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The Role of Leukocytes, Keratinocytes, and

Allergen-Specific IgE in the Development ofAtopic DermatitisThomas Werfel1

This review provides an overview of the inflammatory mechanisms and immunological aspects specific toatopic 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 furtherfocus lies on keratinocyteT-cell interactions, which may be of particular relevance in eczema. Mechanisms ininnate and adaptive immunity that result in susceptibility to skin infections and in hyperreactivity toenvironmental 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 thecontext of immunology of atopic dermatitis.

Journal of Investigative Dermatology (2009) 129, 18781891; doi:10.1038/jid.2009.71; published online 9 April 2009

INTRODUCTIONAtopic dermatitis (AD) is a chronicinflammatory skin disease that com-monly begins in early infancy, runs acourse of relapses and remissions,and is associated with a characteristicdistribution and morphology of skin

lesions. Furthermore, pruritus and con-sequent sleeplessness are hallmarks ofAD. Numerous trigger factors havebeen identified for AD in recent dec-ades, including inhaled allergens, foodallergens, irritative substances, andinfectious microorganisms, such asStaphylococcus aureus and Malasseziaspecies (Werfel and Kapp, 1998; Akdiset al., 2006; Leung et al., 2007; Bieber,2008).

A complex interaction between sus-ceptibility genes encoding skin barrier

molecules and markers of the inflam-matory response, host environments,infectious agents, and specific immu-nologic responses are involved in thepathophysiology of AD. In this review,the focus is on the immunological and

inflammatory mechanisms. The immu-nohistology of the various phases of thedisease are summarized, and the majorcells involved in cutaneous inflamma-tion are characterized. Clearly,the different T-cell subpopulations(CD4 versus CD8 , T helper 1

(Th1) versus Th2 versus Th17; T-reg-ulatory (T-reg) cells) deserve particularattention. In addition, it is now clearthat dendritic cells (DCs) and keratino-cytes are critical elements in theregulation of skin pathology in AD,and eosinophils may aggravate theinflammatory reaction.

An additional emphasis is placed onthe role of specific IgE and T cells aswell as the antigens that are recognizedby these adaptive elements of theimmune system.

IMMUNOHISTOLOGYAsymptomatic skin in AD differs fromnormal skin: The underlying barrierdefect is associated with filaggrin loss-of-function mutations in more than

30% of patients with AD. This findingwas first published by Palmer et al.(2006) and then confirmed by severalother groups (see reviews: Brown andMcLean, 2009; ORegan and Irvine,2008). The filaggrin loss-of-functionmutations are thought to lead to dry

skin associated with a greater skinresponse to irritants than that of normalhealthy skin. Microscopic studies re-vealed a sparse perivascular T-cell(Th2) infiltrate in unaffected AD skinthat is not seen in normal healthy skin(Leung et al., 1983). Mast cell numbersare also slightly enriched in asympto-matic skin.

Acute skin lesions are characterizedby intensely pruritic, erythematouspapules associated with excoriationand oozing exudation in AD. There is

a marked infiltration of mononuclearcells that is histologically similar to thatin allergic contact dermatitis.

CD4-positive Th cells dominate thecellular infiltrate in AD (Zachary et al.,1985). The CD4/CD8 ratio of dermis-

PERSPECTIVE

878 Journal of Investigative Dermatology (2009), Volume 129 & 2009 The Society for Investigative Dermatology

Received 15 May 2008; revised 1 December 2008; accepted 7 January 2009; published online 9 April 2009

1Department 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: [email protected]

Abbreviations: AD, atopic dermatitis; CLA, cutaneous lymphocyte-associated antigen; DCs, dendritic cells; FcaRI, high-affinity receptor for IgE; IDECs,inflammatory dendritic epidermal cells; LCs, Langerhans cells; MHC, major histocompatibility class; pDCs, plasmacytoid DCs
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infiltrating T cells is similar to that inperipheral blood. Many intralesional Tcells show signs of activation and canfurther be distinguished by CD45RO, amarker of T-memory cells, suggesting aprevious contact with antigen or aller-

gen, and by the cutaneous lymphocyte-associated antigen (CLA). CLA definesthe subset of skin-homing T cells thatbind to E-selectin, an adhesion mole-cule expressed by endothelial cells ininflamed tissues during the first step ofleukocyte extravasation (Picker et al.,1990; Santamaria Babi et al., 1995).Many circulating CLA T cells displaya Th2 phenotype and some are allergenspecific (Akdis et al ., 1997). IL-12appears to be a key cytokine in theregulation of CLA; CLA-negative Th2

cells rapidly upregulate a(1-3)-fucosyl-transferase VII (involved in the expres-sion of CLA) and CLA molecules(Biedermann et al., 2006).

Mononuclear cells and eosinophilgranulocytes can be found mainly inthe dermis (Van Reijsen et al., 1992).Mast cell degranulation can be ob-served in acute lesions. Antigen-pre-senting cells in lesional and, to a lesserextent, in nonlesional skin bear IgEmolecules (Bieber, 2007; Novak et al.,2007).

