Allergy

REVIEW ARTICLE

Atopic dermatitis – from new pathophysiologic insights to

individualized therapy
N. Novak1 & D. Simon2
1
Department of Dermatology and Allergy, University of Bonn, Bonn, Germany; 2Department of Dermatology, Inselspital, University of Bern,
Bern, Switzerland

To cite this article: Novak N, Simon D. Atopic dermatitis – from new pathophysiologic insights to individualized therapy. Allergy 2011; 66: 830–839.

Keywords Abstract
antimicrobial peptides; atopic dermatitis;
filaggrin; immunoglobulin E; individualized
Recently, important novel insights into the complex pathophysiology of atopic der-
therapy; vitamin D. matitis (AD) have been gained. However, in most cases the therapy of AD is limited
to base line therapy with emollients combined with symptomatic, rather general
Correspondence immunosuppressive treatment approaches of the flare-ups. Latest research findings
Natalija Novak, MD, Department of together with experiences from daily clinical practice, which support the concept
Dermatology and Allergy, University of that a combination of general disease features together with specific trigger factors
Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, in the individual patients drive the disease, might be helpful for a subclassification
Germany. of patients with AD based on the most relevant pathophysiologic modifications.
Tel.: +49 228 287 15370 Subclassification of patients with AD seems indispensable to introduce rationale-
Fax: +49 228 287 14333 based, individualized treatment approaches of AD, which target specific modified
E-mail: [email protected] pathways. In this review, we provide an overview about a selection of pathophysio-
logic pathways, which hold promise to represent targets of such therapeutic
Accepted for publication 8 February 2011 approaches in the near future.

DOI:10.1111/j.1398-9995.2011.02571.x

Edited by: Hans-Uwe Simon

Atopic dermatitis (AD) is one of the most frequent chronic to symptomatic, unspecific anti-inflammatory or immuno-
inflammatory skin diseases, affecting up to 25% of children suppressive treatment of the flare-ups and the disturbed skin
and 1–3% of adults worldwide. Pathophysiology of AD is barrier in general (2). Within recent years, much research
complex and regulated by a multitude of genetic and envi- efforts have been focused on the identification of main trig-
ronmental factors. In contrast to the multifaceted trigger ger factors and have elucidated stepwise different aspects
factors of AD, the clinical picture is rather homogenous and facets of this fascinating disease (3). Thus, it became
and dominated by chronic eczematous skin lesions in typical more and more clear that AD might be based on very
localizations (1). This implies shared common disease-related heterogeneous and different aspects, which act in the fore-
factors on the one hand, supplemented by individual trig- ground as triggers in the single patient. Therefore, a first
gers on the other hand as a disease model for AD. How- step toward an individualized, rationale-based therapy of
ever, treatment of AD is often frustrating in the clinical AD would be to carefully classify subgroups of patients
practice, because most of the approaches are mainly limited with AD, such as AD patients with genetically predeter-
mined skin barrier defects, deficiencies on the level of innate
Abbreviations or adaptive immunity or autoreactivity reactions, which
AD, atopic dermatitis; AMP, antimicrobial peptides; DCs, dendritic initiate or perpetuate the disease. As a second step, indivi-
cells; EH, eczema herpeticum; FceRI, high-affinity receptor for IgE; dualized therapeutic approaches targeting specific pathways
FLG, filaggrin; hBD, human beta defensin; IL, interleukin; IgE, of relevance for the different subgroups should be
immunoglobulin E; MnSOD, manganese superoxide dismutase; conducted. In this review, we provide an overview of
M. sympodialis, Malassezia sympodialis; S. aureus, Staphylococcus selected pathophysiologic aspects identified recently in AD
aureus; SIT, specific immunotherapy; TLR, toll-like receptor. (Fig. 1), which might hold promise to serve as targets for

830 Allergy 66 (2011) 830–839 ª 2011 John Wiley & Sons A/S
Novak and Simon Individualized therapy of AD

Figure 1 Summary of target cells and pathways for individualized AMP, antimicrobial peptide; DC, dendritic cell; T reg, regulatory T
therapeutic approaches. Red arrows indicate therapeutic strategies cells.
evaluated in clinical studies and gray arrows show potential targets.

