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well as extracellular enzymes may ulti-
mately be involved in the pathophysiol-
ogy of eczema and pruritus.
Based primarily on the strong asso-
ciation of inherited abnormalities in
filaggrin (FLG) expression, atopic der-
matitis (AD), at least in Euro-Americans,
is now increasingly considered a prima-
ry disorder of SC structure and function
(Hudson, 2006; Irvine and McLean,
2006; Palmer et al., 2006; Smith et al.,
2006; Weidinger et al., 2006). Thus,
AD can be considered a disease of pri-

to “Outside”) Pathogenic Mechanisms mary barrier failure, characterized by

both a defective permeability (Proksch

in Atopic Dermatitis et al., 2006, and references therein)

and antimicrobial function (Baker,
2006; Boguniewicz and Leung, 2006).
Peter M. Elias1,2 and Martin Steinhoff 2,3
Although both of these abnormalities
The pathogenesis of atopic dermatitis (AD) has been attributed largely to are well-recognized features of AD,
abnormalities in the adaptive immune system, with key roles played by T-help- they have been widely assumed to
er 1(Th1)/Th2 cell dysregulation, IgE production, dendritic cell signaling, and reflect downstream consequences of a
mast-cell hyperactivity, resulting in the pruritic, inflammatory dermatosis that primary immunologic abnormality (the
characterizes AD (Leung et al., 2004). Accordingly, therapy has been focused historical inside–outside view of AD
on ameliorating Th2-mediated inflammation and pruritus (e.g., Leung, 2000). pathogenesis). We and others have long
Indeed, there is emerging evidence that inflammation in AD results first from proposed that the permeability-bar-
inherited and acquired insults that converge to alter epidermal structure and rier abnormality in AD is not merely an
function, followed by immune system activation, which in turn has negative epiphenomenon but rather the “driver”
consequences for skin-barrier homeostasis. This cycle comprises an “outside– of disease activity (i.e., the reverse,
inside–outside” model of AD pathogenesis (Elias et al., in press). outside–inside view of disease patho-
Journal of Investigative Dermatology (2008), 128, 1067–1070. doi:10.1038/jid.2008.88 genesis) (Elias and Feingold, 2001),
because (1) the extent of the permeabil-
ity-barrier abnormality parallels sever-
ity of disease phenotype in AD, (2) both
The epidermis generates an impres- important for lipid processing and des- clinically uninvolved skin sites and skin
sive set of critical defensive functions quamation and at least two key anti- cleared of inflammation for as long as
(Elias, 2005; Elias and Choi, 2005) microbial peptides (Aberg et al., 2007,

|
that include the permeability barrier, and references cited therein), are deliv-
allowing survival in a potentially des- ered to the extracellular matrix through
iccating external environment, and an secretion of epidermal lamellar body
Inflammation in AD
antimicrobial barrier, which simulta- contents. Whereas lamellar body– may begin with insults
neously encourages colonization by derived proteases and their inhibitors from without.
nonpathogenic “normal” flora while orchestrate the orderly digestion of cor-
resisting growth of microbial patho- neodesmosomes, allowing cells to shed
gens (Elias, 2007). The permeability invisibly at the skin surface (Brattsand
barrier resides in the stratum corneum et al., 2005; Stefansson et al., 2008), 5 years continue to display significant
(SC), where multiple layers of anucleate the lipid-processing enzymes (β-gluco- barrier abnormalities, (3) emollient
corneocytes are embedded in an extra- cerebrosidase, acidic sphingomyelin- therapy comprises effective ancillary
cellular matrix, enriched in ceramides ase, and secretory phospholipase A2) therapy, and (4) specific replacement
(Cer), cholesterol, and free fatty acids, generate the Cer and free fatty acids therapy, which targets the prominent
arranged as planar lamellar sheets that, along with cholesterol, form the lipid abnormalities that account for
(Elias and Menon, 1991). These lipids, extracellular lamellar membrane (Elias the barrier abnormality in AD, not only
as well as an assortment of hydrolases and Menon, 1991). Thus, proteases as corrects the permeability-barrier abnor-
mality but also comprises effective anti-
1
Dermatology Service, Veterans Affairs Medical Center, and Department of Dermatology, University of
inflammatory therapy for AD (Chamlin
California, San Francisco, California, USA; 2Department of Dermatology, University of California, San
Francisco, California, USA; 3Department of Dermatology, University of Muenster, Muenster, Germany et al., 2002; Figure 1).
Correspondence: Dr Peter M. Elias, Dermatology Service (190), VA Medical Center, 4150 Clement Still, how loss of FLG (an intracellular
Street, San Francisco, California 94121, USA. E-mail: eliasp@derm.ucsf.edu protein) provokes a permeability-bar-