Chronic inflammation generallycauses tissue remodeling, which is alsoobserved in chronic lesions of AD. Thiscan be observed as thickened plaqueswith increased skin markings (lichenifi-cation), increased collagen deposition inthe dermis, and dry fibrotic papules.Dermal macrophages are markedly in-creased in the dermal infiltrate duringthe chronic phase. Intact eosinophils areless commonly found, but eosinophilicproducts can be identified in chroniclesions of AD. T cells remain present in

the chronic phase, although in smallernumbers than seen in acute AD.

Taken together, both asymptomaticskin and the different stages of eczemaare associated with the infiltration ofleukocytes (mainly T cells) that char-acterizes the histology of this disease.

EARLY EVENTS IN ADDEVELOPMENTEarly events initiating atopic skin in-flammation involve mechanical traumaand skin barrier disruption, which may

occur after the skin is scratched. Thisresults in the rapid upregulation ofproinflammatory mediators such as IL-1a, IL-1b, TNF-a, and GM-CSF (Homeyet al., 2006). These proinflammatorycytokines bind to receptors on the

vascular endothelium, activate cellularsignaling, and induce the expression ofvascular endothelial cell adhesion mo-lecules. These events initiate the pro-cess of adhesion to the endothelium,tethering, and transmigration of infil-trating cells. This process is tightlyregulated and involves an activecommunication process betweenendothelial cells and leukocytes. Tcellendothelial cell interactions arethus crucial in acute AD. In addition,there is crosstalk between endothelial

cells and other cutaneous cells, such asmast cells and perivascular dermalmacrophages (Steinhoff et al., 2006).

Once inflammatory cells have infil-trated into the tissue, they respond tochemotactic gradients established bycytokines and chemokines, which ori-ginate from sites of injury or infection.These molecules play a central role indefining the nature of the inflammatoryinfiltrate in AD. For example, IL-16produced by Langerhans cells (LCs)may help in the recruitment of T cells

and has been reported in AD lesions(Reich et al., 2002). Several homeo-static and inflammatory chemokines,including CCL2 (MCP-1), CCL5(RANTES), CCL17 (TARC), CCL18(PARC), CCL29 (LARC), CCL22(MDC), and CCL27 (CTACK), havebeen shown to be increased in ADand thus may support leukocyte re-cruitment (Homey et al, 2006). Of note,cutaneous T-cell-attracting chemokine(CCL27) is significantly upregulated inAD and preferentially attracts cuta-

neous lymphocyte antigen-positive Tcells into the skin. Selective recruit-ment of CCR4-expressing Th2 cells ismediated by macrophage-derived che-mokine (CCL22) and thymus and acti-vation-regulated cytokine (CCL17),which are increased in patients withAD. Interestingly, serum levels of anumber of chemokines (for example,CCL17, CCL22, and CCL27) correlatewith disease activity, suggesting animportant role in the pathogenesis ofAD (Homey et al., 2006).

The maintenance of chronic ADinvolves the production of GM-CSFand the Th1-like cytokines IL-12 andIL-18 (Hamid et al., 1994), as well asseveral remodeling-associated cyto-kines, such as IL-11 and TGF-b1, which

are expressed preferentially in chronicforms of the disease (Toda et al., 2003).

In summary, early events includeendothelialT-cell interaction and therelease of chemokinesthe under-standing of these events is of particularimportance for a recurrent disease suchas AD.

T-LYMPHOCYTESCD4 and CD8 T cells in ADPatients suffering from AD have in-creased levels of activated circulating

T cells. A study revealing increasedtelomerase activity and shortened telo-mere length in AD indicates that T cellsare chronically stimulated and have anincreased cellular turnover in vivo(Wuet al., 2000).

The high number of circulating Tcells results from increased numbers ofCD4 cells, whereas the absolutenumber of CD8 lymphocytes isnormal or even decreased in peripheralblood. However, acute psychologicalstress has been shown to lead to rapid,

significantly higher increases in thenumber of circulating CD8 T-lym-phocytes in AD patients compared withhealthy controls. This may indicate thatthere are larger pools of this cell typeclose to the circulation that can betranslocated into the blood duringpsychological stress (Schmid-Ottet al., 2001a).

The role of CD8 T cells in atopicskin inflammation is still not welldefined. It has been shown that CLACD8 T cells isolated from the circu-

lation are as potent as CLA CD4 Tcells in the induction of IgE andenhancement of eosinophil survival.This suggests that these cells have morethan bystander functions in AD (Akdiset al., 1999). Later, a significant asso-ciation between the frequency of aller-gen-specific (that is, Der p 1-specific)CD8 T cells and disease activitywas described (Seneviratne et al .,2002). Recent data from a mousemodel indicate that allergen-primedCD8 T cells are required for the

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development of AD-like lesions in vivo(Hennino et al., 2007).

In summary, although CD4 cellsclearly dominate over CD8 cells inthe skin in AD, there is some evidencethat CD8 cells are also of relevance

in this disease.

T-cell cytokines in AD. The onset ofacute AD is strongly associated withthe production of Th2 cytokines, nota-bly IL-4, IL-13, and IL-31, levels ofwhich are significantly higher in ADindividuals compared with control sub-

jects (Hamid et al., 1994; Neis et al.,2006).

