Expert Review of Clinical Immunology

ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: http://www.tandfonline.com/loi/ierm20

The adaptive immune system in atopic dermatitis

and implications on therapy

Lennart M. Roesner, Thomas Werfel & Annice Heratizadeh

To cite this article: Lennart M. Roesner, Thomas Werfel & Annice Heratizadeh (2016) The
adaptive immune system in atopic dermatitis and implications on therapy, Expert Review of Clinical
Immunology, 12:7, 787-796, DOI: 10.1586/1744666X.2016.1165093

To link to this article: http://dx.doi.org/10.1586/1744666X.2016.1165093

Accepted author version posted online: 11

Mar 2016.
Published online: 28 Mar 2016.

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 EXPERT REVIEW OF CLINICAL IMMUNOLOGY, 2016
VOL. 12, NO. 7, 787–796
http://dx.doi.org/10.1586/1744666X.2016.1165093

REVIEW

The adaptive immune system in atopic dermatitis and implications on therapy

Lennart M. Roesner , Thomas Werfel and Annice Heratizadeh
Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany

ABSTRACT ARTICLE HISTORY

In atopic dermatitis (AD), the skin inflammation is believed to occur due to a misdirected immune Received 12 January 2016
reaction against harmless antigens on the one hand, and to a disturbed skin barrier on the other. In Accepted 9 March 2016
recent years, vast efforts have been made to investigate the relevance and details of the immune Published online
29 March 2016
response to allergens. Clinically, it was demonstrated for the first time that aeroallergen exposure leads
to worsening of AD symptoms. An overexpression of Th2 cytokines has been observed in acute and KEYWORDS
subacute lesions of AD. The clinical impact of the key Th2 cytokines IL-4 and IL-13 on atopic dermatitis Inhalant sensitization;
has recently been shown in clinical studies with dupilumab, a monoclonal antibody which blocks the IL- allergen-specific immune
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4/IL-13 receptor. In vitro data indicate, however, that the T cell response is not solely Th2-polarized but response; S. aureus; skin
may lead to heterogeneous cytokine production involving IFN-γ and IL-17 in an allergen-dependent inflammation
manner. Classical thymus-derived Foxp3 T cells have interestingly been detected in elevated numbers
in the circulation of AD patients. Therapeutic approaches with allergen specific immunotherapy aim to
induce regulatory T cells of the Tr1 type. The strikingly altered microbiome of AD skin with diminished
diversity of bacteria on lesional skin but increases of S. aureus colonization and the sensitization against
microbial allergens and homologue self-proteins deserve special attention. For the treatment of itch
symptoms, which still represent a challenge in daily practice, promising data have been published on
the relevance of the H(histamine)4-receptor and on mediators such as IL-31, TSLP.

Introduction cells are activated even in circulation [3], a systemic character

of AD is meanwhile generally accepted. While high numbers
Atopic dermatitis (AD) is considered to be the most common
of myeloid antigen presenting cells do also in infiltrate the
inflammatory skin disease with a prevalence of 10–15% in
skin, different dendritic cell types are supposed to traffic to the
children an 1–2% in adults in industrialized countries [1].
lymph nodes in order to present allergens. This inflammatory
Since in AD a disrupted skin and inflammation processes
axis from antigen presentation to T cell activation leading to
come together, it has always been argued on which problem
IgE production by B cells has to be studied in detail to under-
underlies/precedes the other. While supporters of the outside-
stand the disease. This review focuses on the immune system
in theory claim that the inflammation occurs due to facilitated
in AD and reflects recent findings in allergen exposure, aller-
skin penetration of allergens and stress factors, passionate
gens, and inflammatory mediators. In particular, we aim to
advocates of the inside-out theory would answer that an
summarize new insights and findings regarding the allergen-
ongoing inflammation first of all perforates the skin.
specific immune response, the influence of the inflammation
Genome-wide association studies have discovered muta-
on the skin barrier, as well as the pruritic nature of the disease,
tions that are associated with AD, located in genes of the
published within the last 5 years.
skin barrier as well as of the inflammatory network. However,
even the top-impact mutations do not lead in every case to
AD. Also, the risk of developing an allergy throughout life is Allergen-specific immune responses in AD
genetically inherited, but it is meanwhile common knowledge,
Most adult patients with AD are IgE-sensitized to a variety of
that environmental factors play a major role regarding allergic
seasonal or perennial allergens (so-called extrinsic type of AD).
sensitizations [2]. Bacterial infections represent an important
While in a subgroup of children with AD sensitization to
trigger factor in AD and it has been shown that the composi-
food allergens represents a relevant trigger factor of AD [4,5],
tion of the microbial colonization changes upon skin
this phenomenon is much less frequent in adults. Here, birch-
inflammation.
pollen-associated food allergens might contribute to a dete-
The inflammatory cell-skin infiltrate is common in all AD
rioration of skin symptoms in a subgroup of AD patients IgE-
lesions. Mostly located at the basal layer, mononuclear cells
sensitized to birch pollen [6]. Indeed, airborne allergens gain
intrude into the dermal epidermal layers. The most frequent
in importance during adolescence and adulthood. Both seaso-
cell type make up the T helper cells, while cytotoxic T cells,
nal and perennial allergens seem to have a substantial impact
making up 20% of the T cell infiltrate in skin lesions, may also
on the course of the so-called atopic march. In a recent study,
have distinct roles in the pathogenesis of the disease. Since T

