Вы находитесь на странице: 1из 14

PERSPECTIVE

The Role of Leukocytes, Keratinocytes, and


Allergen-Specific IgE in the Development of
Atopic Dermatitis
Thomas Werfel1

This review provides an overview of the inflammatory mechanisms and immunological aspects specific to
atopic dermatitis. The review discusses publications on the roles of different T-cell subsets (that is, T helper 1
(Th1), Th2, T-regulatory, and Th17 cells), myeloid and plasmacytoid dendritic cells, and eosinophils. A further
focus lies on keratinocyte–T-cell interactions, which may be of particular relevance in eczema. Mechanisms in
innate and adaptive immunity that result in susceptibility to skin infections and in hyperreactivity to
environmental stimuli, influencing the course and severity of atopic dermatitis, are summarized. Because the
Journal of Investigative Dermatology has recently published reviews of specific features of barrier defects,
defects in innate immunity, and, in this issue, genetics, these topics are only briefly discussed here in the
context of immunology of atopic dermatitis.
Journal of Investigative Dermatology (2009) 129, 1878–1891; doi:10.1038/jid.2009.71; published online 9 April 2009

INTRODUCTION inflammatory mechanisms. The immu- 30% of patients with AD. This finding
Atopic dermatitis (AD) is a chronic nohistology of the various phases of the was first published by Palmer et al.
inflammatory skin disease that com- disease are summarized, and the major (2006) and then confirmed by several
monly begins in early infancy, runs a cells involved in cutaneous inflamma- other groups (see reviews: Brown and
course of relapses and remissions, tion are characterized. Clearly, McLean, 2009; O’Regan and Irvine,
and is associated with a characteristic the different T-cell subpopulations 2008). The filaggrin loss-of-function
distribution and morphology of skin (CD4 þ versus CD8 þ , T helper 1 mutations are thought to lead to dry
lesions. Furthermore, pruritus and con- (Th1) versus Th2 versus Th17; T-reg- skin associated with a greater skin
sequent sleeplessness are hallmarks of ulatory (T-reg) cells) deserve particular response to irritants than that of normal
AD. Numerous trigger factors have attention. In addition, it is now clear healthy skin. Microscopic studies re-
been identified for AD in recent dec- that dendritic cells (DCs) and keratino- vealed a sparse perivascular T-cell
ades, including inhaled allergens, food cytes are critical elements in the (Th2) infiltrate in unaffected AD skin
allergens, irritative substances, and regulation of skin pathology in AD, that is not seen in normal healthy skin
infectious microorganisms, such as and eosinophils may aggravate the (Leung et al., 1983). Mast cell numbers
Staphylococcus aureus and Malassezia inflammatory reaction. are also slightly enriched in asympto-
species (Werfel and Kapp, 1998; Akdis An additional emphasis is placed on matic skin.
et al., 2006; Leung et al., 2007; Bieber, the role of specific IgE and T cells as Acute skin lesions are characterized
2008). well as the antigens that are recognized by intensely pruritic, erythematous
A complex interaction between sus- by these adaptive elements of the papules associated with excoriation
ceptibility genes encoding skin barrier immune system. and oozing exudation in AD. There is
molecules and markers of the inflam- a marked infiltration of mononuclear
matory response, host environments, IMMUNOHISTOLOGY cells that is histologically similar to that
infectious agents, and specific immu- Asymptomatic skin in AD differs from in allergic contact dermatitis.
nologic responses are involved in the normal skin: The underlying barrier CD4-positive Th cells dominate the
pathophysiology of AD. In this review, defect is associated with filaggrin loss- cellular infiltrate in AD (Zachary et al.,
the focus is on the immunological and of-function mutations in more than 1985). The CD4/CD8 ratio of dermis-

1
Department of Immunodermatology and Allergy Research, Hannover Medical School, Hannover, Germany
Correspondence: Professor Thomas Werfel, Department of Immunodermatology and Allergy Research, Hannover Medical School, Ricklinger 5, Hannover,
D-30629 Germany. E-mail: werfel.thomas@gmx.de
Abbreviations: AD, atopic dermatitis; CLA, cutaneous lymphocyte-associated antigen; DCs, dendritic cells; FcåRI, high-affinity receptor for IgE; IDECs,
inflammatory dendritic epidermal cells; LCs, Langerhans cells; MHC, major histocompatibility class; pDCs, plasmacytoid DCs
Received 15 May 2008; revised 1 December 2008; accepted 7 January 2009; published online 9 April 2009

1878 Journal of Investigative Dermatology (2009), Volume 129 & 2009 The Society for Investigative Dermatology
T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

infiltrating T cells is similar to that in occur after the skin is scratched. This The maintenance of chronic AD
peripheral blood. Many intralesional T results in the rapid upregulation of involves the production of GM-CSF
cells show signs of activation and can proinflammatory mediators such as IL- and the Th1-like cytokines IL-12 and
further be distinguished by CD45RO, a 1a, IL-1b, TNF-a, and GM-CSF (Homey IL-18 (Hamid et al., 1994), as well as
marker of T-memory cells, suggesting a et al., 2006). These proinflammatory several remodeling-associated cyto-
previous contact with antigen or aller- cytokines bind to receptors on the kines, such as IL-11 and TGF-b1, which
gen, and by the cutaneous lymphocyte- vascular endothelium, activate cellular are expressed preferentially in chronic
associated antigen (CLA). CLA defines signaling, and induce the expression of forms of the disease (Toda et al., 2003).
the subset of skin-homing T cells that vascular endothelial cell adhesion mo- In summary, early events include
bind to E-selectin, an adhesion mole- lecules. These events initiate the pro- endothelial–T-cell interaction and the
cule expressed by endothelial cells in cess of adhesion to the endothelium, release of chemokines—the under-
inflamed tissues during the first step of tethering, and transmigration of infil- standing of these events is of particular
leukocyte extravasation (Picker et al., trating cells. This process is tightly importance for a recurrent disease such
1990; Santamaria Babi et al., 1995). regulated and involves an active as AD.
Many circulating CLA þ T cells display communication process between
a Th2 phenotype and some are allergen endothelial cells and leukocytes. T T-LYMPHOCYTES
specific (Akdis et al., 1997). IL-12 cell–endothelial cell interactions are CD4 þ and CD8 þ T cells in AD
appears to be a key cytokine in the thus crucial in acute AD. In addition, Patients suffering from AD have in-
regulation of CLA; CLA-negative Th2 there is crosstalk between endothelial creased levels of activated circulating
cells rapidly upregulate a(1-3)-fucosyl- cells and other cutaneous cells, such as T cells. A study revealing increased
transferase VII (involved in the expres- mast cells and perivascular dermal telomerase activity and shortened telo-
sion of CLA) and CLA molecules macrophages (Steinhoff et al., 2006). mere length in AD indicates that T cells
(Biedermann et al., 2006). Once inflammatory cells have infil- are chronically stimulated and have an
Mononuclear cells and eosinophil trated into the tissue, they respond to increased cellular turnover in vivo (Wu
granulocytes can be found mainly in chemotactic gradients established by et al., 2000).
the dermis (Van Reijsen et al., 1992). cytokines and chemokines, which ori- The high number of circulating T
Mast cell degranulation can be ob- ginate from sites of injury or infection. cells results from increased numbers of
served in acute lesions. Antigen-pre- These molecules play a central role in CD4 þ cells, whereas the absolute
senting cells in lesional and, to a lesser defining the nature of the inflammatory number of CD8 þ lymphocytes is
extent, in nonlesional skin bear IgE infiltrate in AD. For example, IL-16 normal or even decreased in peripheral
molecules (Bieber, 2007; Novak et al., produced by Langerhans cells (LCs) blood. However, acute psychological
2007). may help in the recruitment of T cells stress has been shown to lead to rapid,
Chronic inflammation generally and has been reported in AD lesions significantly higher increases in the
causes tissue remodeling, which is also (Reich et al., 2002). Several homeo- number of circulating CD8 þ T-lym-
observed in chronic lesions of AD. This static and inflammatory chemokines, phocytes in AD patients compared with
can be observed as thickened plaques including CCL2 (MCP-1), CCL5 healthy controls. This may indicate that
with increased skin markings (lichenifi- (RANTES), CCL17 (TARC), CCL18 there are larger pools of this cell type
cation), increased collagen deposition in (PARC), CCL29 (LARC), CCL22 close to the circulation that can be
the dermis, and dry fibrotic papules. (MDC), and CCL27 (CTACK), have translocated into the blood during
Dermal macrophages are markedly in- been shown to be increased in AD psychological stress (Schmid-Ott
creased in the dermal infiltrate during and thus may support leukocyte re- et al., 2001a).
the chronic phase. Intact eosinophils are cruitment (Homey et al, 2006). Of note, The role of CD8 þ T cells in atopic
less commonly found, but eosinophilic cutaneous T-cell-attracting chemokine skin inflammation is still not well
products can be identified in chronic (CCL27) is significantly upregulated in defined. It has been shown that CLA þ
lesions of AD. T cells remain present in AD and preferentially attracts cuta- CD8 þ T cells isolated from the circu-
the chronic phase, although in smaller neous lymphocyte antigen-positive T lation are as potent as CLA þ CD4 þ T
numbers than seen in acute AD. cells into the skin. Selective recruit- cells in the induction of IgE and
Taken together, both asymptomatic ment of CCR4-expressing Th2 cells is enhancement of eosinophil survival.
skin and the different stages of eczema mediated by macrophage-derived che- This suggests that these cells have more
are associated with the infiltration of mokine (CCL22) and thymus and acti- than bystander functions in AD (Akdis
leukocytes (mainly T cells) that char- vation-regulated cytokine (CCL17), et al., 1999). Later, a significant asso-
acterizes the histology of this disease. which are increased in patients with ciation between the frequency of aller-
AD. Interestingly, serum levels of a gen-specific (that is, Der p 1-specific)
EARLY EVENTS IN AD number of chemokines (for example, CD8 þ T cells and disease activity
DEVELOPMENT CCL17, CCL22, and CCL27) correlate was described (Seneviratne et al.,
Early events initiating atopic skin in- with disease activity, suggesting an 2002). Recent data from a mouse
flammation involve mechanical trauma important role in the pathogenesis of model indicate that allergen-primed
and skin barrier disruption, which may AD (Homey et al., 2006). CD8 þ T cells are required for the