www.jidonline.org 1067
 COMMENTARY

S. aureus stored in large quantities in the cytosol

colonization
Cer, free
Acquired stressors
fatty acids,
pH, RH, PS
sphingosine
Th1 Th2
Sustained barrier defect
Cer synthesis
Inhereited
defects
FLG
LEKTI
Specific Ige
Scratching/excoriations
Figure 1. Secondary infections can further aggravate barrier abnormality in atopic dermatitis.
AD, atopic dermatitis; AMP, adenosine monophosphate; Cer, ceramide; FLG, filaggrin; LEKTI,
lymphoepithelial Kazal-type related trypsin inhibitor; PS, psychological stress; RH, relative humidity;
Th1, T-helper 1; Th2, T-helper 2 (Modified from Elias et al., in press.)
rier abnormality is not known. In addi-
tion, it is not clear what drives barrier
dysfunction in the skin of AD patients
without a FLG mutation. Although it
has been hypothesized that loss of FLG
could cause corneocyte deformation,
the barrier abnormality more likely
is linked to lack of FLG as a substrate
for proteolytic processing and further
deimination into polycarboxylic acids,
such as pyrrolidine carboxylic acid and
trans-urocanic acid. These metabo-
lites normally act as osmolytes (natural
moisturizing factors), drawing water
into corneocytes, partially account-
ing for corneocyte hydration. Hence,
the most immediate result of FLG defi-
ciency is decreased SC hydration, a
well-recognized feature of AD. A steep-
er water gradient would inexorably
accelerate transcutaneous water loss,
particularly if a paucity of extracellular
lipids results in decreased water-retain-
ing ability. However, either corneocyte
flattening or decreased SC hydration
can suffice to enhance antigen penetra-
tion. We suspect that another mecha-
nism is operative, because another
inevitable consequence of decreased
downstream production of polycarbox-
ylic acid metabolites is an increase in
the SC pH (Krien and Kermici, 2000),
sufficient to increase the activities of
of corneocytes (Hachem et al., 2002;
Nylander-Lundqvist et al., 1996), the
first step in the cytokine cascade that
Toxin- + superantigen- we propose initiates inflammation in
AMP producing S. aureus
AD (Figure 2).
Another cause of inflammation in
AD doubtless includes sustained anti-
Folliculitus/ gen ingress through a defective bar-
AD lesion impetigo
rier, leading to a T-helper 2 (Th2)-domi-
nant infiltrate (Hudson, 2006). Yet FLG
T- B-cell
mutations alone do not provoke AD, as
activation
Keratinocytes demonstrated in ichthyosis vulgaris, in
protease which the same single- or double-allele
Pruritus dysregulation
FLG mutations reduce FLG content, but
neuropeptides
inflammation (i.e., AD) does not inevi-
tably occur (Sandilands et al., 2007).
We and others have suggested that
certain acquired stressors could elic-
it disease by aggravating the barrier
abnormality. Indeed, a barrier-depen-
dent increase in pH (and serine protease
activity) likely accounts for the precipi-
tation of AD following the use of neu-
tral-to-alkaline soaps (Figure 1) (Cork et
the multiple serine proteases in SC, al., 2006). Likewise, prolonged expo-
which all exhibit neutral-to-alkaline sure to reduced environmental humid-
pH optima (Brattsand et al., 2005; ity, a well-known risk factor for AD,
Stefansson et al., 2008; Steinhoff et al., likely accelerates transcutaneous water
2005). Increased serine protease activ- loss rates across defective SC in AD,
ity could generate the active forms of further aggravating the barrier abnor-
the primary cytokines IL-1α and IL-1β mality. Finally, psychological stress,
from their 33-kDa pro-forms, which are which aggravates permeability-barrier
Barrier
perturbation
Stratum corneum
Inhibitory Ions Cer, FLG Cytokines/growth factor Proteases
Lamellar body
Lipid and hBD2 DNA synthesis
secretion
Epidermis Permeability and antimicrobial Epidermal Cytokines/
barrier restoration hyperplasia growth factors
Chemokines
Dermis Th2 cytokines
Inflammation
Figure 2. “Outside–inside–outside” model of AD. Cer, ceramide; FLG, filaggrin; hBD2, human β-defensin-2;
Th2, T-helper 2. (From Figure 2. Cer, ceramide; FLG, filaggrin; hBD2, human β-defensin-2; Th2, T-helper 2.
(From Steinhoff et al., 2005; modified from Elias et al., in press.)