rationale-based therapeutic approaches of defined subgroups time points of life seems to increase the risk for eczema devel-
of patients with AD in the future (Fig. 2). opment in particular in the subgroup of FLG-loss-of-function
mutation carriers (11, 12).
Besides a genetic predisposition, factors from the character-
Loss-of-function mutations in the filaggrin gene
istic microenvironment in AD skin lesions, such as high levels
With the discovery of associations of loss-of-function muta- of Th2 cytokines seem to reduce secondarily the expression of
tions in the filaggrin (FLG) gene with AD, the model of AD FLG in the skin (13, 14). Based on the insights gained into
as a disease based on a primary genetic epithelial barrier the regulation of the FLG expression in the skin as well as its
defect with consecutive, secondary modified immune function, therapeutic approaches aimed at the reversion of
responses has revised our understanding of the pathogenesis low FLG expression by different pharmacological substances
of AD and the atopic diathesis in general. In the Caucasian and drugs as well as at the reduction in the overexpression of
population, loss-of-function mutations in the FLG gene are soluble factors such as interleukin (IL)-4 and IL-13, which
detectable in about one-third of patients with AD (4). Filag- have been demonstrated to downregulate FLG expression in
grin is released from the keratohyalin F granules as an inac- the skin, might represent novel therapeutic approaches to
tive precursor protein and is converted into FLG later on counteract this deficiency. Just recently, IL-25 that is pro-
after proteolysis and dephosphorylation (5). Its main function duced by activated eosinophils, basophils and dendritic cells
is to bundle the keratin cytoskeleton and to form macrofibrils and has been detected in AD skin was reported to decrease
(6). Modification of the degradation of FLG into short FLG mRNA expression by keratinocytes, so that reduction in
peptides and free amino acids leads to the lack of hygro- IL-25 should be considered as well (15, 16).
scopic amino acids, resulting in decreased epidermal water Besides that, preventive measures, such as avoidance of
retention. Besides that, FLG seems to be involved also in the frequent exposure to environmental factors that increase the
regulation of the transcription of other proteins of the epider- risk for eczema development, including cat allergens or
mal differentiation complex. Considering the important role nickel, might be conducted in FLG-mutation carriers (9, 11).
of FLG for the maintenance of the skin barrier, it is obvious
that FLG haplo-insufficiency might contribute to the impair-
Patient selection
ment of the skin barrier in AD and increase the risk for
severe courses of AD and concomitant development of Because routine genotyping of multiple but rare FLG muta-
asthma (5). Moreover, first data evaluated in murine-model tions might be difficult in daily clinical practice, identification
systems together with data available on genetic associations of specific Raman signatures with Raman spectroscopy as a
in humans provide evidence for a link between low FLG noninvasive method (17, 18) might represent an alternative,
expression in the skin and increased risk for the development helpful tool to identify of FLG-mutation carriers among
of sensitizations to allergens as well as haptens such as nickel patients with AD or children at risk for atopic diseases at
via the cutaneous route (7–10). In addition, distinct environ- earliest time points of life possible, such as immediately after
mental co-factors, such as exposure to cat allergens at early birth.

Allergy 66 (2011) 830–839 ª 2011 John Wiley & Sons A/S 831
Individualized therapy of AD Novak and Simon

Figure 2 Schematic diagram of potential subgroups of patients with AD based on frequent and important pathogenic factors and related
individualized therapeutic approaches.