www.jidonline.org 1879
T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

development of AD-like lesions in vivo response to surviving Th2 cells as a and in psoriasis—its role in AD has to
(Hennino et al., 2007). mechanism for Th2 predominance in be defined (Piskin et al., 2006). Inter-
In summary, although CD4 þ cells the circulation and in acute lesions action with activated T cells via
clearly dominate over CD8 þ cells in (Akdis et al., 2003; Akkoc et al., CD40–CD40L may enhance IL-23 pro-
the skin in AD, there is some evidence 2008). Moreover, patients with AD duction by keratinocytes, which may
that CD8 þ cells are also of relevance have a genetic background of a enhance IFN-g production by memory
in this disease. general systemic Th2 polarization T cells (Wittmann and Werfel, 2006).
(Brown and McLean, 2009), which IL-18 is another cytokine that func-
T-cell cytokines in AD. The onset of contributes to the higher number of tions in parallel with IL-12 (Dinarello,
acute AD is strongly associated with circulating T cells capable of producing 2007). Keratinocytes functionally re-
the production of Th2 cytokines, nota- Th2 cytokines. spond to IL-18 with upregulation of
bly IL-4, IL-13, and IL-31, levels of IL-4, which is a strong inducer of a major histocompatibility class (MHC) I,
which are significantly higher in AD type 2 cytokine milieu itself, is pro- reinforcement of the IFN-g-induced
individuals compared with control sub- duced by ‘‘early’’ skin-infiltrating T MHC class II expression, and produc-
jects (Hamid et al., 1994; Neis et al., cells, but it may also come from mast tion of the chemokine CXCL10 (Witt-
2006). cells, basophils, or eosinophils during mann et al., 2005). This supports the
Th1 and Th2 cytokines may contri- an acute eczematous skin reaction. It is notion that IL-18 is involved in the
bute to the pathogenesis of local skin interesting to note that the high fre- pathogenesis of local Th1 responses in
inflammation in AD with the relative quency of IL-4-producing T cells in the chronic inflammatory skin diseases.
contribution of each cytokine dependent skin is not necessarily associated with The molecular mechanism of the
on the duration of the skin lesion. In atopy given that mRNA for IL-4 and T cytokine switch from Th2 in the acute
previous studies, the majority of aller- cells expressing IL-4 are also found in phase to Th1 in the chronic phase is
gen-specific T cells derived from skin nickel-induced patch test reactions complex and involves different Th2
lesions that had been provoked by (Neis et al., 2006; Szepietowski et al., cytokine-producing cells in the acute
epicutaneous application of inhalant 1997; Werfel et al., 1997b). phase (for example, T cells, basophils,
allergens were found to produce pre- Acute lesions show a reduced expres- mast cells) and Th1-polarizing cyto-
dominantly Th2 cytokines such as IL-4, sion of IL-12, a key cytokine of Th1 kines, which are produced primarily by
IL-13, or IL-5. This was initially consid- polarization, which was shown at the antigen-presenting cells.
ered to be a specific feature reflecting mRNA level by in situ hybridization in
immune dysregulation in AD (Sager acute skin lesions (Hamid et al., 1996). Effects of T-cell cytokines on the
et al., 1992; Van Reijsen et al., 1992). The reason for the relative lack in the inflammatory reaction in the skin in
It was subsequently shown that the expression of IL-12 is not completely AD. In lymphoid organs, IL-4 and IL-13
expression of IFN-g rather than of IL-4 understood. sCD40L was shown to mediate the IgE isotype switch in B
predominates in spontaneous or older inhibit IL-12 upregulation by an intracel- cells. In acute eczema, IL-4 and IL-13
patch test lesions in AD (Grewe et al., lular ERK-dependent signal-transducing induce a variety of local responses,
1995; Thepen et al., 1996). Importantly, pathway (Wittmann et al., 2002). These such as the induction of the adhesion
patient treatments that resulted in lesion results were reproduced later and ex- molecules on endothelial cells and Fc
improvement could be correlated with tended to skin-infiltrating CD40L þ T receptors on eosinophils or chemo-
downregulation of IFN-g expression, but cells, which may thus contribute to the kines (Leung et al., 2004). In contrast
not of IL-4, in the skin (Grewe et al., relative inability to upregulate IL-12 in to IL-5, IL-4 induces apoptosis in
1995). Also, allergen-specific T-cell acute eczema, leading to a refractory eosinophils (Wedi et al., 1998).
clones from spontaneous AD lesions state of constitutive antigen-presenting Recent findings demonstrate that IL-
differed from allergen-specific T cells cells (Wittmann et al., 2004). 4 and IL-13 have effects on keratino-
isolated from inhalant allergen patch test A number of factors may be in- cytes: both cytokines function via the
lesions by virtue of their capacity to volved in the switch from Th2 to Th1 same receptor (Purwar et al., 2007b).
produce IFN-g (Werfel et al., 1996). cytokines in older lesions. The polar- IL-13- or IL-4-stimulated keratinocytes
The cytokine switch from Th2 in the ization of T cells along the Th1 lineage, attract CCR4 þ CD4 þ Th2 cells via
acute phase toward Th1 in the chronic resulting in IFN-g production, is sup- CCL22 (Purwar et al., 2006). Moreover,
phase is accepted for AD and appears ported by IL-12, IL-23, IL-27, and IL-18 IL-13 induces the expression of MMP-9
to be relevant in allergic contact (Hunter, 2005). IL-12 subunits have in keratinocytes (Purwar et al., 2007a),
dermatitis as well. been found to be expressed by anti- which may play a crucial role in atopic
gen-presenting cells and by human skin inflammation by facilitating the
Factors contributing to cytokine milieu keratinocytes. However, it is not clear migration of leukocytes into the epi-
in AD. In patients with AD, activated T whether keratinocytes are indeed a dermis.
cells with skin-homing properties, relevant source of bioactive IL-12. Some AD patients have a filaggrin
which express high levels of IFN-g, IL-23 has recently been shown to be loss-of-function mutation leading to
may predominantly undergo apoptosis produced by DCs and by human reduced filaggrin expression in the skin
in the circulation, skewing the immune cultured keratinocytes in healthy skin (Brown and McLean, 2009). Recently it

1880 Journal of Investigative Dermatology (2009), Volume 129


T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

was shown that filaggrin expression Th17 lymphocytes in AD peripheral tolerance to self-antigens.
was reduced in AD even in the absence Recently, a novel and unique subset of CD4 þ Foxp3 þ T-reg cells have been
of a loss-of-function mutation (Howell IL-17-producing CD4 þ Th17 cells, dis- referred to as ‘‘naturally occurring’’ T-
et al., 2007). Keratinocytes differen- tinct from Th1 and Th2 cells, was reg cells to distinguish them from
tiated in the presence of IL-4 and IL-13 discovered. Th17 cells appear to be adaptive T-reg cells, which are gener-
exhibited significantly reduced filag- involved in protection against bacterial ated upon activation. A major popula-
grin gene expression compared with pathogens. In addition, Th17 cells may tion of adaptive T-reg cells is
medium alone. Neutralization of IL-4 also be crucial in the pathogenesis of characterized by the secretion of high
and IL-13 may improve skin barrier various chronic inflammatory diseases levels of IL-10 or transforming growth
integrity (Howell et al., 2007). This that were formerly categorized as Th1- factor (Akdis et al., 2005). Mutations in
indicates that the atopic immune re- mediated disorders. Whereas IL-17 may FOXP3, a nuclear factor expressed in
sponse directly contributes to the skin play an important role in the pathogen- natural T-reg cells and a subpopulation
barrier defect in AD. esis of psoriasis and contact hypersensi- of adaptive T-reg cells, result in im-
A ‘‘new’’ Th2-associated cytokine, tivity, its role in AD is still under mune dysregulation polyendocrinopa-
IL-31, has been shown to be highly investigation (van Beelen et al., 2007). thy enteropathy X-linked syndrome
expressed in acute eczema (that is, in In skin biopsy specimens recovered from characterized by hyper-IgE, food al-
both acute atopic and acute allergy acute and chronic skin lesions from lergy, and eczema (Torgerson and
contact dermatitis) (Neis et al., 2006). patients with AD, IL-17 mRNA was Ochs, 2007), which suggests a possible
IL-31 is produced by T cells that preferentially associated with acute le- role of T-reg cells in AD.
express CLA and localize to the skin sions (Toda et al., 2003). In a recent Increased numbers of peripheral
(Bilsborough et al., 2006). It appears to study, the percentage of Th17 cells was blood CD4 þ CD25 þ T cells and an
be a link between skin-infiltrating T shown to be higher in the peripheral overexpression of FOXP3 have been
cells and pruritus in the skin, as blood of AD patients and associated with found in the blood of AD patients
demonstrated in a mouse model (Ta- the severity of AD. Immunohistochemi- compared with psoriasis patients and
kaoka et al., 2006). In humans, IL-31 is cally, IL-17 þ cells infiltrated the papil- healthy controls (Ou et al., 2004).
significantly overexpressed in itching lary dermis of atopic eczema more Staphylococcal enterotoxin B inhibits
skin inflammation such as AD (Sonkoly markedly in acute lesions than in chronic natural T-reg cells in vitro (Ou et al.,
et al., 2006; Raap et al., 2008). lesions (Koga et al., 2008). 2004). Superantigens have been shown
Staphylococcal superantigens and his- Epicutaneous immunization with to upregulate glucocorticoid-induced
tamine induce IL-31 expression in ovalbumin, which causes allergic skin TNF-receptor-related protein ligand on
atopic individuals (Gutzmer et al., inflammation with many characteristics monocytes, resulting in the prolifera-
2009). These data suggest that IL-31 of the skin lesions of AD in a mouse tion of natural T-reg cells and abroga-
may be an itch-causing mediator in model, was found to drive IL-17 tion of their immunosuppressive
patients with AD derived from skin- expression. Epicutaneous, but not in- activity (Cardona et al., 2006).
infiltrating T cells. traperitoneal, immunization of mice In the skin, adaptive T-reg cells, but no
In chronic lichenified AD skin le- with ovalbumin drove the generation FOXP3 þ natural T-reg cells, were de-
sions, fewer IL-4 and IL-13 mRNA- of IL-17-producing T cells in both the tectable in AD in a series of biopsies from
expressing cells are present, but greater spleen and the draining lymph nodes eight AD patients (Verhagen et al., 2006).
numbers of IL-5, GM-CSF, IL-12, and and increased serum IL-17 levels. DCs However, in recent studies, the numbers
IFN-g mRNA-expressing cells are de- trafficking from skin to lymph nodes of FOXP3 þ natural T-reg cells were
tected (Hamid et al., 1994). The rise in expressed more IL-23 and induced similar or higher in AD patients com-
IL-5 expression during the transition more IL-17 secretion by naive T cells. pared with healthy controls (Franz et al.,
from acute to chronic AD probably This was inhibited by neutralizing IL-23 2007; Schnopp et al., 2008). It is
plays a role in the prolongation of in vitro and by intradermal injection of noteworthy that the number of natural
eosinophil survival and function (Wedi anti-TGF-b-neutralizing antibody T-reg cells did not change significantly
et al., 1999). Some of the other in vivo. These data suggest that initial after medium-dose UVA-1 radiation
cytokines mentioned above support cutaneous exposure to protein antigens (Schnopp et al., 2007).
the function of macrophages and pro- may selectively induce the production In summary, most recent studies have
mote the Th1-type inflammation more of IL-17 in AD (He et al., 2007). identified T-reg cells in the skin of AD
characteristic of chronic AD (Fiset Taking together these findings, Th17 patients. It remains to be determined
et al., 2006). Effects of IFN-g on cells are present in the skin of AD. The whether the differences in functional
keratinocytes are discussed below. role of these cells in acute eczema for the activities of T-reg cells shown in vitro
In summary, T-cell cytokines have course of AD remains to be elucidated. are relevant for the course of AD in vivo.
numerous effects on skin inflammation,
ranging from the induction of chemo- T-reg cells in AD DCs
kines and downmodulation of barrier- T-reg cells control the activation of Myeloid DCs in AD
associated molecules to the induction autoreactive and T-effector cells and DCs are specialized antigen-presenting
of pruritus. are crucial for the maintenance of cells found in lymphoid tissues and in