CONTACT Lennart M. Roesner Roesner.lennart@mh-hannover.de

© 2016 Informa UK Limited, trading as Taylor & Francis Group
 788 L. M. ROESNER ET AL.

the measurement of specific IgE at 3, 5, and 11 years of age allergens like Der p10, 11, 14, and 18 which are found in
revealed a strong association between early onset of grass mite bodies rather than in the feces appear to be more
pollen sensitization as well as house dust mite (HDM) sensiti- often recognized by specific IgE in AD patients compared to
zation and the comorbidity of atopic asthma, rhinitis, and atopic individuals with other clinical manifestations [12].
dermatitis [7]. Likewise, sensitizations against the newly discovered major
However, the actual relevance of sensitization in AD is still allergen Der p23, which is found mainly in mite feces, are
controversially discussed. In the following, we aimed to pro- more often accompanied by asthma than AD [13]. Of note,
vide an overview on recently published data on the role of the mite-body allergen Der p11 was found to be of specific
allergen-specific immune responses for skin inflammation and relevance in AD in a European and African patient cohort [12].
highlight the potential clinical impact of findings from basic However, also in AD patients specific IgE directed against
research. these minor allergens is detectable in lower levels in serum
compared to the type 1 and 2 HDM major allergens, against
which 66–82% or 81–95% of mite-allergic patients are sensi-
Perennial inhalant allergens: HDM tized, respectively [12,14]. Der p1 deserves special attention,
since the enzymatic activity is involved in the maturation
Adult patients with AD are very commonly sensitized to HDM. processes of other mite allergens and has therefore been
The atopy patch test (APT) has been established a further termed ‘the maestro’ [15]. Furthermore, Der p1 protease activ-
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diagnostic tool particularly for AD patients sensitized to inha- ity is capable of disrupting the epithelial barrier and to signal
lant allergens [8]: By epicutaneous application of allergens, via protease-activated receptors and thereby facilitates sensi-
such as HDM, on unaffected back skin eczematous lesions tization against further allergens in an AD mouse model [16].
can be induced (Figure 1). Eczematous reactions usually However, Landheer et al. [17] sound a note of caution report-
occur after 48–72 h indicating a potential clinical relevance ing that HDM allergens release thymic stromal lymphoprotein
of the respective allergen in a subgroup of AD patients [9]. (TSLP) when applied to mouse but not human skin, thereby
Allergen challenge represents the ‘gold standard’ in diagnos- creating a species bias. Nevertheless, the British Manchester
ing allergy, to our knowledge only one study used this Asthma and Allergy Study cohort confirmed the Der p1 dom-
approach to investigate the impact of HDM allergens on AD: inance detecting higher odds rations for Der p1/Der f1 com-
Here, 20 patients with AD underwent bronchial provocations pared to Der p2/Der f2 to be associated with AD [7].
with HDM in a double-blind, randomized, placebo-controlled With regard to causal treatment options, a multi-center,
setup [10]. Within 1.5–17 h after the challenge an exacerbation randomized, dose-finding trial using HDM-allergens for sub-
of preexisting lesions, new lesions formation or both in nine cutaneous specific immunotherapy was performed (SIT). The
patients occurred. These data clearly implicate that not only overall efficacy of SIT with HDM-extract was only moderate in
skin contact as observed by APT, but also respiratory exposure AD [18]. It might be supposed that the HDM extract used for
to an inhalant allergen might induce and amplify skin inflam- SIT in these studies probably did not contain sufficient
mation in AD. amounts of those HDM-specific T cell epitopes which particu-
Strategies of allergen reductions such as mattress encasing, larly play a key role in HDM-specific immune responses in AD.
for example, are recommended for patients with AD sensitized To better understand the characteristics of allergen-specific
to HDM [11]. In this regard, it is noteworthy that HDM T cells in humans, we investigated HDM-specific T cells in AD
patients in more depth [19]. Applying major histocompatibility
complex (MHC) class II tetramers specific for HDM major aller-
gens directly ex vivo, specific T cells were visualized and
assigned to the effector memory Th2, Th17, and Th2/Th17
mixed subtypes. Cytokine data from T cell lines supported
the likewise production of IL-4 and IL-17 in response to
HDM. The Th2/Th17 polarization seems to be tightly con-
nected to the HDM sensitization since other allergen-specific
T cells have been mostly described as Th2-polarized so far [20].
Increased numbers of HDM-specific Th2/Th17 cells have
also been described in allergic asthma by means of transcrip-
tion factor expression and T cell clones, respectively [21,22].
While focusing on the Th1/Th2 imbalance in allergic rhinitis,
Wambre et al. measured IL-17 gene transcription in HDM-
specific T cells in only a subset of patients but found one
out of four eliciting a mixed Th2/Th17 response [23]. Th2/
Th17 T cells bear strong pro-inflammatory capacities in cyto-
kine production and attraction of eosinophils, neutrophils,
macrophages, and lymphocytes into the lung in a mouse
model [22].
The Th2, Th17, and Th2/Th17 mixed HDM-specific pheno-
Figure 1. Eczematous lesion after skin application of HDM allergen by APT. type may be explained with the perennial and ubiquitous
 EXPERT REVIEW OF CLINICAL IMMUNOLOGY 789