Staphylococcus aureus (S. aureus) infections, which is a char-

Targeting antimicrobial peptide expression
acteristic feature of a subgroup of patients with AD (25).
The innate immune system consists of a billion years proved Moreover, anti-viral activity of LL-37 and hBD-3 was
and tested composition of mechanisms, which work hand in detected in vitro (26, 27). Therefore, lower LL-37 expression
hand together to sense danger signals from the environment in the skin of AD patients with a history of one or more epi-
by pattern recognition receptors and to rapidly react with sodes of eczema herpeticum (EH), a severe, disseminated
sophisticated defensive immune responses. Several lines of infection of the skin caused by herpes simplex virus, has been
evidence indicate abnormalities on the level of the innate interpreted as a putative risk factor for this complication
immune system as a cause for increased susceptibility to (28).
bacterial and viral infections, which aggravate the course of With regard to AMP regulation, it has been demonstrated
the diseases in a subgroup of patients with AD. In this con- that 1-25-dihydroxyvitamin D3 upregulates the expression of
text, antimicrobial peptides such as human beta defensins both, the toll-like receptor (TLR) coreceptor CD14 and
(hBD) as well as cathelicidins, which are expressed by skin AMPs by human keratinocytes, resulting in an enhanced
cells and exhibit antimicrobial activities to avoid uncontrolled antimicrobial function against S. aureus in vitro (29, 30). The
growth of microbes, have been supposed to play a role (19). reason for the inducibility of AMPs by vitamin D3 is that
In terms of antimicrobial peptide expression, only hBD-1 promoters of the human cathelicidin and defensin beta2 gene
is constitutively expressed in the epidermis and sweat glands, contain consensus vitamin D response elements (29, 31).
while hBD-2, hBD-3 and hBD-4 production is induced by As a consequence, AMP deficiency in AD skin should be
cytokines, bacterial infection, differentiation or other stimuli compensated as therapeutic approach in the future. Addition
(20). Antimicrobial peptides (AMP) including cathelicidins of vitamin D(3)-1,25-dihydroxyvitamin D(3) to in vitro-
such as LL-37 display direct antimicrobial activity on the one cultured human keratinocytes increased their cathelicidine
hand and induce a host response characterized by cytokine expression (30). In line with these in vitro observations, oral
release, chemotaxis, inflammation, angiogenesis and re-epi- administration of vitamin D was reported to induce the cath-
thelialization on the other hand (21). When compared to elicidin production in the skin of patients with AD. In addi-
other chronic inflammatory skin diseases such as psoriasis, tion, supplementation of vitamin D3 went along with an
deficiency of LL-37 and hBD-2 (22) as well as hBD-3 and improvement in the disease (32–35). Furthermore, pimecroli-
dermicidin has been observed in AD (23, 24). Lower expres- mus enhanced the expression of cathelicidin, hBD-2 and
sion of those peptides has been linked to higher propensity to hBD-3 in human keratinocytes stimulated with a TLR2/6