1068 Journal of Investigative Dermatology (2008), Volume 128


function in humans (Altemus et al.,
2001), is both a well-known precipitant
of AD and a cause of resistance to ther-
apy. Moreover, a dysregulation of prote-
ases, highly expressed by keratinocytes,
protease inhibitors, and protease-acti-
vated receptors, may be important for
neuronal–epidermal communication
during barrier dysfunction (Demerjian
et al., 2008; Hachem et al., 2006;
Steinhoff et al., 2000, 2005).
Despite accumulating evidence in
support of a barrier-initiated patho-
genesis of AD, recent studies suggest
specific mechanisms whereby Th2-
generated cytokines could also further
aggravate AD. As described in this issue
by Kurahashi et al. (2008), exogenous
applications of the Th2 cytokine, IL-4,
impede permeability-barrier recov-
ery after acute perturbations. The basis
for the negative effects of IL-4 could
include the prior observation by these
authors that exogenous IL-4 inhibits
Cer synthesis (Hatano et al., 2005). But
IL-4 also inhibits expression of both
FLG (Howell et al., 2007) and desmo-
glein 3 (Kobayashi et al., 2004), which
also could further compromise barrier
function, completing a potential out-
side–inside–outside pathogenic loop in
AD (Figure 2). Furthermore, nerves may
be activated by “barrier stressors” such
as UV light, toxic or allergic agents,
and microbial agents. Therefore, nerve-
derived mediators could also modulate
enzyme production, antimicrobial pep-
tide (defensin) generation, pH changes,
or SC humidity, thereby influencing
keratinocyte function (Paus et al., 2006;
Roosterman et al., 2006; Steinhoff et
al., 2006).
Together, the converging pathogenic
features described above create a strong
rationale for the deployment of specific
strategies to restore barrier function in
AD. When used under nursing super-
vision, moisturizers have been shown
to reduce topical steroid usage (Cork
et al., 2003). Of various barrier-repair
approaches, a mixture of the three SC
lipids in a Cer-dominant formulation
(TriCeram, Osmotics Cosmeceuticals)
demonstrated improved clinical sta-
tus, permeability-barrier function, and
SC integrity when this technology was
substituted for standard moisturizers in
children with severe, recalcitrant AD
(Chamlin et al., 2002). More recently,
a higher-strength, FDA cleared formu-
lation (EpiCeram cream, Ceragenix
Pharmaceuticals) demonstrated efficacy
that was comparable to that of a mid-
potency steroid (fluticasone; Cutivate
cream) in an investigator-blinded,
multicenter clinical trial of pediat-
ric patients with moderate to severe
AD (Sugarman and Parish, in press).
These studies, although still prelimi-
nary, suggest that correction of the lipid
biochemical abnormality that is respon-
sible for the barrier defect in AD could
also downregulate the further inside-
to-outside alterations provoked by IL-4
and could comprise a new or ancillary
approach to the therapy of AD.
CONFLICT OF INTEREST
Dr Elias is a co-inventor of Cer-dominant
formulation (TriCeram, Osmotics Corp.), a
patented technology, and an officer of Ceragenix
Pharmaceuticals, the licensee of this technology.
Dr Steinhoff states no conflict of interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the superb editorial
assistance of Joan Wakefield and Jerelyn
Magnusson, including preparation of the
graphics. This work was supported by National
Institutes of Health grant AR19098, Department
of Defense grant W81XWH-05-2-0094, and the
Medical Research Service, Department of Veterans
Affairs, grants DFG (STE 1014/2-2) (M.S.) and SFB
293 (M.S.). No company provided support for this
article.
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