www.jidonline.org 1881
T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

peripheral organs such as the skin. pDCs products, physical injury, or inflamma-
Two major subtypes of DCs have Activated pDCs are able to produce tory cytokines (Allakhverdi et al.,
been shown to play an important antiviral type I interferons. pDCs in the 2007). Moreover, a recent paper de-
role in the pathophysiology of AD peripheral blood of patients with AD monstrated a strong link between TSLP
in humans: myeloid DCs and plasma- have been shown to bear the trimeric and skin barrier disruption (Demehri
cytoid DCs (pDCs) (Novak et al., variant of FceRI on their cell surface, et al., 2008).
2007). which is occupied by IgE molecules. The general role of chemokines in
Myeloid DCs can be further differ- pDCs can take up allergens by FceRI- the initiation and perpetuation of AD
entiated into two subtypes that IgE, process them, and promote Th2- has been reviewed by Homey et al.
have been found in lesional skin of type immune responses (Novak et al., (2006). Keratinocytes stimulated with
AD patients: LCs and inflammatory 2007). Increased numbers of pDCs proinflammatory cytokines have been
dendritic epidermal cells (IDECs). have been found in the peripheral identified as an important cellular
Both LCs and IDECs express the blood of AD patients, but only low source of chemokines, which attract T
high-affinity receptor for IgE (FceRI) numbers of pDCs are detectable in skin cells of different subtypes (Wittmann
(Bieber, 2007), but they have different lesions in AD, in contrast to other and Werfel, 2006). For example,
functions in AD. LCs play a predomi- inflammatory skin diseases (Wollen- CXCR3 ligands such as CXCL10 pre-
nant role in the initiation of the berg et al., 2002). ferentially attract Th1 cells (Albanesi
allergic immune response and prime The lack of pDCs in the skin has et al., 2001). CCL22 and CCL17 pre-
naive T cells into T cells of the Th2 type been shown to contribute to the high ferentially attract Th2 cells by binding
with high IL-4-producing capacity, susceptibility of AD patients to viral to CCR4 (Purwar et al., 2006). CCL2 is
which predominate in the initial skin infections, such as herpes simplex- effective on both Th1 and Th2 subsets.
phase of AD (Novak et al., 2004). induced eczema herpeticum. CCL27, which is constitutively ex-
Activated LCs can also present aller- pressed by keratinocytes, binds to
gen-derived peptides to antigen-speci- KERATINOCYTE–T-CELL CCR10 expressed on most skin-homing
fic T cells in the skin. The aggregation INTERACTIONS lymphocytes (Homey et al., 2002).
of FceRI on the surface of LCs induces There is growing evidence supporting Keratinocytes are also important
the release of chemotactic factors (for keratinocytes as enhancer cells of the cellular sources of cytokines such as
example, CCL2, CCL22, CCL17, or IL- inflammatory response in AD (Witt- the T-cell growth factor IL-15 in the
16) and may facilitate allergen presen- mann and Werfel, 2006; Holgate, skin (Han et al., 1999) (Figure 1B). IL-
tation to T cells (Maintz and Novak, 2007). Keratinocytes play a role in 15 has been implicated in the patho-
2007). innate immunity by expressing Toll-like genesis of different skin diseases by
IgE-bearing FceRI þ IDECs become receptors and producing antimicrobial virtue of its action on the maintenance
more prominent in chronic AD lesions. peptides in response to invading mi- of T cells—possibly intraepithelial
After allergen challenge, invasion of crobes (McGirt and Beck, 2006; De T cells.
high numbers of IDECs has been Benedetto et al., 2009). Keratinocytes respond to both Th1
shown, emphasizing their crucial Keratinocytes secrete a unique pro- and Th2 cytokines from T cells (Figure
role in the development of eczema file of chemokines and cytokines after 1C). Among them, IFN-g is one of the
(Kerschenlohr et al., 2003). IDECs are exposure to proinflammatory cytokines most potent keratinocyte-activating
also found exclusively at inflammatory (Figure 1A and B). Keratinocyte-derived factors. It induces surface molecules
sites, suggesting an involvement thymic stromal lymphopoietin (TSLP) (for example, ICAM-1, MHC class I and
in cell recruitment and IgE-mediated may be of particular importance in AD II, CD40, and Fas), chemokines (for
antigen presentation to T cells. In (Soumelis and Liu, 2004; Homey et al., example, CCL2, CCL3, CCL4, CCL5,
contrast to LCs, these cells promote 2006): This protein is not detected in CCL18, CCL22, and CXCL10) and
Th1 cytokine production from T cells. normal skin or in nonlesional skin in cytokines (for example, IL-1, IL-6, IL-
In this context it has been shown patients with AD, but it is highly 18, and TGF-b) in keratinocytes. Many
that stimulation of FceRI on the surface expressed in lesions in both acute and other molecules, such as matrix metal-
of IDECs induces the release of IL-12 chronic AD. TSLP instructs human DCs loproteinases, growth factors, enzymes,
and IL-18. This may contribute to the to create a Th2-permissive microenvir- and transcription factors/pathway
switch from the initial Th2 immune onment by inducing the expression of molecules, are also upregulated.
response in acute AD to the Th1 OX40L, which triggers the differentia- (Homey et al., 2006; Wittmann and
polarization of T cells in the chronic tion of inflammatory Th2 cells (Ito Werfel, 2006). Pastore et al. (1998,
phase (Novak et al., 2004). et al., 2005). Recently it was shown 2000) observed differences in the re-
In summary, both resident and that TSLP, synergistically with IL-1 and sponsiveness to cytokines of keratino-
infiltrating myeloid DC populations TNFa, stimulates the production of cytes from AD patients as compared
are crucial in AD. The expression of high levels of Th2 cytokines by human with healthy controls or psoriasis pa-
Fc receptors for IgE on these cells may mast cells. In that study, TSLP was tients (Giustizieri et al., 2001).
be of importance for facilitated allergen shown to be released by primary It has been shown that IFN-g in-
presentation in AD. epithelial cells in response to microbial duces Fas on keratinocytes, which

1882 Journal of Investigative Dermatology (2009), Volume 129


T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

a Keratinocytes attract T cells thus remains a potential target for the


by chemokine production treatment of AD (Akdis et al., 2006).
Both CXCR3 þ CD4 þ and CCR4 þ
CD4 þ T cells migrate in response to
Keratinocytes IFN-g-treated human primary keratino-
cytes (Purwar et al., 2006). It is inter-
esting to note that IFN-g also induces
CCL2/MCP-1 T cell CCL5/RANTES CCL22 production in human keratino-
CCL18/PARC CCL22/MDC cytes. Many IFN-g-inducible molecules
CXCL10/IP-10 CCL27/CTACK are reinforced by IL-4 or IL-13 in
human keratinocytes, such as CD54,
CCL2, CCL5, and CXCL10 (Albanesi
et al., 2000; Purwar et al., 2006).
Keratinocytes have been shown to
express the IL-1 and IL-33 receptor,
ST2, in the acute phase of eczema in
b Keratinocytes stimulate skin-infiltrating AD. A significant genetic association
T cells via cytokines between AD and a single-nucleotide
polymorphism has been found in the
distal promoter region of the ST2 gene
(Shimizu et al., 2005). This polymorph-
ism is associated with an upregulation
of the transcriptional activity of the ST2
gene. The ligand of ST2, IL-33, induces
IL-1 IL-27 the expression of IL-4, IL-5, and IL-13
IL-8 IL-23 in vivo, which may explain higher IgE
IL-18
serum levels found in patients with the
ST2 polymorphism in AD.
Taken together, these observations
suggest that keratinocytes are important
regulatory and effector cells in skin
diseases involving the epidermis as a
c T cells stimulate keratinocytes particular feature.
via cytokines
EOSINOPHILS
Eosinophils play an important role in
AD, characterized by activated eosino-
phils in the peripheral blood and in the
lesional skin (Leiferman et al., 1985;
Kapp, 1993; Simon et al., 2004).
IFN-γ IL-4 Increased numbers of circulating eosi-
IL-13
nophils are frequently observed in
patients with AD. Inhibition of eosino-
phil apoptosis in AD, probably
mediated by IL-5 and GM-CSF, appears
to be a relevant mechanism for the
eosinophil accumulation observed in
Figure 1. Keratinocyte–T-cell interactions. (a) Keratinocytes attract T cells by chemokine production. (b) AD (Wedi et al., 1999). Interestingly,
Keratinocytes stimulate skin-infiltrating T cells via cytokines. (c) T cells stimulate keratinocytes via acute psychosocial stress leads to
cytokines. further increases in eosinophil counts
and IL-5 þ T cells in the peripheral
renders them susceptible to apoptosis contacts between keratinocytes that blood (Schmid-Ott et al., 2001a, b).
induction by infiltrating FasL þ T cells are undergoing apoptosis result in Eosinophils are recruited to tissue
(Trautmann et al., 2000). This has been spongioform morphology in the epider- sites mainly by chemokines (for exam-
interpreted as an important event in mis. This morphology is regarded as a ple, eotaxin and RANTES (regulated on
eczema, mainly in AD. There is further hallmark of eczematous lesions (Traut- activation, normal T-cell expressed and
evidence that cleavage of E-cadherin mann et al., 2001). Suppression of secreted)). A survey on the chemokine
and sustained desmosomal cadherin keratinocyte activation and apoptosis receptor repertoire of human peripheral

