dermatitis. Journal
of Investigative Dermatology 2000; 115: 406–13.
43. Murata Y, Ogata J, Higaki Y et al. Abnormal expression of sphin-
gomyelin acylase in atopic dermatitis: an etiologic factor for
ceramide deficiency? Journal of Investigative Dermatology
1996; 106: 1242–9.
44. Okamoto R, Arikawa J, Ishibashi M et al. Sphingosyl-
phosphorylcholine is upregulated in the stratum corneum of
patients with atopic dermatitis. Journal of Lipid Research 2003;
44: 93–102.
45. Peiser M, Zuberbier T, Wanner R et al. Atopic skin is associ-
ated with a lack of phosphatidylcholine–sphingomyelin trans-
acylase activity. Journal of Investigative Dermatology 2007;
12: 973–5.
46. Chamlin SL, Kao J, Frieden IJ et al. Ceramide-dominant barrier
repair lipids alleviate childhood atopic dermatitis: changes in
barrier function provide a sensitive indicator of disease activity.
Journal of the American Academy of Dermatology 2002; 47:
198–208.
47. Madaan A. Epiceram for the treatment of atopic dermatitis.
Drugs of Today (Barcelona, Spain) 2008; 44: 751–5.
48. Seguchi T, Cui CY, Kusuda S et al. Decreased expression of fil-
aggrin in atopic skin. Archives of Dermatological Research 1996;
288: 442–6.
49. Irvine AD, McLean WH. Breaking the (un)sound barrier: filaggrin
is a major gene for atopic dermatitis. Journal of Investigative
Dermatology 2006; 126: 1200–2.
50. Nomura T, Sandilands A, Akiyama M et al. Unique mutations in
the filaggrin gene in Japanese patients with ichthyosis vulgaris
and atopic dermatitis. Journal of Allergy and Clinical Immunology
2007; 119: 434–40.
51. Hamada T, Sandilands A, Fukuda S et al. De novo occurrence of
the filaggrin mutation p.R501X with prevalent mutation
c.3321delA in a Japanese family with ichthyosis vulgaris compli-
cated by atopic dermatitis. Journal of Investigative Dermatology
2008; 128: 1323–5.
52. Ekelund E, Liedén A, Link J et al. Loss-of-function variants of the
filaggrin gene are associated with atopic eczema and associated
phenotypes in Swedish families. Acta Dermato-Venereologica
2008; 88: 15–9.
53. Baurecht H, Irvine AD, Novak N et al. Toward a major risk
factor for atopic eczema: meta-analysis of filaggrin polymor-
phism data. Journal of Allergy and Clinical Immunology 2007;
120: 1406–12.
54. Palmer CN, Irvine AD, Terron-Kwiatkowski A et al. Common
loss-of-function variants of the epidermal barrier protein filaggrin
are a major predisposing factor for atopic dermatitis. Nature
Genetics 2006; 38: 441–6.
55. O’Regan GM, Irvine AD. The role of filaggrin in the atopic diathe-
sis. Clinical and Experimental Allergy 2010; 40: 965–72.
245
Marsella et al.
56. Weidinger S, Illig T, Baurecht H et al. Loss-of-function variations
within the filaggrin gene predispose for atopic dermatitis with
allergic sensitizations. Journal of Allergy and Clinical Immunol-
ogy 2006; 118: 214–9.
57. Hudson TJ. Skin barrier function and allergic risk. Nature Genet-
ics 2006; 38: 399–400.
58. Weidinger S, Rodrı́guez E, Stahl C et al. Filaggrin mutations
strongly predispose to early-onset and extrinsic atopic dermati-
tis. Journal of Investigative Dermatology 2007; 127: 724–6.
59. McGrath JA, Uitto J. The filaggrin story: novel insights into skin-
barrier function and disease. Trends in Molecular Medicine
2008; 14: 20–7.
60. Howell MD, Kim BE, Gao P et al. Cytokine modulation of atopic
dermatitis filaggrin skin expression. Journal of Allergy and Clini-
cal Immunology 2007; 120: 150–5.
61. Irvine AD. Fleshing out filaggrin phenotypes. Journal of Investi-
gative Dermatology 2007; 127: 504–7.
62. Henderson J, Northstone K, Lee SP et al. The burden of disease
associated with filaggrin mutations: a population-based, longitu-
dinal birth cohort study. Journal of Allergy and Clinical Immunol-
ogy 2008; 121: 872–7.
63. Brown SJ, Irvine AD. Atopic eczema and the filaggrin story.
Seminars in Cutaneous Medicine and Surgery 2008; 27: 128–37.
64. Moniaga CS, Egawa G, Kawasaki H et al. Flaky tail mouse
denotes human atopic dermatitis in the steady state and by topi-
cal application with Dermatophagoides pteronyssinus extract.
American Journal of Pathology 2010; 176: 2385–93.
65. Caubet C, Jonca N, Brattsand M et al. Degradation of corne-
odesmosome proteins by two serine proteases of the kallikrein
family, SCTE ⁄ KLK5 ⁄ hK5 and SCCE ⁄ KLK7 ⁄ hK7. Journal of
Investigative Dermatology 2004; 122: 1235–44.
66. Borgoño CA, Michael IP, Komatsu N et al. A potential role for
multiple tissue kallikrein serine proteases in epidermal desqua-
mation. Journal of Biological Chemistry 2007; 282: 3640–52.
67. Vasilopoulos Y, Cork MJ, Murphy R et al. Genetic association
between an AACC insertion in the 3¢ UTR of the stratum corne-
um chymotryptic enzyme gene and atopic dermatitis. Journal of
Investigative Dermatology 2004; 123: 62–6.
68. Komatsu N, Saijoh K, Kuk C et al. Human tissue kallikrein
expression in the stratum corneum and serum of atopic dermati-
tis patients. Experimental Dermatology 2007; 16: 513–9.
69. Voegeli R, Rawlings AV, Breternitz M et al. Increased stratum
corneum serine protease activity in acute eczematous atopic
skin. British Journal of Dermatology 2009; 161: 70–7.
70. Voegeli R, Rawlings AV, Doppler S et al. Increased basal trans-
epidermal water loss leads to elevation of some but not all stra-
tum corneum serine proteases. International Journal of
Cosmetic Science 2008; 30: 435–42.
71. Tarroux R, Assalit MF, Licu D et al. Variability of enzyme mark-
ers during clinical regression of atopic dermatitis. Skin Pharma-
cology and Applied Skin Physiology 2002; 15: 55–62.
72. Badertscher K, Brönnimann M, Karlen S et al. Mast cell chym-
ase is increased in chronic atopic dermatitis but not in psoriasis.
Achives of Dermatological Research 2005; 296: 503–6.
73. Komatsu N, Saijoh K, Jayakumar A et al. Correlation between
SPINK5 gene mutations and clinical manifestations in Netherton
syndrome patients. Journal of Investigative Dermatology 2008;
128: 1148–59.
74. Walley AJ, Chavanas S, Moffatt MF et al. Gene polymorphism
in Netherton and common atopic disease. Nature Genetics
2001; 29: 175–8.
75. Kato A, Fukai K, Oiso N et al. Association of SPINK5 gene poly-
morphisms with atopic dermatitis in the Japanese population.
British Journal of Dermatology 2003; 148: 665–9.
76. Nishio Y, Noguchi E, Shibasaki M et al. Association between
polymorphisms in the SPINK5 gene and atopic dermatitis in the
Japanese. Genes and Immunology 2003; 4: 515–7.
77. Roedl D, Traidl-Hoffmann C, Ring J et al. Serine protease inhibi-
tor lymphoepithelial Kazal type-related inhibitor tends to be
decreased in atopic dermatitis. Journal of European Academy of
Dermatology and Venereology 2009; 23: 1263–6.
246
78. Proksch E, Brandner JM, Jensen JM. The skin: an indispensable
barrier. Experimental Dermatology 2008; 17: 1063–72.
79. Fartasch M, Bassukas ID, Diepgen TL. Structural relationship
between epidermal lipid lamellae, lamellar bodies and desmo-
somes in human epidermis: an ultrastructural study. British Jour-
nal of Dermatology 1993; 128: 1–9.
80. Fartasch M, Bassukas ID, Diepgen TL. Disturbed extruding
mechanism of lamellar bodies in dry non-eczematous skin
of atopics. British Journal of Dermatology 1992; 127: 221–7.
81. Watson A, Fray T, Clarke S et al. Reliable use of the ServoMed
evaporimeter EP2 to assess transepidermal water loss in the
canine. Journal of Nutrition 2002; 132: 1661S–4S.
82. Shimada K, Yoshihara T, Konno K et al. Increase in transepider-
mal water loss and decrease in ceramide content in the lesional
and non-lesional skin of canine atopic dermatitis. Veterinary Der-
matology 2008; 19: 19.
83. Shimada K, Yoshihara T, Yamamoto M et al. Transepidermal
water loss (TEWL) reflects skin barrier function of dog. The Jour-
nal of Veterinary Medical Science 2008; 70: 841–3.
84. Beco L, Fontaine J. Cornéométrie et perte d’eau transépidermi-
que: validation des techniques chez des chiens sains. Annales
de Médecine Vétérinaire 2000; 144: 329–33.
85. Lau-Gillard PJ, Hill PB, Chesney CJ et al. Evaluation of a hand-
held evaporimeter (VapoMeter) for the measurement of trans-
epidermal water loss in healthy dogs. Veterinary Dermatology
2010; 21: 136–45.
86. Oh WS, Oh TH. Mapping of the dog skin based on biophysical
measurements. Veterinary Dermatology 2010; 21: 367–72.
87. Oh WS, Oh TH. Measurement of transepidermal water loss
from clipped and unclipped anatomical sites on the dog. Austra-
lian Veterinary Journal 2009; 87: 409–12.
88. Hightower K, Marsella R, Creary E et al. Evaluation of transepi-
dermal water loss in canine atopic dermatitis: a pilot study in
beagle dogs sensitized to house dust mites. Veterinary Derma-
tology 2010; 21: 89–96.
89. Reiter LV, Torres SMF, Wertz PW. Characterization and quantifi-
cation of ceramides in the non-lesional skin of canine patients
with atopic dermatitis compared to controls. Veterinary Derma-
tology 2009; 20: 260–6.
90. Bardagi M, Vala H, Fondevila D et al. Immunohistochemical
detection of filaggrin in the skin of different species. Veterinary
Dermatology 2007; 18: 388.
91. Marsella R, Samuleson D, Harrington L. Evaluation of filaggrin
expression in sensitized atopic beagles and in normal controls
before and after allergen exposure. Veterinary Dermatology
2009; 20: 547–54.
92. Santoro D, Marsella R, Bunick D et al. Expression and distribu-
tion of canine filaggrin in the skin of healthy and atopic beagles.
Veterinary Dermatology 2010; 21: 323.
93. Chervet L, Galichet A, McLean WH et al. Missing C-terminal fil-
aggrin expression, NFkappaB activation and hyperproliferation
identify the dog as a putative model to study epidermal dysfunc-
tion in atopic dermatitis. Experimental Dermatology 2010; 19:
e343–6.
94. Barros Roque J, O’Leary CA , Kyaw-Tanner M et al. Haplotype
sharing excludes canine orthologous Filaggrin locus in atopy in
West Highland White Terriers. Animal Genetics 2009; 40: 793–4.
95. Wood SH, Clements DN, Ollier WE et al. Gene expression in
canine atopic dermatitis and correlation with clinical severity
scores. Journal of Dermatological Science 2009; 55: 27–33.
96. Stenshamn K, Bongcam-Rudloff E, Salmon Hillbertz N et al.
Evaluation of kallikrein 7 as a disease-causing gene for canine
atopic dermatitis using microsatellite-based association map-
ping. Animal Genetics 2006; 377: 601–3.
97. Inman AO, Olivry T, Dunston SM et al. Electron microscopic
observations of stratum corneum intercellular lipids in normal
and atopic dogs. Veterinary Pathology 2001; 38: 720–3.
98. Piekutowska A, Pin D, Rème CA et al. Effects of a topically
applied preparation of epidermal lipids on the stratum corneum
barrier of atopic dogs. Journal of Comparative Pathology 2008;
138: 197–203.
ª 2011 The Authors. Veterinary Dermatology
ª 2011 ESVD and ACVD, Veterinary Dermatology, 22, 239–248.
 Skin barrier dysfunction in atopic dermatitis