presence of dust mite particles inside buildings. Possibly, indicating a Th2-immune response in grass pollen exposed
microbial compounds like LPS, endotoxins, and other natural patients compared to those exposed to clean air. Further in
adjuvants which accompany HDM allergens and are detected vitro analyses revealed a significantly higher increase in the
by antigen-presenting cells in parallel account for this phe- serum levels of the chemokine-ligands (CCL)-17 and CCL-22
nomenon [24]. It was shown before that TLR2 signaling leads which both reflect the disease activity in AD. Further studies
to Th17-polarizing conditions via IL-23 secretion of antigen- using this model of allergen exposure are needed in order to
presenting cells [25]. Over the past 5 years, another pattern- further elucidate the underlying immune response
recognition receptor, the C-type lectin receptor Dectin-2, was mechanisms.
investigated to respond to HDM particles and to signal toward Allergen-specific T cell reactivity has been studied several
Th2 and Th17 in mice [26,27]. Taken together, these new data, times applying MHC-tetramer staining. In most of the studies,
but also further studies on allergen-specific immune responses however, the patient cohort was not further divided into the
typical for AD are essential for the development of highly different atopic diseases. So far, the T cell response to peren-
efficient disease-specific therapeutic strategies. nial and seasonal allergens has been investigated by the
model antigens HDM versus birch pollen in allergic rhinitis
and interestingly the response to both allergens was different:
Seasonal inhalant allergens: birch and grass pollen
While T cells specific to Bet v1 appeared to be of an Th2
In epidemiological- and population-based studies, seasonal effector memory type in sensitized donors, Der p1-specific T
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variation of AD symptoms has been reported [28]. In daily cells expressed surface markers well-known for central mem-
routine, sensitization to inhalant allergens such as birch or ory T cells like CD62L and secreted a heterogeneous set of
grass pollen in AD is diagnosed by determination of specific cytokines [23].
IgE antibodies or skin prick test. The APT has been developed Follow-up studies on patients suffering from allergic rhinitis
as an additional diagnostic tool for AD patients with suspected and/or asthma revealed that SIT does not necessarily result in
clinically relevant inhalant sensitization and rather is per- reduced T cell proliferative responses to allergens [32] or to
formed in clinical studies than in daily clinical routine [8]. lower specific IgE serum levels [33]. Interestingly, a closer look
Indeed, a higher specificity with regard to the patient’s history at the specific T cells revealed differences in the quality of the
can be achieved by APT with grass pollen allergen than by response after a successful SIT. Alder-pollen-specific T cells
skin prick test or in vitro diagnostic [9,29]. Since the diagnostic displayed a phenotype after SIT resembling less differentiated
validity of APT still is not comparable with that of provocations T cells, that is a lower proportion of effector-like T cells was
tests, recent studies focused on challenging AD patients to observed [34]. More precise, the absence of the cell surface
imitate ‘real life conditions’. For this purpose, a cohort of AD markers CD27 and CCR7 is a hallmark of repeated antigen
patients sensitized to birch pollen was orally challenged with contact and cell differentiation to effector cells. Since these
birch-pollen-related food in a double-blind placebo-controlled cells express also CD7, it is assumed that these cells are prone
manner [6]. Seventeen out of 37 patients showed a significant to apoptosis, which may explain the rapid vanishing during
deterioration of eczematous lesions (responders). Remarkably, SIT [34].
birch-pollen-specific T cell proliferation could be detected in For grass pollen, a grass-subfamily-wide T cell cross-reactiv-
lesional skin of responders. By contrast, responders could not ity in allergic patients was described applying state-of-the-art
be differentiated from nonresponders by birch-pollen-speci- methods [35]. Unfortunately, the cohort was not further differ-
fic IgE. entiated regarding different atopic diseases. However, an epi-
In a recent single-center, double-blind placebo-controlled tope mapping revealed a promising tolerance-inducing
study, we studied the clinical relevance of IgE-sensitization to peptide [36]: The discovered 20mer of the timothy-grass-pol-
grass pollen: adult patients with moderate AD and accompa- len allergen Phl p5 contains a motif highly conserved among
nying IgE-sensitization to grass pollen were challenged with grass allergens and showed strong binding affinity to a wide
grass pollen [30]. On two consecutive days, patients stayed in range of common HLA-types making it an ideal candidate for
a challenge chamber over a period of 4 h and were exposed to peptide-SIT. In mice, tolerance against Phl p5 was induced by
either grass pollen (4000 pollen grains/m3, verum group) or intranasal pretreatment with the peptide. Established timothy-
clean air (placebo group). The area and intensity of eczema- grass-pollen SIT was shown to result in a reduction of Phl p1-
tous lesions was assessed by objective SCORAD and, more- specific Th2 cells, leading to an overweight of Phl p1-specific
over, air-exposed and textile-covered skin areas were Th1 and regulatory Tr1-T cells, as determined by MHC-II-tetra-
separately evaluated by local SCORAD. In the verum group, a mer staining and confirming data from alder pollen-specific T
significantly higher increase in objective SCORAD could be cells [34,37]. This Tr1 subtype is defined as a Th1 cell that
observed from pre-challenge to post-challenge day 3. produces TGF-beta and IL-10 in excess to the usual IFN-γ,
Interestingly, deterioration of eczema rather occurred in air- thereby diminishing the immune response. In healthy indivi-
exposed than in textile-covered skin areas. These data impli- duals, most allergen-specific T cells are of this Tr1-type [20,38].
cate that induction of a flare-up might be due to direct con- Longitudinal observation of birch–pollen SIT over 3 years con-
tact of the allergen to pre-activated cells of the innate and firmed the loss of Th2-polarized T cells after the first year and
adaptive immune system in the skin. It is hypothesized that discovered also, that the expansion of Tr1 cells is a transient
the allergen directly penetrates into the skin as has also been but essential phenomenon [39].
postulated for microbial allergens [31]. In this study, a signifi- These findings show the impressive potential regarding the
cantly higher increase of serum IL-4 levels was observable regulation of the allergic immune response by Th1/Tr1 cells.
 790 L. M. ROESNER ET AL.