www.jidonline.org 1883
T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

blood eosinophils draws a confusing Recent evidence suggests that a acquired defects of innate immunity
picture of receptors (Homey et al., deficiency of the antimicrobial pep- may explain the predisposition of the
2006). However, the expression of tides dermcidin, cathelicidin LL-37, skin in AD to bacterial, viral, or fungal
CCR3 on eosinophils seems to be of human b-defensin (HBD)-2, and HBD- infection or colonization.
particular importance; a number of 3 contributes to the susceptibility of
findings suggest that CCR3-driven path- atopic patients to skin infections IgE IMMUNOREACTIVITY
ways are essential for the recruitment of (McGirt and Beck, 2006). Defensins In approximately 80% of adult patients
eosinophils to sites of atopic skin are broad-spectrum antibiotics that kill with AD, the disease is associated
inflammation (Hoechstetter et al., bacterial and fungal pathogens. LL-37 with increased serum IgE levels
2000). In the skin lesions of AD, has been shown to display antimicro- (4150 kU l1), sensitization to aeroal-
CCR3 ligands are candidates that med- bial activity against viral pathogens in lergens and food allergens, and/or
iate the influx of eosinophils into the addition to bactericidal and fungicidal concomitant food allergy, allergic rhi-
skin (Gombert et al., 2005). actions (Howell et al., 2006). The nitis, and asthma (Werfel and Kapp,
The interaction of eosinophil expression of antimicrobial peptides 1998; Leung et al., 2004). Recent
surface molecules with endothelial by keratinocytes is increased in re- epidemiologic data suggest a contribu-
cell vascular cell adhesion molecule 1 sponse to inflammatory cytokines. tory role for IgE-mediated immunologic
and intercellular adhesion molecule 1 However, IL-4 and IL-13 have been processes in the onset and course of
are important for eosinophil extravasa- shown to downregulate the expression AD, especially in patients with severe
tion and activation. Activated eosino- of b-defensins and of LL-37 in the skin disease. (Williams and Flohr, 2006).
phils are capable of releasing a variety in AD (Ong et al., 2002; Nomura et al., However, 20% of adult patients
of potent cytotoxic granule proteins 2003; Howell et al., 2006). This can with eczematous skin lesions clinically
and chemical mediators contributing predispose to S. aureus colonization and histologically indistinguishable
to tissue inflammation (Elsner and and to severe eczema herpeticatum. from AD lack sensitization and other
Kapp, 1999), as shown by the deposi- Recently it was shown that mono- clinical manifestations of the atopic
tion of eosinophil products in the cytes from AD patients are functionally diseases. This subtype of AD often has
inflamed skin (Bruijnzeel-Koomen defective in their ability to produce a late onset (420 years of age) and a
et al., 1992). proinflammatory cytokines on Toll-like lack of IgE sensitization to inhalant or
Eosinophils play a relevant role in receptor 2 stimuli (Hasannejad et al., food allergens (Werfel and Kapp, 1999;
neuroimmunologic interactions—en- 2007; Niebuhr et al., 2009). Moreover, Novak and Bieber, 2003). In children, a
hanced levels of brain-derived growth Toll-like receptor 2 with a single- transient form of AD with low IgE
factor can be detected in the sera and nucleotide polymorphism was found serum levels and without any detect-
plasma of patients with AD. Brain- in higher frequency in patients with able sensitization has been observed; it
derived growth factor has been shown severe AD compared with control develops into the extrinsic variant of
to reduce eosinophil apoptosis while groups (Ahmad-Nejad et al., 2004). AD with increasing IgE serum levels
enhancing chemotaxis of eosinophils Cells with this polymorphic Toll-like and development of sensitization to
in vitro (Raap et al., 2006). receptor 2 show altered responses to aeroallergens and food allergens later
In summary, eosinophils infiltrate peptidoglycans and lipoteichoic acid in life (Novembre et al., 2001).
the skin of AD patients and aggravate from staphylococcal cell walls, which Despite the clinical similarity,
the inflammatory response. may further contribute to the innate AD patients with IgE-mediated allergy
immune defect in AD (Niebuhr et al., exhibit higher tissue eosinophilia,
DEFECTS IN THE INNATE IMMUNE 2008 and Mrabet-Dahbi et al., 2008). enhanced lesional cytokine expression,
RESPONSE IN AD Patients with the head and neck and higher surface expression of the
Most patients with AD are colonized variant of AD are frequently colonized FceRI on epidermal DCs compared
with Staphylococcus aureus and ex- with Malassezia species (Scheynius with non-allergic eczema patients.
perience exacerbation of their skin et al., 2002). Malassezia sympodialis Specific IgE may play a critical role
disease after infection with this organ- cells produce, express, and release in cutaneous inflammation in the
ism (De Benedetto et al., 2009). In allergens to a greater extent when activation of mast cells and DCs via
patients with AD with bacterial infec- cultured at the higher pH resembling high-affinity Fc receptors (Bieber,
tion, treatment with anti-staphylococ- the high pH in the skin of AD. This was 2007). IgE-mediated histamine release
cal antiseptics and antibiotics can particularly true of the major allergen from cutaneous mast cells may aggra-
result in the improvement of skin Mala s 12, suggesting that the skin vate AD through the itch–scratch cycle.
lesions (Breuer et al., 2002). Binding barrier in AD patients provides an Moreover, increased cutaneous inflam-
of S. aureus to skin is enhanced by AD environment that can enhance the mation, mediated via histamine recep-
skin inflammation. This is supported by release of allergens from M. sympodia- tors, on T-lymphocytes (Jutel et al.,
clinical studies demonstrating that lis, which can in turn contribute to the 2001; Gutzmer et al., 2009), antigen-
treatment with topical corticosteroids inflammation (Selander et al., 2006). presenting cells (Gutzmer et al., 2005;
or tacrolimus reduces S. aureus counts Together, these findings indicate Gutzmer et al., 2005; Dijkstra et al.,
in AD. that a number of constitutive and 2007), and keratinocytes (Giustizieri

1884 Journal of Investigative Dermatology (2009), Volume 129


T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

et al., 2004) is probable. IgE-facilitated responses to food proteins and specific AEROALLERGENS
allergen presentation by DCs and T-cell clones can be generated from Pruritus and skin lesions can develop after
activation of DCs via high-affinity Fc patients with food-induced eczema intranasal or bronchial inhalation chal-
receptors in the skin are discussed (Reekers et al., 1996; Werfel et al., lenge with aeroallergens in patients with
above (Bieber, 2007). 1997a; van Reijsen et al., 1998). In AD. Epicutaneous application of aero-
Despite many in vitro and ex vivo addition, milk-induced eczema has allergens (house dust mites, weeds, ani-
findings, the importance of IgE to the been reported to be associated with a mal danders, and molds) on
clinical severity of AD is difficult to higher rate of CLA þ lymphocytes asymptomatic skin of patients with AD
evaluate. In a recent study of adult upon in vitro stimulation with casein elicits eczematous reactions in a sub-
patients with AD, it became clear that (Abernathy-Carver et al., 1995). group of patients with AD. The so-called
patients with greater IgE-mediated sensi- A murine model of food-induced AD atopy patch test has been used in recent
tization suffer from more severe disease confirmed the important role of food- years as a model for studying allergen-
(Salt et al., 2007). In proof-of-concept specific T cells in eczema. C3H/HeJ induced changes in the skin of AD
trials, some—but not all—patients trea- mice were orally sensitized to cow’s patients (Darsow et al., 2004; Turjanmaa
ted with anti-IgE antibodies improved in milk or peanuts and then subjected to et al., 2006). Aeroallergen-specific T cells
terms of eczema severity (Lane et al., low-grade allergen exposure. An ecze- were first isolated from skin sites from
2006; Vigo et al., 2006; Belloni et al., matous eruption developed in approxi- atopy patch test lesions (Sager et al.,
2007; Forman and Garrett, 2007). How- mately one-third of mice after low-grade 1992; Van Reijsen et al., 1992). Similar
ever, extremely high total IgE serum exposure to milk or peanut proteins. techniques were applied later to isolate
levels in AD present a major problem for Histologic examination of the lesional aeroallergen-specific T cells from sponta-
treatment with anti-IgE. A controlled skin revealed spongiosis and a cellular neous lesional skin (Werfel et al., 1996).
study with anti-IgE is therefore required infiltrate consisting of CD4 þ lympho- A combination of effective measures
(Beck and Saini, 2006). cytes, eosinophils, and mast cells. IL-5 to control house dust mites has been
In summary, specific IgE not only is and IL-13 mRNA expression was ele- reported to improve AD, but the
relevant to immediate reactions but vated only in the skin of mice with the clinical effect varied in different clin-
may contribute to delayed eczematous eczematous eruption (Li et al., 2001). ical studies (Tan et al., 1996; Holm
skin reactions in AD as well. Patients sensitized to pollen aller- et al., 2001; Oosting et al., 2002).
gens often develop an IgE-response to Specific immunotherapy directly ad-
ALLERGEN-SPECIFIC T CELLS cross-reactive food allergens. Con- dresses an adaptive mechanism in
Primary T-cell immunodeficiency dis- sumption of birch pollen-related foods hypersensitivity reactions. A recent
orders are frequently associated with such as hazelnuts, carrots, apples, and meta-analysis of specific immunother-
high serum IgE levels and eczematous celery (that is, foods that are cross- apy studies revealed positive effects of
skin lesions, which clear after success- reactive to birch pollen allergens, subcutaneous immunotherapy in the
ful bone marrow transplantation (Akdis mainly the major allergen Bet v1) may majority of studies performed to date
et al., 2006). In animal models of AD, lead to an exacerbation of eczema in a on AD (Bussmann et al., 2006). In the
the eczematous rash does not occur in subpopulation of patients with AD largest cohort study, subcutaneous im-
the absence of T cells (Spergel et al., sensitized to birch pollen antigens. A munotherapy with mite allergens was
1999). birch pollen-specific T-cell response effective in moderate to severe AD
could be detected in lesional skin of (Werfel et al., 2006). In contrast,
FOOD ALLERGENS these responding patients (Reekers sublingual immunotherapy with mite
Food allergy and AD may occur in the et al., 1999): Birch pollen-related food allergens, which has recently been
same patient. In addition to typical may also induce allergic symptoms in a studied in children with AD, was
immediate types of allergic reactions subgroup of children with AD (Breuer effective only in patients with mild
(that is, noneczematous reactions), et al., 2004). Recently, Bohle et al. eczema (Pajno et al., 2007). During
which are observed in AD patients, (2006) showed that T-cell cross-reac- specific immunotherapy of AD, the
foods can provoke flares of AD; this has tivity between Bet v1 and related food level of the tolerogenic cytokine IL-10
been demonstrated in placebo-con- allergens can occur independent of IgE increased in the sera of patients,
trolled food challenge studies (Werfel cross-reactivity in vitro and in vivo. In whereas the levels of CCL17 and IL-
and Breuer, 2004). The serum levels of patients with AD, the resulting immune 16 decreased (Bussmann et al., 2007).
food-specific IgE can be predictive for reaction that manifested as late ecze- In summary, evidence of the clinical
the outcome of oral provocation tests matous skin reactions to cooked food role of adaptive immune responses to
with foods, as observed in cohort was shown to elicit T cell- but not IgE- aeroallergens for AD come from atopy
studies with children with AD who mediated responses. patch tests and therapy studies on
had immediate reactions to foods In summary, T-cell responses and specific immunotherapy.
(Sampson, 2001; Mehl et al., 2005). specific IgE to food allergens may
Specific T cells have been shown to be explain flare-ups of eczema upon oral MICROBIAL ALLERGENS
involved in the late eczematous re- food challenges in sensitized patients S. aureus can exacerbate AD by secret-
sponse to food; higher proliferative with AD. ing exotoxins. Some of them function