99. Marsella R, Samuelson D, Doerr K. Transmission electron
microscopy studies in an experimental model of canine atopic
dermatitis. Veterinary Dermatology 2010; 21: 81–8.
100. Dunstan R, Herdt TH, Olivier B et al. Age and breed-related dif-
ferences in canine skin surface lipids and pH. Advances in Veter-
inary Dermatology 2000; 4: 37–42.
101. Wirén K, Nohlgård C, Nyberg F et al. Treatment with a barrier-
strengthening moisturizing cream delays relapse of atopic
dermatitis: a prospective and randomized controlled clinical
trial. Journal of the European Academy of Dermatology and
Venereology 2009; 23: 1267–72.
102. Chamlin SL, Frieden IJ, Fowler A et al. Ceramide-dominant, bar-
rier-repair lipids improve childhood atopic dermatitis. Archives in
Dermatology 2001; 137: 1110–2.
103. Watson AL, Fray TR, Bailey J et al. Dietary constituents are able
to play a beneficial role in canine epidermal barrier function.
Experimental Dermatology 2006; 15: 74–81.
104. Marsh KA, Ruedisueli FL, Coe SL et al. Effects of zinc and lino-
leic acid supplementation on the skin and coat quality of dogs
receiving a complete and balanced diet. Veterinary Dermatology
2000; 11: 277–84.
105. Campbell KL, Dorn GP. Effects of oral sunflower oil and olive oil
on serum and cutaneous fatty acid concentrations in dogs.
Research in Veterinary Science 1992; 53: 172–8.
106. Fujimura M. Up-to-date information about canine atopic dermati-
tis and clinical effects of topical product for improvement of skin
barrier function. Companion Animal Practice Japan 2010; 2:
80–5.