However, it should be emphasized that these studies cited specific IgG antibodies upon immunization that are focused
here were conducted on allergic patients in general and lack to the major IgE-binding sites on the allergens [48,49].
information about the subfraction of AD patients. However, the outcome of clinical trials investigating the
Classical thymus-derived Foxp3+ Tregs are not in the efficacy of SIT in AD with inhalant sensitization still is hetero-
focus as a marker for successful treatment. Our recent geneous. Actually, SIT still is indicated for treatment of allergic
data revealed elevated numbers in severe AD, indicating airway diseases. Regarding beneficial effects on AD, the num-
that many Tregs per se do not sufficiently suppress the ber of study patients included was too low in many studies for
inflammation [40]. We applied for the first time a detection achieving any statistically significant effects [18]. For this rea-
technique that is unaffected by antibody-staining impreci- son, SIT can actually be recommended for those AD patients
sion on adult AD patients: The detection of DNA-methyla- additionally suffering from inhalant allergy of the airways. In
tion in the Foxp3-promotor region ‘TSDR’ (Treg-specific selected cases of severe AD with accompanying inhalant sen-
demethylated region) is believed to be the most robust sitization suspected to be relevant for skin inflammation, SIT
marker to detect thymus-derived Tregs [41]. On cord might also be considered to treat AD symptoms [11].
blood, this technique was applied to show a negative cor- Regarding options of causal therapy in future, existence of
relation between Treg numbers and the risk of developing heterogeneously polarized allergen-specific T cells in AD
AD [42] and to describe higher Treg frequencies after mater- patients as shown for HDM [19] opens new therapeutic per-
nal farm exposure [43]. Therefore, Foxp3+ Tregs seem to spectives targeting IgE and relevant T cell cytokines. Anti-IgE
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play a role in the sensitization phase of AD, but not after antibody (Omalizumab) did not lead to improvements of the
the disease status is established. SCORAD in a small clinical trial; although the reaction to APT
Analog to Tregs, regulatory B cells producing IL-10 have been was reduced in some cases [50].
described. These can be divided into the subgroups Br1 (also Regarding Th2 responses, studies involving anti-IL-13 and
called Br10), BR3, and Breg (analog to Tr1, Tr3, Treg). While in anti-CRTH2 antibodies are currently performed (https://clinical
vitro it could be shown that patients with a delayed type immune trials.gov) and [51]. A phase II trial subcutaneous application of
response to food allergens lack proliferation of TGF-β-producing dupilumab, which is a fully human monoclonal IL-4R antibody,
regulatory B cells [44,45], currently less is known regarding AD. led to significant improvement of AD symptoms in patients
Aside from IL-10, immunoregulation after a successful SIT suffering from moderate-to-severe disease [52]. To encounter
to pollen allergens has also been explained by the generation Th17, anti-IL 17 might represent a further promising therapeu-
of specific IgG antibodies. In these studies on patients suffer- tic option [53]. Additionally, epidermal growth factor might be
ing from allergic rhinoconjunctivitis and/or asthma, long-last- the utilized, since Th17 responses as well as IL-6 production
ing IgG4 antibody populations were observed that are capable are diminished in a mouse model of AD [54].
of blocking IgE-binding [33]. In contrast to the generation of
Tregs, these immunoregulatory antibodies increased steadily
Microbial antigens and the microbiome in AD
during the course of the SIT leading to a peak of IgE-blocking
ability at the end of the therapy. Staphylococcus aureus
Patients with AD are characterized by a higher susceptibility for
Therapeutic implications/inhalant sensitization skin colonization and clinically apparent superinfection of ecze-
Strategies of allergen avoidance are still part of the present matous lesions with Staphylococcus (S.) aureus [55]. More than
therapeutic concept for secondary prevention. With regard to 50% of all skin colonizing S. aureus strains have been reported to
HDM, the use of encasing materials for beddings can be secrete exotoxins contributing to inflammation in AD. On the
considered for those AD patients who are sensitized to HDM. one hand, these superantigens lead to T cell proliferation. On
By contrast, avoidance strategies of dust mite allergens for the other hand, they may elicit an allergen-specific immune
reasons of primary prevention do not alter the risk of devel- responses leading to staphyloccocal-exotoxin-specific IgE
oping an AD in childhood (meta-analysis by [46]). [56,57]. For IgE sensitization to SEB, a correlation with the sever-
From experimental and clinical data mentioned above it ity of AD has been demonstrated [58].
can be concluded that the immune response to different These exotoxins stimulate MHC II positive antigen present-
allergens is very heterogeneous and not restricted to the ing as well as T cells which in turn release a number of
classical allergic Th2 cytokines. This may indicate a require- cytokines including pro-inflammatory T cell cytokines such as
ment for different anti-inflammatory treatment strategies: for IL-31 [59] and IL-17. Significant amounts of the Th2 cytokine
AD patients with proven clinically relevant inhalant sensitiza- IL-31 could be detected in severe itching AD lesions.
tion innovative causal therapy options are needed. Therefore, IL-31 is suspected to play a pivotal role for promot-
Ongoing research improving the SIT led to recombinant ing the so-called itch–scratch-circle in AD (see also The role of
allergen components that have limited capacity to induce cytokines in itch in AD section). For IL-17A, ‘tissue remodeling’
IgE-responses. This approach is desirable for patients with properties during the acute phase of inflammation in AD have
first and foremost IgE-mediated immediate-type immune reac- been published and mouse data suggest that IL-17 promotes
tions. The delayed-type T cell reactivity remains, as it has been Th2 differentiation [60]. In addition, SEB induced the produc-
shown applying Bet v1 hypoallergenic proteins via the APT tion of IL-22 ex vivo. IL-22 belongs to the IL-10 cytokine family
[47]. In AD, one forward-looking SIT-approach includes a novel and seems to be relevant for cellular immune responses since
approach with allergen-derived, but nonallergenic peptides increased numbers of IL-22 producing CD4+ and CD8+ T were
fused to a carrier protein. Fusion proteins induce allergen- detectable in AD skin [58].
 EXPERT REVIEW OF CLINICAL IMMUNOLOGY 791