www.jidonline.org 1885
T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

as superantigens, which stimulate acti- Within ‘‘non-allergic’’ patients with tase (MnSOD) from the skin-colonizing
vation of T cells and MHC þ antigen- atopic eczema, some exhibit IgE yeast M. sympodialis cross-reacts with
presenting cells, macrophages, or ker- sensitization against microbial anti- human MnSOD. Patients with AD
atinocytes. Major effects elicited by gens, such as S. aureus enterotoxins sensitized to human MnSOD have
superantigens are summarized in and Candida albicans or M. sympodia- been shown to also be sensitized
Figure 2A. Some patients with AD lis antigens (Novak et al., 2003). The against the M. sympodialis MnSOD
produce specific IgE antibodies directed presence of specific IgE to Malassezia (Schmid-Grendelmeier et al., 2005).
against staphylococcal superantigens antigens in the non-allergic variant of Lens epithelium-derived growth fac-
(Figure 2B), to an extent that correlates AD was confirmed in a recent study tor/dense fine speckles 70 kDa protein
with skin disease severity (Bunikowski (Casagrande et al., 2006). In a larger (LEDGF/DFS70) is another defined
et al., 1999; Breuer et al., 2000). cohort, however, it was found that autoantigen in patients with AD. Auto-
Superantigens have been shown to antimicrobial IgE antibodies were un- antibodies to this protein have been
penetrate into the dermis (Skov et al., common in patients with AD with low found in Japan in approximately 30%
2000), and higher doses have been IgE levels (Reefer et al., 2007). of AD patients. It is located predomi-
shown to induce cutaneous inflamma- In summary, microbial allergens nantly in the nucleus of the basal
tion when applied to the skin in patch may worsen the skin condition in AD. epidermal cells and translocates into
tests (Strange et al., 1996). Low doses the cytoplasm during differentiation.
that do not induce visible clinical SELF-ALLERGENS Once in the cytoplasm, LEDGF/DFS70
inflammation are still able to amplify Autoimmunity to human proteins may accumulates in the keratohyalin gran-
aeroallergen-induced patch test re- also contribute to the pathophysiology ules in the granular layer (Sugiura et al.,
sponses (Langer et al., 2007). of AD. IgE against autoantigens has 2007).
There is increasing evidence that the been shown to stimulate type 1 hyper- The role of self-allergens remains to
opportunistic yeast Malassezia species sensitivity reactions and DCs (Valenta, be elucidated in more detail in future
is a contributing factor in AD. Several 2009). Autoallergens induce the prolif- studies. The concept of AD as an
studies have demonstrated the pre- eration of CLA þ autoreactive T cells in autoimmune disease has therapeutic
sence of specific serum IgE, a positive the blood, and T-cell clones specific for implications and may explain the
skin prick test response, and a positive autoallergens can be generated from chronicity of the disease in ‘‘autoaller-
patch test response against Malassezia the skin of patients with AD (Heratiza- gic’’ patients.
species in adults with AD (Scheynius deh et al., submitted). Interestingly,
et al., 2002). IgE sensitization to Ma- autoallergen-specific IgE was found as CONCLUSION
lassezia species is specific for patients early as in infancy in AD (Mothes et al., Immunological responses to defined
with AD; it is not seen in patients with 2005). Cross-reactivity between in- allergens, inflammatory reactions to
asthma or allergic rhinitis (Scalabrin haled allergens and autoantigens may microbial agents, and a complex inter-
et al., 1999; Schmid-Grendelmeier lead to autoimmunity: For example, IgE play of cells and mediators belonging
et al., 2006). against manganese superoxide dismu- to the skin immune system contribute
to the clinical appearance of AD.
Allergens may reach the skin from the
bloodstream or through the epidermis,
• Induction of T-cell proliferation as depicted in Figure 3. Specific IgE,
T cell • Induction of IL-2, IL-5, IL-13 and which is bound to Fc receptors on DCs
IFNγ production by T cells
• Induction of CLA expression on T cells
(LC, IDECs, dermal DCs) and on
TCR
• Reversal of suppressive activity of cutaneous mast cells, may facilitate
Exotoxin regulatory T cells (Treg) allergen presentation to specific T cells
MHC II • Release of cytokines (e.g. IL-12) (Th2 cells in the acute phase, Th1 cells
from MHC+ APC
in the chronic phase). Figure 3 high-
• Release of proinflammatory cytokines
APC
from activated MHCII+ positive cells lights only some key mediators of AD—
the Th2 cytokine IL-4 and histamine in
MHC II the acute phase and Th1-related cyto-
Exotoxin kines IL-12 and IL-18 in the chronic
Induction
TCR Specific of
phase. A number of other mediators are
αβ IgE specific IgE currently being investigated, with IL-17
IL-2 and IL-31 representing extensively
T cell IL-4
IL-13 studied cytokines with regard to AD at
present. More knowledge of these
Figure 2. Function of staphylococcal exotoxins as superantigens or as allergens. Staphylococcal
exotoxins can function as superantigens as depicted on the upper part of the figure. In this way exotoxins
factors may contribute to the develop-
induce strong effects on both T cells and antigen-presenting cells, as summarized in the gray box. ment of specific approaches for phase-
Exotoxins can also function as allergens in atopic dermatitis (depicted in the lower part of the figure) dependent therapies in this chronic
inducing specific IgE and specific Th2 responses. relapsing skin disease.

1886 Journal of Investigative Dermatology (2009), Volume 129


T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

Albanesi C, Scarponi C, Sebastiani S, Cavani A,


Federici M, Sozzani S et al. (2001) A
Aeroallergens Microbial “allergens”
cytokine-to-chemokine axis between T-lym-
phocytes and keratinocytes can favor Th-1
cell accumulation in chronic inflammatory
Stratum skin diseases. J Leukoc Biol 70:617–23
corneum
Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR,
Brewer A, Chartier S et al. (2007) Thymic
T cell stromal lymphopoietin is released by human
epithelial cells in response to microbes,
IgE trauma, or inflammation and potently acti-
Epidermis MHCII vates mast cells. J Exp Med 204:253–8
Langerhans Beck LA, Saini S (2006) Wanted: A study with
cell IL-12
IL-1 omalizumab to determine the role of IgE-
IL-18 Inflammatory mediated pathways in atopic dermatitis. J
dendritic Am Acad Dermatol 55:540–1
epidermal cell
Belloni B, Ziai M, Lim A, Lemercier B, Sbornik M,
BMZ Weidinger S et al. (2007) Low-dose anti-IgE
Th-2 therapy in patients with atopic eczema with
Th-1
high serum IgE levels. J Allergy Clin Im-
IL-16 munol. 120:1223–5
CCL-2 IL-4
CCL-16 Histamine
Bieber T (2007) The pro- and anti-inflammatory
properties of human antigen-presenting
Mast cells expressing the high affinity receptor
Dermis cell
Dermal for IgE (Fc epsilon RI). Immunobiology
dendritic 212:499–503
cell
Food
Bieber T (2008) Atopic dermatitis. N Engl J Med
allergens 358:1483–94
Capillary
Aeroallergens (?) Biedermann T, Lametschwandtner G, Tangemann
K, Kund J, Hinteregger S, Carballido-Perrig N
et al. (2006) IL-12 instructs skin homing of
Figure 3. Effects of allergens on the cutaneous inflammation in atopic dermatitis. Allergens can enter human Th2 cells. J Immunol 177:3763–70
the skin both through the bloodstream (for example, food allergens) or through the stratum corneum
Bilsborough J, Leung DY, Maurer M, Howell M,
(for example, inhaled allergens). In the skin, IgE bound on Fc receptors on cutaneous mast cells and on
Boguniewicz M, Yao L et al. (2006) IL-31 is
dendritic cells contributes, together with specific T cells, to the inflammatory response. associated with cutaneous lymphocyte anti-
gen-positive skin homing T-cells in patients
with atopic dermatitis. J Allergy Clin Im-
munol 117:418–25
CONFLICT OF INTEREST by CLA- memory T-cells. J Immunol 159: Bohle B, Zwolfer B, Heratizadeh A, Jahn-Schmid
The author states no conflict of interest. 4611–9 B, Antonia YD, Alter M et al. (2006) Cooking
Akdis M, Blaser K, Akdis CA (2005) T regulatory birch pollen-related food: divergent conse-
cells in allergy: novel concepts in the quences for IgE- and T-cell-mediated reac-
pathogenesis, prevention, and treatment of tivity in vitro and in vivo. J Allergy Clin
REFERENCES
allergic diseases. J Allergy Clin Immunol Immunol 118:242–9
Abernathy-Carver KJ, Sampson HA, Picker LJ, 116:961–8 Breuer K, Haeussler S, Kapp A, Werfel T (2002)
Leung DY (1995) Milk-induced eczema is Staphylococcus aureus: colonizing features
associated with the expansion of T-cells Akdis M, Simon HU, Weigl L, Kreyden O, Blaser
K, Akdis CA (1999) Skin homing (cutaneous and influence of an antibacterial treatment in
expressing cutaneous lymphocyte antigen. J adults with atopic dermatitis. Br J Dermatol
lymphocyte-associated antigen-positive)
Clin Invest 95:913–8 147:55–61
CD8+ T-cells respond to superantigen and
Ahmad-Nejad P, Mrabet-Dahbi S, Breuer K, Klotz contribute to eosinophilia and IgE produc- Breuer K, Wittmann M, Bosche B, Kapp A, Werfel
M, Werfel T, Herz U et al. (2004) The toll- tion in atopic dermatitis. J Immunol T (2000) Severe atopic dermatitis is asso-
like receptor 2 R753Q polymorphism defines 163:466–75 ciated with sensitization to staphylococcal
a subgroup of patients with atopic dermatitis enterotoxin B (SEB). Allergy 55:551–5
Akdis M, Trautmann A, Klunker S, Daigle I,
having severe phenotype. J Allergy Clin Breuer K, Wulf A, Constien A, Tetau D, Kapp A,
Kucuksezer UC, Deglmann W et al. (2003) T
Immunol 113:565–7 helper (Th) 2 predominance in atopic dis- Werfel T (2004) Birch pollen-related food as
Akdis CA, Akdis M, Bieber T, Bindslev-Jensen C, eases is due to preferential apoptosis of a provocation factor of allergic symptoms in
Boguniewicz M, Eigenmann P et al. (2006) circulating memory/effector Th1 cells. FAS- children with atopic eczema/dermatitis syn-
Diagnosis and treatment of atopic dermatitis EB J. 17:1026–35 drome. Allergy 59:988–94
in children and adults: European Academy of Akkoc T, de Koning PJ, Rückert B, Barlan I, Akdis Brown SJ, McLean WHI (2009) Eczema genetics:
Allergology and Clinical Immunology/Amer- M, Akdis CA (2008) Increased activation- current state of knowledge and future goals. J
ican Academy of Allergy, Asthma and induced cell death of high IFN-gamma- Invest Dermatol 129:543–52
Immunology/PRACTALL Consensus Report. producing T(H)1 cells as a mechanism of Bruijnzeel-Koomen C, Storz E, Menz G, Bruijn-
J Allergy Clin Immunol 118:152–69 and T(H)2 predominance in atopic diseases. J zeel P (1992) Skin eosinophilia in patients
Allergy 61: 969–87 Allergy Clin Immunol. 121:652–8 with allergic and nonallergic asthma and
Akdis M, Akdis CA, Weigl L, Disch R, Blaser K Albanesi C, Scarponi C, Sebastiani S, Cavani A, atopic dermatitis. J Allergy Clin Immunol
(1997) Skin-homing, CLA+ memory T-cells Federici M, De Pita O et al. (2000) 89:52–9
are activated in atopic dermatitis and IL-4 enhances keratinocyte expression of Bunikowski R, Mielke M, Skarabis H, Herz U,
regulate IgE by an IL-13-dominated CXCR3 agonistic chemokines. J Immunol Bergmann RL, Wahn U et al. (1999) Pre-
cytokine pattern: IgG4 counter-regulation 165:1395–402 valence and role of serum IgE antibodies to