Résumé La dermatite atopique (DA) est une maladie à multiples facettes résultant d’interactions
complexes entre facteurs génétiques et environnementaux. Ces deux facteurs peuvent modifier la
fonction de barrière cutanée et la réponse immunologique des patients prédisposés. Il existe des pre-
uves croissantes que la barrière cutanée endommagée joue un rôle dans la DA humaine et canine.
Bien que des défauts de barrière cutanée aient déjà été documentés dans le passé chez l’homme, la
récente identification des mutations de la filaggrine et le fait que de telles mutations sont désormais
considérées comme le facteur de risque le plus important dans le développement de la DA, ont
appuyés davantage la pertinence d’un dysfonctionnement épidermique dans la DA humaine. On en
sait beaucoup moins en médecine vétérinaire mais des éléments se construisent rapidement autour
du rôle d’un dysfonctionnement de barrière cutanée dans la DA canine. La DA canine partage de
nombreuses similitudes cliniques et immunologiques avec son homologue humain. Les lésions clini-
ques sont distribuées de manière similaire et l’importance de la voie épicutanée d’exposition allergén-
ique incitent à l’étude du rôle des défauts de la barrière cutanée dans la dermatite atopique canine.
L’objectif de cette étude comparative est de présenter les preuves actuelles de défauts de barrière à
la fois dans la DA humaine et canine.