We reported that the skin of 34% of all AD was colonized of AD lesions involving the antigen uptake by Langerhans
with S. aureus strains secreting the exotoxin alpha-toxin [57]. cells [66].
Regarding the clinical impact of immune responses to this
toxin, we described that patients who were colonized with Therapeutic implications/microbiome
alpha-toxin secreting S. aureus showed higher specific IgE In view of these new insights, recommendations on antimicro-
levels particularly to inhalant allergens [55]. A possible inter- bial treatment have now been modified. According to current
action of alpha-toxin – which can non-specifically activate guidelines and position papers on the treatment of AD, anti-
immune cells in sublytic concentrations via the NLPR3 inflam- microbial therapy is reserved for those AD patients with clini-
masome – with adaptive immune response has to our knowl- cally apparent bacterial superinfection of the skin. In these
edge not studied in depth so far. cases, a course with systemic antibiotics (such as first genera-
Remarkably, specific IgE-sensitization and T cell prolifera- tion cephalosporin) is recommended (e.g. [11], Wollenberg
tion is not only induced by S. aureus exotoxins but also et al. ETFAD position paper, JEADV submitted). By contrast,
by proteins such as S. aureus fibronectin-binding protein-1 topical treatment with antibiotics should be avoided due to
(FBP-1) [61]. Among AD patients with high-total IgE levels, the risk for antibiotic resistance and epicutaneous
the frequency of sensitization to S. aureus FBP was higher; sensitization.
however, this IgE sensitization could also be observed in
patients with low IgE levels. Malassezia
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First data to this effect indicate that S. aureus FBP-1 also Malassezia (M.) species are part of the resident skin flora in
contributes to a release of further pro-inflammatory cytokines healthy individuals, especially in those body regions where
relevant for AD. many sebaceous glands are present [67]. However, in a sub-
With regard to antimicrobial treatment recent findings on group of AD patients, M. ssp. species might act as trigger
the relevance of S. aureus for the cutaneous microbiome factor due to specific immune responses perpetuating skin
kicked-off a paradigm shift: It was shown that the diversity inflammation [68,69]. Approximately, 50% of adult AD patients
of the cutaneous microbiota is significantly reduced in lesional and also a subgroup of diseased infants show IgE-sensitization
skin in AD patients. Therefore, attention should now be to M. sympodialis. This phenomenon is specific for AD since it
focused also on ‘beneficial’ components of the microbiome. is rare in patients with other allergic diseases and not obser-
This implies that antimicrobial interventions should be vable in healthy individuals [70]. Moreover, a correlation
restricted in order contribute to reconstitution of a balanced between disease severity of AD and levels of specific IgE to
skin microbiome in AD patients [62]. M. ssp. species was reported [71].
By next generation DNA sequencing of 16S ribosomal From clinical practice it is well known that determination of
RNA bacterial genes, the bacterial diversity of the skin micro- IgE levels to M. ssp. species alone does not prove the clinical
biome of healthy individuals and children with AD was relevance of this sensitization. For this reason, further studies
compared [63]. In acute flares of AD, the proportion of focused on identification of a distinct clinical pattern asso-
Staphylococcus, especially S. aureus, was significantly ciated with sensitization to M. alassezia. Data published so
increased within the skin microbiome, making up to over far indicate that AD patients with head-neck-shoulder derma-
90% on untreated lesions. Post-flare and at baseline on titis have a higher risk for sensitization to M. alassezia and,
formerly lesional skin this predisposition was still apparent moreover, show significant higher M. ssp. -specific IgE levels
compared to the skin of healthy individuals. Here, the com- than those whose eczema occurs in other body regions [72].
position of the microbiome was very diverse with 14 major
phyla involved to substantial amounts. Tauber and collea- Therapeutic implications/microbiome
gues [64] confirmed the overwhelming colonization of S. For topical treatment with ciclopiroxolamine as well as for
aureus on non-lesional and lesional AD compared to healthy systemic therapy with ketoconazole beneficial effects on AD
skin with a rather simple PCR technique, allowing rapid severity have been reported [73,74]. Based on these data,
estimation of colonization density. Although staphylococcal antifungal treatment can be considered in adolescent or
sequences was found in considerable percentages as well on adult AD patients with head–neck–shoulder dermatitis who
healthy control skin samples, deep characterization revealed are clearly IgE-sensitized to M. ssp. species [11].
that most of them belonged to S. epidermidis and not to S.
aureus [63].
Autoallergy
This is of importance since S. aureus and S. epidermidis are
both known to induce profound but different effects on It has been an issue of discussion for several years whether
immune cells. For example, S. aureus-secreted factors led to sensitizations against uncommon (bacterial) allergens or auto-
a strong secretion of IFN-γ and other cytokines by monocyte- allergens might be relevant for the severity and the cause of
derived dendritic cells in young children with AD. In contrast, AD. In terms of autoallergens, some microbial antigens are in
the secretome of S. epidermidis led to the production of IL-10 the focus of research since IgE and T cell cross-reactivity to
without IFN-γ. The secretome of S. aureus, but not of S. epi- several human proteins have been described [75]. Especially
dermidis, was also efficiently inducing CD4+ T cell proliferation for M. alassezia antigens, cross-reactivity to self-proteins has
in an autologous in vitro approach. Of interest, in this study, been studied in detail [69,76].
the S. aureus colonization was correlated to the total of serum Reaction against self is a phenomenon that has been
IgE [65]. S. aureus was confirmed as a driver of the formation observed already decades ago in AD, and meanwhile it is
 792 L. M. ROESNER ET AL.