832 Allergy 66 (2011) 830–839 ª 2011 John Wiley & Sons A/S
Novak and Simon Individualized therapy of AD

ligand and thus their capacity of bacterial killing of S. aureus (41). For a long time, AD has been excluded from the list of
(36) in vitro (34). This could represent another way to indications for SIT because of putative side effects and
actively enforce antimicrobial defense by topical treatment in unwanted exacerbations of symptoms under therapy as well
patients with AD. Because innate immune signaling in kerati- as lack of a substantial number of controlled studies (42).
nocytes is in part regulated by B-cell leukemia (Bcl)-3, silenc- Nevertheless, a recent study conducted in adult patients sensi-
ing of Bcl-3 by small interfering RNA (siRNA) has been tized against house dust mites revealed promising results in
shown to enhance vitamin D3-induced AMP expression of terms of efficacy of SIT in AD (43). Moreover, in parallel
keratinocytes in vitro (37). Whether such an approach could with a decrease in AD severity of and reduction in concomi-
be transferred to in vivo application has to be tested in future tant medications, the quality of life improved upon SIT in
clinical studies. patients with AD sensitized to birch pollen allergen (44). In
As an alternative to the induction of endogenous AMP addition to allergen-specific tolerance, a reduction in allergen-
production, synthetic antimicrobial compounds, which mimic specific IgE and increase in allergen-specific IgG4 as well as
the structure and function of antimicrobial peptides, the decrease in serum factors correlating with the severity of AD
so-called ceragenins, have been developed. Topical applica- such as IL-16, CCL18 or CCL22 has been observed (45, 46).
tion of exogenous antimicrobial compounds to the skin is Because in most of the adult patients with AD, specific
supposed to be helpful in AD patients with active dissemi- IgE to distinct allergens is elevated in the blood and the
nated virus infections. As a first step toward such treatment patients have multiple positive skin-prick test results, selec-
approaches, topical application of ceragenin CSA-13 was tion of the allergens as main triggers of the disease is strongly
shown to exhibit direct antiviral effects and induce endogenous dependent on the clinical symptoms and correlates with flare-
LL-37 and hBD-3 expression and thus inhibited vaccinia virus ups of AD upon allergen exposure. However, in view of the
replication in infected keratinocytes in vitro (38). satisfactory results of SIT with a single allergen in patients
Taken together, direct supplementation of AMPs expressed with AD, which are most often sensitized against a plethora
in reduced levels in the skin as well as topical treatment of of different allergens, an allergen-specific effect combined
skin with pimecrolimus and oral supplementation of vitamin with a general positive modulation of the immune system of
D3 represent putative novel approaches to compensate AMPs patients with AD as a result of SIT is very likely. Most of
deficiency in the skin of a subgroup of patients with AD at the studies available have been conducted using subcutaneous
risk for bacterial and/or virus infections. rout of immunotherapy, while less data on allergen applica-
tion via the sublingual route exist (42).
Concerning sensitizations to food allergens (47), approaches
Patient selection
using oral immunotherapy with selected food of relevance in
Selection of applicable patients could be achieved by sub- AD, such as cow’s milk, hen’s egg or peanuts, are still under
dividing patients into patients with active, severe bacterial or clinical investigation. First results of small double-blind
viral infection and patients with frequent episodes of severe placebo controlled food challenge studies revealed some posi-
bacterial or viral skin infections in their history. Further- tive results, mirrored in the threshold of the amount of food
more, prophylactic treatment could be conducted in patients tolerated without the development of symptoms (48, 49).
with known risk factors for bacterial or viral infections, such However, studies are still ongoing but might result in for
as single nucleotide polymorphisms in the TLR2 gene, which rationale-based treatment approaches in food-sensitized indi-
have been shown to be associated with AD complicated by viduals in the near future.
severe bacterial infections (39). As another group, patients
with high total immunoglobulin E (IgE) and thymus and
Patient selection
activation-regulated chemokine and cutaneous T-cell-attract-
ing chemokine (TARC) levels, multiple sensitizations, eosino- Patients with clinically relevant sensitizations to house dust
philia and frequent infections with S. aureus and Molluscum mite, birch or grass pollen allergen or in terms of children
contagiosum virus could be selected as it has been demon- sensitizations to hen’s egg or cow’s milk have to be identified.
strated that those patients are at higher risk for EH (Fig. 1) Before starting immunotherapy, the relevance of allergen
(28, 40). sensitizations for eczema development should be evaluated by
atopy patch testing, skin-prick testing and evaluation of the
level of allergen-specific serum IgE or double-blind placebo-
Targeting allergen sensitizations
controlled food challenges, respectively.
Allergen sensitizations play an important role as triggers of
AD. While food allergens such as cow’s milk or hen’s egg
Targeting IL-31 and H4 receptor
aggravate AD in particular in children, aeroallergens such as
house dust mites, birch or grass pollen allergens might be of Puritus is a key symptom of AD that together with sub-
relevance in both children and adults. However, allergen sequent sleeplessness and restlessness profoundly impairs the
avoidance including encasing strategies is of limited success quality of life of the patients. Treatment of pruritus in AD is
in controlling allergen-dependent flare-ups of the disease. difficult and often frustrating. Histamine receptor 1 anta-
Specific immunotherapy (SIT) represents a well-established gonists are of limited value. Novel insights into the patho-
treatment for patients with allergic rhinitis or mild asthma genesis of pruritus in AD have been gained with the

Allergy 66 (2011) 830–839 ª 2011 John Wiley & Sons A/S 833
Individualized therapy of AD Novak and Simon