www.jidonline.org 1887
T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

the Staphylococcus aureus-derived super- Giustizieri ML, Albanesi C, Fluhr J, Gisondi P, dermatitis–a placebo-controlled trial of 12
antigens SEA and SEB in children with atopic Norgauer J, Girolomoni G (2004) H1 hista- months’ duration. Allergy 56:152–8
dermatitis. J Allergy Clin Immunol mine receptor mediates inflammatory re- Homey B, Alenius H, Muller A, Soto H, Bowman
103:119–24 sponses in human keratinocytes. J Allergy EP, Yuan W et al. (2002) CCL27-CCR10
Bussmann C, Bockenhoff A, Henke H, Werfel T, Clin Immunol 114:1176–82 interactions regulate T-cell-mediated skin
Novak N (2006) Does allergen-specific im- Gombert M, Dieu-Nosjean MC, Winterberg F, inflammation. Nat Med 8:157–65
munotherapy represent a therapeutic option Bunemann E, Kubitza RC, Da Cunha L et al. Homey B, Steinhoff M, Ruzicka T, Leung DY
for patients with atopic dermatitis? J Allergy (2005) CCL1-CCR8 interactions: an axis (2006) Cytokines and chemokines orches-
Clin Immunol 118:1292–8 mediating the recruitment of T-cells and trate atopic skin inflammation. J Allergy Clin
Bussmann C, Maintz L, Hart J, Allam JP, Vrtala S, Langerhans-type dendritic cells to sites of Immunol 118:178–89
Chen KW et al. (2007) Clinical improvement atopic skin inflammation. J Immunol
174:5082–91 Howell MD, Kim BE, Gao P, Grant AV, Bogunie-
and immunological changes in atopic der- wicz M, Debenedetto A et al. (2007)
matitis patients undergoing subcutaneous Grewe M, Walther S, Gyufko K, Czech W, Schopf Cytokine modulation of atopic dermatitis
immunotherapy with a house dust mite E, Krutmann J (1995) Analysis of the cytokine filaggrin skin expression. J Allergy Clin
allergoid: a pilot study. Clin Exp Allergy pattern expressed in situ in inhalant allergen Immunol 120:150–5
37:1277–85 patch test reactions of atopic dermatitis
patients. J Invest Dermatol 105:407–10 Howell MD, Wollenberg A, Gallo RL, Flaig M,
Cardona ID, Goleva E, Ou LS, Leung DY (2006) Streib JE, Wong C et al. (2006) Cathelicidin
Staphylococcal enterotoxin B inhibits regu- Gutzmer R, Diestel C, Mommert S, Kother B, deficiency predisposes to eczema
latory T-cells by inducing glucocorticoid- Stark H, Wittmann M et al. (2005) Histamine
herpeticum. J Allergy Clin Immunol
induced TNF receptor-related protein ligand H4 receptor stimulation suppresses IL-12p70
117:836–41
on monocytes. J Allergy Clin Immunol production and mediates chemotaxis in hu-
117:688–95 man monocyte-derived dendritic cells. Hunter CA (2005) New IL-12-family members: IL-
J Immunol 174:5224–32 23 and IL-27, cytokines with divergent
Casagrande BF, Fluckiger S, Linder MT, Johansson
functions. Nat Rev Immunol 5:521–31
C, Scheynius A, Crameri R et al. (2006) Gutzmer R, Mommert S, Gschwandtner M,
Sensitization to the yeast Malassezia sympo- Zwingmann K, Stark H, Werfel T (2009) Ito T, Wang YH, Duramad O, Hori T,
dialis is specific for extrinsic and intrinsic The histamine H4 receptor is functionally Delespesse GJ, Watanabe N et al. (2005)
atopic eczema. J Invest Dermatol expressed on T(H)2 cells. J Allergy Clin TSLP-activated dendritic cells induce an
126:2414–21 Immunol 123:619–25 inflammatory T helper type 2 cell response
through OX40 ligand. J Exp Med
Darsow U, Laifaoui J, Kerschenlohr K, Wollen- Hamid Q, Boguniewicz M, Leung DY (1994)
202:1213–23
berg A, Przybilla B, Wuthrich B et al. (2004) Differential in situ cytokine gene expression
The prevalence of positive reactions in the in acute versus chronic atopic dermatitis. Jutel M, Watanabe T, Klunker S, Akdis M, Thomet
atopy patch test with aeroallergens and food J Clin Invest 94:870–6 OA, Malolepszy J et al. (2001) Histamine
allergens in subjects with atopic eczema: a regulates T-cell and antibody responses by
Hamid Q, Naseer T, Minshall EM, Song YL,
European multicenter study. Allergy differential expression of H1 and H2 recep-
Boguniewicz M, Leung DY (1996) In vivo
59:1318–25 tors. Nature 413:420–5
expression of IL-12 and IL-13 in atopic
De Benedetto A, Agnihothri R, McGirt LY, Bank- dermatitis. J Allergy Clin Immunol Kapp A (1993) The role of eosinophils in the
ova LG, Beck LA (2009) Atopic dermatitis: a 98:225–31 pathogenesis of atopic dermatitis–eosinophil
disease caused by innate immune defects? J granule proteins as markers of disease
Han GW, Iwatsuki K, Inoue M, Matsui T, Nishibu
Invest Dermatol 129:14–30 activity. Allergy 48:1–5
A, Akiba H et al. (1999) Interleukin-15
Demehri S, Liu Z, Lee J, Lin MH, Crosby SD, is not a constitutive cytokine in the epider- Kerschenlohr K, Decard S, Przybilla B, Wollen-
Roberts CJ et al. (2008) Notch-deficient mis, but is inducible in culture or inflamma- berg A (2003) Atopy patch test reactions
skin induces a lethal systemic B-lymphopro- tory conditions. Acta Derm Venereol. show a rapid influx of inflammatory dendri-
liferative disorder by secreting TSLP a 79:37–40 tic epidermal cells in patients with extrinsic
sentinel for epidermal integrity. PLoS Biol atopic dermatitis and patients with intrinsic
Hasannejad H, Takahashi R, Kimishima M,
27:6–e123 atopic dermatitis. J Allergy Clin Immunol
Hayakawa K, Shiohara T (2007) Selective
111:869–74
Dijkstra D, Leurs R, Chazot P, Shenton FC, Stark impairment of Toll-like receptor 2-mediated
H, Werfel T et al. (2007) Histamine down- proinflammatory cytokine production by Koga C, Kabashima K, Shiraishi N, Kobayashi M,
regulates monocyte CCL2 production monocytes from patients with atopic derma- Tokura Y (2008) Possible pathogenic role of
through the histamine H4 receptor. J Allergy titis. J Allergy Clin Immunol 120:69–75 Th17 cells for atopic dermatitis. J Invest
Clin Immunol 120:300–7 Dermatol. 128:2625–30
He R, Oyoshi MK, Jin H, Geha RS (2007)
Dinarello CA (2007) Interleukin-18 and the Epicutaneous antigen exposure induces a Lane JE, Cheyney JM, Lane TN, Kent DE, Cohen
pathogenesis of inflammatory diseases. Th-17 response that drives airway inflamma- DJ (2006) Treatment of recalcitrant atopic
Semin Nephrol 27:98–114 tion after inhalation challenge. Proc Natl dermatitis with omalizumab. J Am Acad
Elsner J, Kapp A (1999) Regulation and modula- Acad Sci U S A 104:15817–22 Dermatol 54:68–72
tion of eosinophil effector functions. Allergy Hennino A, Vocanson M, Toussaint Y, Rodet K, Langer K, Breuer K, Kapp A, Werfel T (2007)
54:15–26 Benetiere J, Schmitt AM et al. (2007) Skin- Staphylococcus aureus-derived enterotoxins
Fiset PO, Leung DY, Hamid Q (2006) Immuno- infiltrating CD8+ T-cells initiate atopic der- enhance house dust mite-induced patch test
pathology of atopic dermatitis. J Allergy Clin matitis lesions. J Immunol 178:5571–7 reactions in atopic dermatitis. Exp Dermatol
Immunol 118:287–90 Hoechstetter R, Dobos G, Kimmig D, Dulkys Y, 16:124–9

Forman SB, Garrett AB (2007) Success of omali- Kapp A, Elsner J (2000) The CC chemokine Leiferman KM, Ackerman SJ, Sampson HA,
zumab as monotherapy in adult atopic receptor 3 CCR3 is functionally expressed on Haugen HS, Venencie PY, Gleich GJ (1985)
dermatitis: case report and discussion of the eosinophils but not on neutrophils. Eur J Dermal deposition of eosinophil-granule
high-affinity immunoglobulin E receptor, Immunol 30:2759–64 major basic protein in atopic dermatitis.
FcepsilonRI. Cutis 80:38–40 Holgate ST (2007) The epithelium takes centre Comparison with onchocerciasis. N Engl J
stage in asthma and atopic dermatitis. Trends Med. 313:282–5
Franz B, Fritzsching B, Riehl A, Oberle N, Klemke
CD, Sykora J et al. (2007) Low number of Immunol 28:248–51 Leung AK, Hon KL, Robson WL (2007) Atopic
regulatory T cells in skin lesions of patients Holm L, Bengtsson A, Hage-Hamsten M, Ohman dermatitis. Adv Pediatr 54:241–73
with cutaneous lupus erythematosus. Arthri- S, Scheynius A (2001) Effectiveness of Leung DY, Bhan AK, Schneeberger EE, Geha RS
tis Rheum 56:1910–20 occlusive bedding in the treatment of atopic (1983) Characterization of the mononuclear