established that IgE- and T cell autoreactivity occur frequently IL-31 is supposed to be a direct link between skin inflam-
in AD patients [77]. A contribution to a chronification of the mation in AD and itch [59] and serum levels correlate with
disease by perpetuating skin inflammation is discussed, but it severity of the disease in children [95]. Aside from itch signal-
is difficult to assess to what extent the ‘autoallergy’ [78] con- ing, keratinocytes are affected by IL-31. The IL-31 receptor is
tributes to the disease. upregulated by IFN-γ in these cells [96], and signaling leads to
The immune response against IgE-reactive self-proteins downregulation of filaggrin and a defect in the skin bar-
appears not to be shaped in a classical, Th2-fashioned way. rier [97].
T cell clones specific for human thioredoxin (hTrx), which is the The receptor IL-31R is expressed on normal dorsal root
human homologue to the M. ssp. antigen Mala s 13, have ganglia and nerve fibers within the AD dermis [98] and
been shown to display very heterogeneous polarization pat- therefore, underlines the role of a direct link to itch signal-
terns like Th2, Th17, and Th22, but predominantly Th1 in ing [99]. While Bilsborough et al. [100] showed skin-infiltrat-
blood and lesional AD skin [69]. Human alpha chain of nas- ing cells to be a source; Szegedi et al. [101] detected
cent-polypeptide-associated complex (α-NAC), for which no substantial amounts of IL-31 in Th2 and to lesser extent in
homology to an allergen has been identified so far, led to Th22 cells derived from chronic lesional AD skin. Stott and
significant proliferation of skin-homing T cells in AD patients. colleagues [102] confirmed that IL-31 is indeed expressed by
Moreover, α-NAC-specific T cell clones generated from lesional Th2 cells and not by any other Th-cell lineage, but it cannot
skin predominantly produced IFN-γ and sometimes IL-17 be seen as a classical Th2 cytokine in general. Blocking of IL-
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[79,80] while significant numbers of α-NAC-specific T cell 4 revealed a strong dependence and it was furthermore
clones generated from peripheral blood of AD patients were possible to evoke IL-31 expression in Th1 cells stimulated
interestingly CD8+. Ongoing studies show that these are of an with IL-4. Another potent stimulus of IL-31 appears to be
effector-memory type in sensitized patients [81]. staphylococcal alpha-toxin [103]. Transcription of IL-31 is
In addition, these two model autoallergens do also affect regulated synergistically by JunB and NFAT1 [104], both
other cells of the immune system in an alarmin-like manner. being well-known players in the inflammatory network
For hTrx, secretion upon stress has been described, leading to of AD.
secretion of IL-13 and IL-10 by peripheral blood mononuclear
cells. Interestingly, cells derived from M. alassezia-sensitizied
Therapeutic implications/pruritus
AD donors produced more IL-13 and less IL-10 in response to
hTrx [82]. Patients sensitized to α-NAC displayed a diminished Regarding antipruritic strategies in AD the present therapeutic
IL-10 response to their autoallergen in vitro, too, while the pro- concept comprises a variety of options. For topical anti-inflam-