discovery of IL-31, which is expressed in enhanced amounts mucosal surfaces might trigger IgE autoreactivity and increase
in the skin of patients with AD. IL-31 production is induced the risk for severe, chronic courses of AD, perpetuated by
upon stimulation of cutaneous lymphocyte antigen + T cells autoreactive immune reactions starting at very early time
with S. aureus enterotoxin. IL-31 induced together with points of life. In terms of therapeutic consequences, allergen
S. aureus enterotoxins proinflammatory cytokine production avoidance should be conducted as early as possible to reduce
of monocytes and macrophages in vitro (50). Furthermore, the degree of allergen-induced inflammation and tissue
IL-31 is involved in the scratching behavior of NC/Nga mice damage causing the exposure of self-antigens. Furthermore,
with atopic-like dermatitis (51–54). IL-31 binds to the IL-31 decrease in IgE autoreactivity was observed upon systemic
receptor A (IL-31RA) and the oncostatin M receptor. treatment with cyclosporine A (64). Based on the hypothesis
IL-31RA transcripts are expressed in dorsal root ganglia, that autoreactivity might perpetuate the disease in a subgroup
where the cell bodies of the primary sensory neurons reside of patients, immunosuppressive therapy might be a rationale-
(51). Interestingly, it has been observed that Th2 cells of based approach to counteract and attenuate autoimmune
patients with AD stimulated by histamine receptor 4 (H4R) reactions in AD for the benefit of the patients.
agonists release significantly higher amounts of IL-31 com-
pared with Th2 cells isolated from healthy control donors
Patient selection
(55). Moreover, H4R stimulation-increased release of inflam-
matory cytokines by distinct DC subtypes in the skin (56). To select patients with IgE autoreactivity, immunoblotting
This links for the first time IL-31/IL-31R signaling to the assays with patients’ sera T-cell proliferation assays or atopy
histamine/histamine receptor pathway, unraveling potential patch tests with selected autoallergens e.g. MnSOD could be
novel therapeutic targets in AD including inhibition of IL-31 applied.
by direct inhibitors (57) or indirectly by histamine receptor
interaction (58, 59).
Targeting B cells and IgE
Variable numbers of B cells have been detected among infil-
Patient selection
trating cells in AD skin (66, 67). In about 80% of adult
All patients suffering from pruritus that usually is recalcitrant patients with AD, elevated total IgE levels and specific IgE
to treatment with H1R antihistamines might be selected for to environmental allergens can be detected (68). Langerhans
this kind of treatment approach. cells of AD skin bearing the high-affinity IgE receptor FceRI
on their surface provide a link between environmental aller-
gen exposure and T-cell activation (69). Furthermore, B cells
Targeting IgE-mediated autoreactivity
act as antigen-presenting cells, activators of T cells and DCs,
The observation that not only exogenous components from and structural cells producing cytokines/chemokines (70, 71).
the environment but also endogenous factors apparently The high expression of CD86 on B cells in AD (72) might
aggravate the course of AD in a subgroup of patients has provide costimulatory signals via CD28 on T cells, resulting
drawn the attention to the phenomenon of IgE autoreactivity in the production of large amounts of IL-5 and IL-13 in AD
in AD. In this context, it is supposed that IgE autoantibodies (73). Moreover, activated B cells produce the chemokines
to human proteins, which are exposed in the skin because of CCL17 (TARC), CCL22 (MDC) and IL-16 and thus may
chronic inflammation and/or mechanical damage, perpetuate recruit other immune cells into the skin (74, 75). The deple-
endogenously the course of the disease (60). This phenomenon tion of B cells with rituximab, an anti-CD20 antibody,
is assumed to be based on a molecular mimicry between com- resulted in a rapid reduction in skin inflammation in all
mon B-cell epitopes of foreign, exogenous antigens and patients with a sustained effect over 5 months in five of six
endogenous proteins (61), leading to misrouted IgE auto- patients (76). Another report on two cases of severe AD
reactivity to self-antigens. One example is the homology of receiving rituximab showed a temporary improvement (77).
the stress-inducible enzyme human manganese superoxide Interestingly, the allergen-specific IgE levels were not affected
dismutase (MnSOD) with the allergen Mala s 11 of the exoge- by rituximab (76). The depletion of B cells in the peripheral
nous yeast Malassezia sympodialis, which is part of the nor- blood and to a lesser extent in the skin was followed by a
mal cutaneous flora (62, 63). Specific IgE antibodies against reduction in T-cell activation including reduced production
M. sympodialis cross-reactive to MnSOD were detectable in of cytokines, in particular IL-5 and IL-13 in the skin (76).
the sera of a subgroup of patients with AD and correlated A further treatment approach is the neutralization of IgE.
with disease severity. Moreover, MnSOD was shown to The anti-IgE antibody omalizumab was shown to exhibit
induce eczematous reactions in patch tests conducted in sensi- dual effects by removing free IgE and thus downregulating
tized patients as well as increase T-cell proliferation in vitro the surface expression of FceRI on basophils, mast cells
(62). A subgroup of AD patients with severe course of the and DCs (78–80). In vitro experiments showed that IgE/
diseases display autoreactive IgE antibodies (64, 65). Even in omalizumab immune complexes trapped allergens resulting in
children between 1 and 6 years with elevated IgE serum levels a decreased antigen-induced activation of FceRI+ cells (81).
and sensitizations to food and/or aeroallergens, a develop- A recent study investigating the effects of omalizumab in AD
ment of IgE autoreactivity is detectable. This implies that confirmed that omalizumab reduced free serum IgE, as well
early allergen contact and related tissue inflammation at as the expression and saturation of FceRI on the surface of