1888 Journal of Investigative Dermatology (2009), Volume 129


T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

cell infiltrate in atopic dermatitis using engagement of Langerhans cell-like Piskin G, Sylva-Steenland RM, Bos JD,
monoclonal antibodies. J Allergy Clin Im- dendritic cells and inflammatory dendritic Teunissen MB (2006) In vitro and in situ
munol 71:47–56 epidermal cell-like dendritic cells induces expression of IL-23 by keratinocytes in
Leung DY, Boguniewicz M, Howell MD, Nomura chemotactic signals and different T-cell healthy skin and psoriasis lesions: enhanced
I, Hamid QA (2004) New insights into atopic phenotypes in vitro. J Allergy Clin Immunol expression in psoriatic skin. J Immunol
dermatitis. J Clin Invest 113:651–7 113:949–57 176:1908–15

Li XM, Kleiner G, Huang CK, Lee SY, Schofield B, Novembre E, Cianferoni A, Lombardi E, Bernar- Purwar R, Kraus M, Werfel T, Wittmann M
Soter NA et al. (2001) Murine model of dini R, Pucci N, Vierucci A (2001) Natural (2007a) Modulation of Keratinocyte-Derived
atopic dermatitis associated with food hy- history of ‘‘intrinsic’’ atopic dermatitis. Al- MMP-9 by IL-13: A Possible Role for the
persensitivity. J Allergy Clin Immunol lergy 56:452–3 Pathogenesis of Epidermal Inflammation. J
107:693–702 Ong PY, Ohtake T, Brandt C, Strickland I, Invest Dermatol 128:59–66

Maintz L, Novak N (2007) Getting more and more Boguniewicz M, Ganz T et al. (2002) Purwar R, Werfel T, Wittmann M (2006) IL-13-
complex: the pathophysiology of atopic Endogenous antimicrobial peptides and skin stimulated human keratinocytes preferen-
eczema. Eur J Dermatol 17:267–83 infections in atopic dermatitis. N Engl J Med tially attract CD4+CCR4+ T-cells: possible
347:1151–60 role in atopic dermatitis. J Invest Dermatol
McGirt LY, Beck LA (2006) Innate immune 126:1043–51
defects in atopic dermatitis. J Allergy Clin O’Regan GM, Irvine AD (2008) The role of
Immunol 118:202–8 filaggrin loss-of-function mutations in atopic Purwar R, Werfel T, Wittmann M (2007b)
dermatitis. Curr Opin Allergy Clin Immunol Regulation of IL-13 receptors in human
Mehl A, Verstege A, Staden U, Kulig M, Nocon M, keratinocytes. J Invest Dermatol 127:1271–4
8:406–10
Beyer K et al. (2005) Utility of the ratio of
Oosting AJ, Bruin-Weller MS, Terreehorst I, Raap U, Werfel T, Goltz C, Deneka N, Langer K,
food-specific IgE/total IgE in predicting
Tempels-Pavlica Z, Aalberse RC, de Monchy Bruder M et al. (2006) Circulating levels of
symptomatic food allergy in children. Al-
JG et al. (2002) Effect of mattress encasings brain-derived neurotrophic factor correlate
lergy 60:1034–9
on atopic dermatitis outcome measures in a with disease severity in the intrinsic type of
Mothes N, Niggemann B, Jenneck C, Hagemann atopic dermatitis. Allergy 61:1416–8
double-blind, placebo-controlled study: the
T, Weidinger S, Bieber T et al. (2005) The
Dutch mite avoidance study. J Allergy Clin Raap U, Wichmann K, Bruder M, Ständer S,
cradle of IgE autoreactivity in atopic eczema
Immunol 110:500–6 Wedi B, Kapp A et al. (2008) Correlation of
lies in early infancy. J Allergy Clin Immunol
Ou LS, Goleva E, Hall C, Leung DY (2004) T IL-31 serum levels with severity of atopic
116:706–9
regulatory cells in atopic dermatitis and dermatitis. J Allergy Clin Immunol
Mrabet-Dahbi S, Dalpke A, Frey M, Niehbuhr M, 122:421–3
subversion of their activity by superantigens.
Draing C, Brand S et al. (2008) The toll-like
J Allergy Clin Immunol 113:756–63 Reefer AJ, Satinover SM, Wilson BB, Woodfolk JA
receptor 2 (TRL-2) R753Q mutation modifies
Pajno GB, Caminiti L, Vita D, Barberio G, (2007) The relevance of microbial allergens
cytokine production and TLR expression in
Salzano G, Lombardo F et al. (2007) to the IgE antibody repertoire in atopic and
atopic dermatitis. J Allergy Clin Immunol
Sublingual immunotherapy in mite-sensi- nonatopic eczema. J Allergy Clin Immunol
121:1013–9
tized children with atopic dermatitis: a 120:156–63
Neis MM, Peters B, Dreuw A, Wenzel J, Bieber T,
randomized, double-blind, placebo-con- Reekers R, Beyer K, Niggemann B, Wahn U,
Mauch C et al. (2006) Enhanced expression
trolled study. J Allergy Clin Immunol Freihorst J, Kapp A et al. (1996) The role of
levels of IL-31 correlate with IL-4 and IL-13
120:164–70 circulating food antigen-specific lympho-
in atopic and allergic contact dermatitis. J
Palmer CN, Irvine AD, Terron-Kwiatkowski A, cytes in food allergic children with atopic
Allergy Clin Immunol 118:930–7
Zhao Y, Liao H, Lee SP et al. (2006) dermatitis. Br J Dermatol 135:935–41
Niebuhr M, Langnickel J, Draing C, Renz H, Kapp
Common loss-of-function variants of the Reekers R, Busche M, Wittmann M, Kapp A,
A, Werfel T (2008) Dysregulation of toll-like
epidermal barrier protein filaggrin are a Werfel T (1999) Birch pollen-related foods
receptor-2 (TLR-2)-induced effects in mono-
major predisposing factor for atopic derma- trigger atopic dermatitis in patients with
cytes from patients with atopic dermatitis:
titis. Nat Genet 38:441–6 specific cutaneous T-cell responses to birch
impact of the TLR-2 R753Q polymorphism.
Giustizieri ML, Mascia F, Frezzolini A, De Pità O, pollen antigens. J Allergy Clin Immunol
Allergy 63:728–34
Chinni LM, Giannetti A et al. (2001) Kerati- 104:466–72
Niebuhr M, Lutat C, Sigel S, Werfel T (2009)
nocytes from patients with atopic dermatitis Reich K, Hugo S, Middel P, Blaschke V, Heine A,
Impaired TLR-2 expression and TLR-2
and psoriasis show a distinct chemokine Gutgesell C et al. (2002) Evidence for a role
mediated cytokine secretion in macrophages
production profile in response to T cell- of Langerhans cell-derived IL-16 in atopic
from patients with atopic dermatitis. Allergy
derived cytokines. J Allergy Clin Immunol dermatitis. J Allergy Clin Immunol
(in press)
107:871–7 109:681–7
Nomura I, Goleva E, Howell MD, Hamid QA,
Pastore S, Corinti S, La Placa M, Didona B, Sager N, Feldmann A, Schilling G, Kreitsch P,
Ong PY, Hall CF et al. (2003) Cytokine
Girolomoni G (1998) Interferon-gamma pro- Neumann C (1992) House dust mite-specific
milieu of atopic dermatitis, as compared to T-cells in the skin of subjects with atopic
motes exaggerated cytokine production in
psoriasis, skin prevents induction of innate dermatitis: frequency and lymphokine profile
keratinocytes cultured from patients with
immune response genes. J Immunol in the allergen patch test. J Allergy Clin
atopic dermatitis. J Allergy Clin Immunol
171:3262–9 Immunol 89:801–10
101:538–44
Novak N, Allam JP, Bieber T (2003) Allergic Salt BH, Boguniewicz M, Leung DY (2007) Severe
Pastore S, Giustizieri ML, Mascia F, Giannetti A,
hyperreactivity to microbial components: a refractory atopic dermatitis in adults is highly
Kaushansky K, Girolomoni G. (2000) Dysre-
trigger factor of ‘‘intrinsic’’ atopic dermatitis? atopic. J Allergy Clin Immunol 119:508–9
gulated activation of activator protein 1 in
J Allergy Clin Immunol 112:215–6
keratinocytes of atopic dermatitis patients Sampson HA (2001) Utility of food-specific IgE
Novak N, Bieber T (2003) Allergic and nonaller- with enhanced expression of granulocyte/ concentrations in predicting symptomatic
gic forms of atopic diseases. J Allergy Clin macrophage-colony stimulating factor. J In- food allergy. J Allergy Clin Immunol
Immunol 112:252–62 vest Dermatol 115:1134–43 107:891–6
Novak N, Peng W, Yu C (2007) Network of Picker LJ, Michie SA, Rott LS, Butcher EC (1990) A Santamaria Babi LF, Picker LJ, Perez Soler MT,
myeloid and plasmacytoid dendritic cells in unique phenotype of skin-associated lym- Drzimalla K, Flohr P, Blaser K et al. (1995)
atopic dermatitis. Adv Exp Med Biol phocytes in humans. Preferential expression Circulating allergen-reactive T-cells from
601:97–104 of the HECA-452 epitope by benign and patients with atopic dermatitis and
Novak N, Valenta R, Bohle B, Laffer S, Haberstok malignant T-cells at cutaneous sites. Am J allergic contact dermatitis express the skin-
J, Kraft S et al. (2004) Fc epsilon RI Pathol 136:1053–68 selective homing receptor, the cutaneous