inflammatory answer includes amongst others IFN-γ, IL-12, IL- matory substances such as glucocorticosteroids as well as
17, and IL-22 [83,84]. This intrinsic effect to produce mediators topical calcineurin inhibitors significant antipruritic effects
of inflammation may aggravate the pro-inflammatory environ- have been demonstrated in a series of large clinical studies
ment, what may explain to some extent, why sensitization in children and adults [105–107]. Remarkably, application of
occurs against these self-proteins. moisturizers and emollients also revealed a reduction of itch
symptoms in several trials [108]. Additionally, systemic immu-
Therapeutic implications/microbiome nosuppressive and immunomodulatory drugs like ciclosporine
Further human studies are needed to better characterize the A or azathioprine show beneficial effects also on subjective
subgroup of AD patients who show clinically relevant autoaller- disease symptoms [109]. By contrast, there is no evidence for
gic reactions. However, data on hTrx should already be consid- sufficient efficacy of topical and oral H1-antihistamines on
ered in AD patients sensitized to M. ssp. species who suffer pruritus in AD. With regard to sedating effects of H1-antihis-
from therapy refractory head–neck–shoulder dermatitis (see the tamines, these might be used only in selected cases of adult-
Microbial antigens and the microbiome in AD section). hood AD during severe flare-ups as adjuvant therapy [11].
Recent data from experimental studies indicate that H4-
receptors might be more relevant in the pathogenesis of AD
The role of cytokines in itch in AD
than H1-receptors. H4-receptors are expressed on different
The so-called itch–scratch cycle [85] describes the aggravation leukocyte subpopulations as well as on peripheral sensory
of AD by scratching the inflamed skin, provoked by a constant nerves [110]. In a first placebo-controlled phase IIa study
strong itch. Several pro-inflammatory molecules are in the with a H4-antagonist a significant, dose-dependent effect on
focus of itch-targeted research in AD. Next to neuropeptides itch symptoms and a trend of improvement of eczema in AD
and histamine, the cytokines IL-31 and TSLP are of high inter- patients were observable. Since two patients developed agra-
est to date [86]. Wilson et al. [87] were able to show in a nulocytosis, the study had to be stopped prematurely. For this
mouse model that keratinocytes communicate via TSLP reason, results from this study are based only on a small
directly with cutaneous sensory neurons and induce itch. So cohort [111].
far, TSLP had an established role in driving T cell polarization A randomized, placebo-controlled phase I/Ib study investi-
toward the Th2 lineage [88]. Keratinocytes are believed to gating the safety and tolerability of a humanized anti-IL-31
release TSLP upon pattern-recognition receptor triggering receptor A monoclonal antibody in AD patients revealed
[89,90], PAR2-signaling [91], IL-33 signaling [92], and possibly further promising results: After single subcutaneous adminis-
physical trauma like scratching [93]. Furthermore, also other tration of this antibody intensity of pruritus significantly was
cell types in the skin express TSLP, like Langerhans cells [94]. reduced at week 4 [112]. An anti-TSLP antibody is currently
 EXPERT REVIEW OF CLINICAL IMMUNOLOGY 793