Resumen La dermatitis atópica (AD) es una enfermedad de múltiples facetas que resulta de una
interacción compleja entre factores ambientales y genéticos. Ambos pueden influir la función de bar-
rera de la piel y la respuesta inmunológica de los pacientes predispuestos. Existen evidencias cada
vez mas claras de que la alteración de esa función de barrera juega un papel de relevancia en AD
canina y humana. Aunque se han documentado muchos defectos en la función de barrera de la piel
en el pasado en el ser humano, la reciente identificación de mutaciones en filagorina y el hecho de
que tales mutaciones se consideran actualmente el factor de riesgo mas importante para el desarrollo
de AD, solo ha hecho que enfatizar la relevancia de la disfunción epidermal en la AD humana. Se
sabe mucho menos en medicina veterinaria, pero poco a poco se van acumulando evidencias que
apoyan la existencia de una alteración de la función de barrera en la AD canina. La AD canina com-
parte muchas similitudes clı́nicas e inmunológicas con la enfermedad equivalente humana. La distribu-
ción similar de las lesiones clı́nicas y la importancia de la ruta epicutánea en la exposición a alergenos
aportan un incentivo para investigar el papel de las alteraciones de la función de barrera de la piel en
la AD canina. El propósito de esta revisión comparativa es presentar los últimos hallazgos de la altera-
ción de la función de barrera tanto en la AD humana como canina.

Zusammenfassung Die atopische Dermatitis (AD) ist eine facettenreiche Erkrankung, die sich aus
einer komplexen Interaktion zwischen Umwelt- und genetischen Faktoren ergibt. Beide Faktoren
können die Funktion der Hautbarriere und die Immunantwort prädisponierter Patienten beeinflussen.
Es besteht zunehmende Evidenz, dass eine beeinträchtigte Hautbarriere sowohl bei der humanen wie
auch bei der Atopie des Hundes eine Rolle spielt. Obwohl in der Vergangenheit bereits zahlreiche Pri-
märdefekte der Hautbarriere beim Menschen beschrieben worden waren, haben die unlängst erfolgte
Identifizierung von Filaggrinmutationen und die Tatsache, dass solche Mutationen mittlerweile als die
wichtigsten Risikofaktoren eine AD zu entwickeln, betrachtet werden, die Bedeutung der epidermalen
Dysfunktion bei der humanen AD noch unterstrichen. Obwohl man darüber in der Veterinärmedizin
wesentlich weniger weiß, nimmt die Evidenz, dass eine Dysfunktion der Hautbarriere auch bei der
AD des Hundes eine Rolle spielt rapide zu. Die canine AD weist viele klinische und immunologische
Ähnlichkeiten mit dem humanen Gegenstück auf. Die ähnliche Verteilung der klinischen Veränderun-
gen und die Wichtigkeit der epikutanen Route der Allergenexposition gaben den Anstoß dazu, die
Rolle einer Beeinträchtigung der Hautbarrierefunktion bei der caninen AD zu untersuchen. Es ist das
Ziel dieser vergleichenden Review die momentane Evidenz der Dysfunktion der Barriere sowohl bei
der AD des Menschen als auch bei der des Hundes zu präsentieren.

ª 2011 The Authors. Veterinary Dermatology

ª 2011 ESVD and ACVD, Veterinary Dermatology, 22, 239–248. 247
Marsella et al.

ª 2011 The Authors. Veterinary Dermatology

248 ª 2011 ESVD and ACVD, Veterinary Dermatology, 22, 239–248.