www.jidonline.org 1889
T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

lymphocyte-associated antigen. J Exp Med Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto Trautmann A, Altznauer F, Akdis M, Simon HU,
181:1935–40 H, Kemeny L et al. (2006) IL-31: a new link Disch R, Brocker EB et al. (2001) The
Scalabrin DM, Bavbek S, Perzanowski MS, between T-cells and pruritus in atopic skin differential fate of cadherins during T-cell-
Wilson BB, Platts-Mills TA, Wheatley LM inflammation. J Allergy Clin Immunol induced keratinocyte apoptosis leads to
(1999) Use of specific IgE in assessing the 117:411–7 spongiosis in eczematous dermatitis. J Invest
relevance of fungal and dust mite allergens Soumelis V, Liu YJ (2004) Human thymic Dermatol 117:927–34
to atopic dermatitis: a comparison with stromal lymphopoietin: a novel epithelial Turjanmaa K, Darsow U, Niggemann B, Rance F,
asthmatic and nonasthmatic control subjects. cell-derived cytokine and a potential key Vanto T, Werfel T (2006) EAACI/GA2LEN
J Allergy Clin Immunol 104:1273–9 player in the induction of allergic inflamma- position paper: present status of the atopy
Scheynius A, Johansson C, Buentke E, Zargari A, tion. Springer Semin Immunopathol patch test. Allergy 61:1377–84
Linder MT (2002) Atopic eczema/dermatitis 25:325–33 Valenta R, Mittermann I, Werfel T, Garn H, Renz
syndrome and Malassezia. Int Arch Allergy Spergel JM, Mizoguchi E, Oettgen H, Bhan AK, H (2009) Linking allergy to autoimmune
Immunol 127:161–9 Geha RS (1999) Roles of TH-1 and TH-2 disease. Trends Immunol 30:109–16
Schmid-Grendelmeier P, Fluckiger S, Disch R, cytokines in a murine model of allergic van Beelen AJ, Teunissen MB, Kapsenberg ML, de
Trautmann A, Wuthrich B, Blaser K et al. dermatitis. J Clin Invest 103:1103–11 Jong EC (2007) Interleukin-17 in inflamma-
(2005) IgE-mediated and T-cell-mediated Steinhoff M, Steinhoff A, Homey B, Luger TA, tory skin disorders. Curr Opin Allergy Clin
autoimmunity against manganese superox- Schneider SW (2006) Role of vasculature in Immunol 7:374–81
ide dismutase in atopic dermatitis. J Allergy atopic dermatitis. J Allergy Clin Immunol Van Reijsen FC, Bruijnzeel-Koomen CA, Kalthoff
Clin Immunol 115:1068–75 118:190–7 FS, Maggi E, Romagnani S, Westland JK et al.
Schmid-Grendelmeier P, Scheynius A, Crameri R Strange P, Skov L, Lisby S, Nielsen PL, Baadsgaard (1992) Skin-derived aeroallergen-specific T-
(2006) The role of sensitization to Malassezia O (1996) Staphylococcal enterotoxin B cell clones of Th-2 phenotype in patients
sympodialis in atopic eczema. Chem Im- applied on intact normal and intact atopic with atopic dermatitis. J Allergy Clin Im-
munol Allergy 91:98–109 skin induces dermatitis. Arch Dermatol munol 90:184–93
Schmid-Ott G, Jaeger B, Adamek C, Koch H, 132:27–33 Van Reijsen FC, Felius A, Wauters EA, Bruijnzeel-
Lamprecht F, Kapp A et al. (2001a) Levels of Sugiura K, Muro Y, Nishizawa Y, Okamoto M, Koomen CA, Koppelman SJ (1998) T-cell
circulating CD8(+) T-lymphocytes, natural Shinohara T, Tomita Y et al. (2007) LEDGF/ reactivity for a peanut-derived epitope in the
killer cells, and eosinophils increase upon DFS70, a major autoantigen of atopic skin of a young infant with atopic dermatitis.
acute psychosocial stress in patients with dermatitis, is a component of keratohyalin J Allergy Clin Immunol. 101:207–9
atopic dermatitis. J Allergy Clin Immunol granules. J Invest Dermatol 127:75–80 Verhagen J, Akdis M, Traidl-Hoffmann C, Schmid-
107:171–7 Szepietowski JC, McKenzie RC, Keohane SG, Grendelmeier P, Hijnen D, Knol EF et al.
Schmid-Ott G, Jaeger B, Meyer S, Stephan E, Kapp Aldridge RD, Hunter JA (1997) Atopic (2006) Absence of T-regulatory cell expres-
A, Werfel T (2001b) Different expression of and non-atopic individuals react to nickel sion and function in atopic dermatitis skin. J
cytokine and membrane molecules by cir- challenge in a similar way. A study Allergy Clin Immunol 117:176–83
culating lymphocytes on acute mental stress of the cytokine profile in nickel-induced Vigo PG, Girgis KR, Pfuetze BL, Critchlow ME,
in patients with atopic dermatitis in compar- contact dermatitis. Br J Dermatol 137: Fisher J, Hussain I (2006) Efficacy of anti-IgE
ison with healthy controls. J Allergy Clin 195–200 therapy in patients with atopic dermatitis. J
Immunol 108:455–62 Takaoka A, Arai I, Sugimoto M, Honma Y, Futaki Am Acad Dermatol 55:168–70
Schnopp C, Rad R, Weidinger A, Weidinger S, N, Nakamura A et al. (2006) Involvement of Wedi B, Raap U, Kapp A (1999) Significant delay
Ring J, Eberlein B et al. (2007) Fox-P3- IL-31 on scratching behavior in NC/Nga of apoptosis and Fas resistance in eosinophils
positive regulatory T-cells are present in the mice with atopic-like dermatitis. Exp Der- of subjects with intrinsic and extrinsic type of
skin of generalized atopic eczema patients matol 15:161–7 atopic dermatitis. Int Arch Allergy Immunol
and are not particularly affected by medium- Tan BB, Weald D, Strickland I, Friedmann PS 118:234–5
dose UVA1 therapy. Photodermatol Photo- (1996) Double-blind controlled trial of effect Wedi B, Raap U, Lewrick H, Kapp A (1998) IL-4-
immunol Photomed 23:81–5 of housedust-mite allergen avoidance on induced apoptosis in peripheral blood eosino-
Selander C, Zargari A, Mollby R, Rasool O, atopic dermatitis. Lancet 347:15–8 phils. J Allergy Clin Immunol 102:1013–20
Scheynius A (2006) Higher pH level, corre- Thepen T, Langeveld-Wildschut EG, Bihari IC, Werfel T, Ahlers G, Schmidt P, Boeker M, Kapp A,
sponding to that on the skin of patients with van Wichen DF, Van Reijsen FC, Mudde GC Neumann C (1997a) Milk-responsive atopic
atopic eczema, stimulates the release of et al. (1996) Biphasic response against dermatitis is associated with a casein-speci-
Malassezia sympodialis allergens. Allergy aeroallergen in atopic dermatitis showing a fic lymphocyte response in adolescent and
61:1002–8 switch from an initial TH-2 response to a TH- adult patients. J Allergy Clin Immunol
Seneviratne SL, Jones L, King AS, Black A, Powell 1 response in situ: an immunocytochemical 99:124–33
S, McMichael AJ et al. (2002) Allergen- study. J Allergy Clin Immunol 97:828–37 Werfel T, Breuer K (2004) Role of food allergy in
specific CD8(+) T cells and atopic disease. Toda M, Leung DY, Molet S, Boguniewicz M, atopic dermatitis. Curr Opin Allergy Clin
J Clin Invest 110:1283–91 Taha R, Christodoulopoulos P et al. Immunol 4:379–85
Shimizu M, Matsuda A, Yanagisawa K, Hirota T, (2003) Polarized in vivo expression of IL-11 Werfel T, Breuer K, Rueff F, Przybilla B, Worm M,
Akahoshi M, Inomata N et al. (2005) Func- and IL-17 between acute and chronic Grewe M et al. (2006) Usefulness of specific
tional SNPs in the distal promoter of the ST2 skin lesions. J Allergy Clin Immunol immunotherapy in patients with atopic
gene are associated with atopic dermatitis. 111:875–81 dermatitis and allergic sensitization to house
Hum Mol Genet 14:2919–27 Torgerson TR, Ochs HD (2007) Immune dysregu- dust mites: a multi-centre, randomized,
Simon D, Braathen LR, Simon HU (2004) lation, polyendocrinopathy, enteropathy, X- dose-response study. Allergy 61:202–5
Eosinophils and atopic dermatitis. Allergy linked: forkhead box protein 3 mutations and Werfel T, Hentschel M, Kapp A, Renz H (1997b)
59:561–70 lack of regulatory T-cells. J Allergy Clin Dichotomy of blood- and skin-derived
Skov L, Olsen JV, Giorno R, Schlievert PM, Immunol 120:744–50 IL-4-producing allergen-specific T-cells
Baadsgaard O, Leung DY (2000) Application Trautmann A, Akdis M, Kleemann D, Altznauer F, and restricted V beta repertoire in nickel-
of Staphylococcal enterotoxin B on Simon HU, Graeve T et al. (2000) T-cell- mediated contact dermatitis. J Immunol
normal and atopic skin induces up-regula- mediated Fas-induced keratinocyte 158:2500–5
tion of T-cells by a superantigen-mediated apoptosis plays a key pathogenetic role in Werfel T, Kapp A (1998) Environmental and other
mechanism. J Allergy Clin Immunol 105: eczematous dermatitis. J Clin Invest major provocation factors in atopic dermati-
820–6 106:25–35 tis. Allergy 53:731–9

1890 Journal of Investigative Dermatology (2009), Volume 129


T Werfel
The Role of Leukocytes, Keratinocytes, and Allergen-Specific IgE

Werfel T, Kapp A (1999) What do we know about monocytes interferes with a TH-1 response. J Wollenberg A, Wagner M, Gunther S,
the etiopathology of the intrinsic type of Allergy Clin Immunol 114:965–73 Towarowski A, Tuma E, Moderer M et al.
atopic dermatitis? Curr Probl Dermatol Wittmann M, Kienlin P, Mommert S, Kapp A, (2002) Plasmacytoid dendritic cells: a new
28:29–36 Werfel T (2002) Suppression of IL-12 pro- cutaneous dendritic cell subset with distinct
Werfel T, Morita A, Grewe M, Renz H, Wahn U, duction by soluble CD40 ligand: evidence role in inflammatory skin diseases. J Invest
Krutmann J et al. (1996) Allergen specificity for involvement of the p44/42 mitogen- Dermatol 119:1096–102
of skin-infiltrating T-cells is not restricted to a activated protein kinase pathway. J Immunol Wu K, Higashi N, Hansen ER, Lund M, Bang K,
type-2 cytokine pattern in chronic skin 168:3793–800 Thestrup-Pedersen K (2000) Telomerase ac-
lesions of atopic dermatitis. J Invest Dermatol Wittmann M, Purwar R, Hartmann C, Gutzmer R, tivity is increased and telomere length
107:871–6 Werfel T (2005) Human keratinocytes shortened in T-cells from blood of patients
Williams H, Flohr C (2006) How epidemiology respond to interleukin-18: implication for with atopic dermatitis and psoriasis. J Im-
has challenged 3 prevailing concepts about the course of chronic inflammatory skin munol 165:4742–7
atopic dermatitis. J Allergy Clin Immunol diseases. J Invest Dermatol 124:1225–33 Zachary CB, Allen MH, MacDonald DM (1985) In
118:209–13 Wittmann M, Werfel T (2006) Interaction of situ quantification of T-lymphocyte subsets
Wittmann M, Alter M, Stunkel T, Kapp A, Werfel keratinocytes with infiltrating lymphocytes and Langerhans cells in the inflammatory
T (2004) Cell-to-cell contact between acti- in allergic eczematous skin diseases. Curr infiltrate of atopic eczema. Br J Dermatol
vated CD4+ T-lymphocytes and unprimed Opin Allergy Clin Immunol 6:329–34 112:149–56

www.jidonline.org 1891

Вам также может понравиться