being investigated in combination with SIT for cat asthmatics chronic-persisting course of the disease, autoallergic phenom-
(https://clinicaltrials.gov). ena might be relevant. This subgroup remains to be better
Assessment of itch symptoms in most clinical studies were characterized in order to recognize appropriate treatment
part of disease symptoms scores such as SCORAD index, but options.
itch symptoms had not exclusively been defined as primary
endpoint. For this reason, further innovative clinical studies
primarily focusing on antipruritic effects and targeting rele- Key issues
vant receptors and molecules are needed. ● The response to allergens has been proven to have signifi-
Experimental and clinical data indicate that the pathogen- cant impact on eczema foundation in a subgroup of
esis of pruritus in AD is multifactorial and still not fully under- patients: Controlled exposure to aeroallergen leads to wor-
stood. Indeed, treatment of pruritus still represents a sening of AD symptoms in sensitized patients.
challenge in daily practice. Individual trigger factors of itch ● Eczema flare-ups on grass–pollen exposure predominantly
symptoms have to be identified and aspects of specific beha- occurred in air-exposed skin areas.
vioral therapy should also be considered. Consistently, partici- ● The T cell response to allergens has been investigated in a
pation of children and adolescents in an educational program detailed manner during the recent years.
with a multi-professional team revealed significant beneficial ● The dogma of a solely Th2-polarized allergic inflammation
effects on itching behavior [113]. For this purpose, a combina- is no longer supported.
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tion of antipruritic medication with behavioral interventions ● Differences in the response to seasonal, perennial, microbial,
such as relaxation exercises, for example, will be indicated in and auto-antigens support an individual character of AD.
most of the patients. ● IgE and T cell autoreactivity are common phenomena
in AD.
Expert commentary ● AD lesions display less microbial diversity with a predomi-
nance of S. aureus.
Genome-wide association studies revealed genes of the skin ● Aside from histamine, new candidates for itch signaling in
barrier as well as of the immune system to be involved in the AD have been identified.
pathogenesis of AD. In parallel, research on allergens decoded
immunogenic features and pro-inflammatory characteristics.
With regard to both reconstitution of the skin barrier function Declaration of Interest
and prevention of allergic sensitization, a consequent use of T Werfel has received consulting and research grants from Regeneron
emollients actually gains in importance in basic and clinical Pharmaceuticals Inc. and Ziarco Pharma Ltd. A Heratizadeh has received
research. The cellular infiltrate of the skin, which is shaping the fees for consulting for Ziarco Pharma Ltd. The authors have no other
picture of dermatitis/eczema, responds to allergens in a het- relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject
erogeneous, allergen-dependent manner. While the focus lies
matter or materials discussed in the manuscript apart from those
on Th2 cytokines, also Th1, Th17, and Th22 are under investi- disclosed.
gation regarding AD treatment. For the development of anti-
pruritic treatment strategies, current studies focus on new
anti-inflammatory agents targeting the Th2-cytokine IL-31 or ORCID
TSLP, but also the H(histamine)4-receptor. Lennart M. Roesner http://orcid.org/0000-0001-6651-0458

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