834 Allergy 66 (2011) 830–839 ª 2011 John Wiley & Sons A/S
Novak and Simon Individualized therapy of AD

blood and skin cells in AD (82). In addition, the numbers of the failure to clear S. aureus in AD (95). IL-17 was reported
IgE + DCs in the skin decreased (82). Upon low-dose anti- to promote IgE production in B cells (96). These observa-
IgE therapy with 10 cycles of 150 mg omalizumab, six of tions point to an important role of Th17 cells in the patho-
11 AD patients with serum IgE levels >1000 kU/l before genesis of AD.
therapy responded as shown by a decrease in SCORAD by IL-21 exerts its effects on both immune cells and resident
more than 50% in 2 and between 25 and 50% in four cells such as epithelial cells (97). IL-21 was shown to be
patients (83). Several studies reported that accompanying AD essential for the maturation of B cells into antibody-secreting
significantly improved in patients receiving omalizumab plasma cells, to influenced antigen-specific T-cell responses
because of severe bronchial asthma (84–86). Nevertheless, the and drive Th17 cell differentiation (97). IL-21 and IL-21
reports on the effects of omalizumab in AD are still contro- receptor (IL-21R) expression were detected in acute skin
versial. In patients with AD receiving omalizumab dosed lesions of patients with AD, in infiltrating cells and the epi-
according to body weight and IgE levels over 16 weeks, no dermis, respectively (98). Upon mechanical injury, the expres-
significant improvement in skin symptoms and pruritus was sion of both IL-21 and IL-21R was upregulated (98). In mice
achieved (82). epicutaneously sensitized with ovalbumin, IL-21 signaling
However, targeting B cells of IgE might represent a ratio- was shown to be critical for CCR7 upregulation on DCs and
nale-based treatment approach for a small subgroup of their migration from the skin to the draining lymph nodes,
patients with AD. where they initiate an immune response (98). IL-21 is
assumed to contribute to the pathogenesis of AD in so far as
skin inflammation and scratching increase the expression of
Patient selection
IL-21 and its receptor followed by an enhanced migration of
According to recent studies, patients with elevated IgE serum DCs carrying antigens from the injured skin to the lymph
levels and severe AD with concomitant asthma should be nodes resulting in further sensitization to environmental aller-
selected for this type of treatment. Furthermore, a decreased gens in AD (98). Thus, blocking of IL-21/IL-21R interaction
sensitivity to allergens in the skin-prick test and atopy patch could prevent cutaneous sensitization in patients with AD.
test was observed, suggesting (82) that omalizumab might be A new subset of skin-homing memory T cells that are dis-
helpful in acute rather than in chronic AD (82). tinct from Th17 cells as they produce IL-22 but no IL-17 or
IFN-c have recently been identified (99). Th22 cells were
shown to promote proinflammatory responses by producing
Targeting Th9, Th17 and Th22 cells
IL-22 and TNF-a, as well as remodeling and wound healing
In addition to Th1 and Th2 cells, new T-cell subsets have (100). In AD, serum IL-22 levels were found to correlate
been identified recently and named according to their pre- with disease severity (101). S. aureus exotoxins significantly
dominant cytokine expression: Th9, Th17 and Th22 cells. enhanced the production of IL-22 by T cells from patients
IL-9, which is regarded as Th2 cytokine, was shown to with AD (102). Investigating the effects of IL-22 on kerati-
enhance inflammation, eosinophil and mast cell infiltration as nocytes revealed a downregulation of genes coding for pro-
well as subepithelial fibrosis (87). Increased IL-9 mRNA teins of the epidermal terminal differentiation pathway
expression in the AD skin has been observed upon allergen including FLG (103) and an induction of epidermal hyper-
challenge correlating with the number of eosinophils (88). plasia (104).
Th17 cells are a source of IL-17, IL-21 and IL-22 (89). A According to these recent observations, Th9, Th17 and Th22
role for Th17 cells has been implicated in host defense, cells as well as their cytokines play an important role in the
autoimmunity and allergy (89). In patients with AD, Th17 pathogenesis of AD and might be considered as therapeutic
cells have been detected in the papillary dermis of lesional targets (Fig. 2). Because these T-cell subsets are also involved
skin and in the peripheral blood correlating with disease in host defense, functional neutralization might potentially
severity (90). Allergen-induced IL-17 expression in acute AD increase the risk of infections (105–107). Currently, anti-IL-17,
lesions was shown to be enhanced upon additional exposure anti-IL-22 and anti-IL-9 antibodies are under clinical investiga-
to S. aureus enterotoxin B (91). Furthermore, autoallergen- tion in autoimmune diseases and asthma. A further interesting
specific T-cell clones isolated from AD skin were found to target for AD therapy would be transforming growth factor-b,
produce IL-17 (92). According to animal and in vitro experi- which regulates the differentiation of proinflammatory Th9,
ments, Th17 cells might contribute to skin barrier dysfunc- Th17 and Th22 cells, but also regulatory T cells (108).
tion as well as to epicutaneous sensitization and asthma
development. In FLG-deficient mice that developed AD-like
Patient selection
lesions, the inflammation was dominated by Th17 cells per-
mitting epicutaneous sensitization to ovalbumin (93). More- Because research on the putative functional relevance of
over, epicutaneous immunization with ovalbumin in Balb/c those T-cell subsets is still ongoing, it is quite too early to
mice was shown to induce local and systemic Th17 responses define clear criteria for patient selection. However, it is con-
(94). Subsequent airway allergen challenge resulted in strong ceivable that a subgroup of patients with AD for example
inflammation with influx of Th17 cells in the lung (94). The with specific microbial infections, high number of sensitiza-
observation that IL-17-induced upregulation of HBD-2 by tions or concomitant asthma might benefit from treatment
keratinocytes was abolished by IL-4, and IL-13 might explain approaches, which target the pathways described earlier.

Allergy 66 (2011) 830–839 ª 2011 John Wiley & Sons A/S 835
Individualized therapy of AD Novak and Simon

Conclusion Acknowledgment
Recent active and ambitious research activities provided new This work was supported by grants from the Deutsche Fors-
information on the complex pathophysiology of AD. These chungsgemeinschaft (KFO 208 TPA1 and SFB704 TPA4), a
new insights into the function and interaction between inflam- BONFOR grant of the University of Bonn (N.N.) and a
matory cells, resident cells, their cytokines and mediators grant from the S.T. Johnson Foundation (D.S.). N.N. was
might pave the way to more rationale-based treatment supported by a Heisenberg-Professorship of the DFG
approaches. New therapeutic approaches aim to specifically NO454/5-2.
target dysregulated structural or immune functions and/or dis-
ease triggers. As there are interindividual variations between
Authors contributions
AD patients in terms of underlying endogenous and exo-
genous disease mechanisms and triggers, subgroups have to be N.N. and D.S. have written the manuscript.
identified to create an individualized and effective treatment.
Such individualized treatment approaches might substantially
Conflict of interest
amend current symptomatic therapies, which target more general
pathways of inflammation and skin barrier function. On a N.N. has received research grants from Alk Abello and
long-time perspective, the introduction of individualized treat- is speaker for Alk Abello, Bencard Allergy Therapeutics,
ment approaches will reduce the risk for severe and chronic Phadia and Novartis/LetiPharma. D.S. was supported by a
AD and improve the quality of life of patients with AD. research grant from Roche Pharma Switzerland.

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