Th1 and Th2 cytokines may contri-bute to the pathogenesis of local skininflammation in AD with the relative

contribution of each cytokine dependenton the duration of the skin lesion. Inprevious studies, the majority of aller-gen-specific T cells derived from skinlesions that had been provoked byepicutaneous application of inhalantallergens were found to produce pre-dominantly Th2 cytokines such as IL-4,IL-13, or IL-5. This was initially consid-ered to be a specific feature reflectingimmune dysregulation in AD (Sageret al., 1992; Van Reijsen et al., 1992).It was subsequently shown that the

expression of IFN-g rather than of IL-4predominates in spontaneous or olderpatch test lesions in AD (Grewe et al.,1995; Thepen et al., 1996). Importantly,patient treatments that resulted in lesionimprovement could be correlated withdownregulation of IFN-g expression, butnot of IL-4, in the skin (Grewe et al.,1995). Also, allergen-specific T-cellclones from spontaneous AD lesionsdiffered from allergen-specific T cellsisolated from inhalant allergen patch testlesions by virtue of their capacity to

produce IFN-g (Werfel et al., 1996).The cytokine switch from Th2 in the

acute phase toward Th1 in the chronicphase is accepted for AD and appearsto be relevant in allergic contactdermatitis as well.

Factors contributing to cytokine milieuin AD. In patients with AD, activated Tcells with skin-homing properties,which express high levels of IFN-g,may predominantly undergo apoptosisin the circulation, skewing the immune

response to surviving Th2 cells as amechanism for Th2 predominance inthe circulation and in acute lesions(Akdis et al ., 2003; Akkoc et al .,2008). Moreover, patients with ADhave a genetic background of a

general systemic Th2 polarization(Brown and McLean, 2009), whichcontributes to the higher number ofcirculating T cells capable of producingTh2 cytokines.

IL-4, which is a strong inducer of atype 2 cytokine milieu itself, is pro-duced by early skin-infiltrating Tcells, but it may also come from mastcells, basophils, or eosinophils duringan acute eczematous skin reaction. It isinteresting to note that the high fre-quency of IL-4-producing T cells in the

skin is not necessarily associated withatopy given that mRNA for IL-4 and Tcells expressing IL-4 are also found innickel-induced patch test reactions(Neis et al., 2006; Szepietowski et al.,1997; Werfel et al., 1997b).

Acute lesions show a reduced expres-sion of IL-12, a key cytokine of Th1polarization, which was shown at themRNA level by in situ hybridization inacute skin lesions (Hamid et al., 1996).The reason for the relative lack in theexpression of IL-12 is not completely

understood. sCD40L was shown toinhibit IL-12 upregulation by an intracel-lular ERK-dependent signal-transducingpathway (Wittmann et al., 2002). Theseresults were reproduced later and ex-tended to skin-infiltrating CD40L Tcells, which may thus contribute to therelative inability to upregulate IL-12 inacute eczema, leading to a refractorystate of constitutive antigen-presentingcells (Wittmann et al., 2004).

A number of factors may be in-volved in the switch from Th2 to Th1

cytokines in older lesions. The polar-ization of T cells along the Th1 lineage,resulting in IFN-g production, is sup-ported by IL-12, IL-23, IL-27, and IL-18(Hunter, 2005). IL-12 subunits havebeen found to be expressed by anti-gen-presenting cells and by humankeratinocytes. However, it is not clearwhether keratinocytes are indeed arelevant source of bioactive IL-12.IL-23 has recently been shown to beproduced by DCs and by humancultured keratinocytes in healthy skin

and in psoriasisits role in AD has tobe defined (Piskin et al., 2006). Inter-action with activated T cells viaCD40CD40L may enhance IL-23 pro-duction by keratinocytes, which mayenhance IFN-g production by memory

T cells (Wittmann and Werfel, 2006).IL-18 is another cytokine that func-

tions in parallel with IL-12 (Dinarello,2007). Keratinocytes functionally re-spond to IL-18 with upregulation ofmajor histocompatibility class (MHC) I,reinforcement of the IFN-g-inducedMHC class II expression, and produc-tion of the chemokine CXCL10 (Witt-mann et al., 2005). This supports thenotion that IL-18 is involved in thepathogenesis of local Th1 responses inchronic inflammatory skin diseases.

The molecular mechanism of thecytokine switch from Th2 in the acutephase to Th1 in the chronic phase iscomplex and involves different Th2cytokine-producing cells in the acutephase (for example, T cells, basophils,mast cells) and Th1-polarizing cyto-kines, which are produced primarily byantigen-presenting cells.

Effects of T-cell cytokines on theinflammatory reaction in the skin inAD. In lymphoid organs, IL-4 and IL-13

mediate the IgE isotype switch in Bcells. In acute eczema, IL-4 and IL-13induce a variety of local responses,such as the induction of the adhesionmolecules on endothelial cells and Fcreceptors on eosinophils or chemo-kines (Leung et al., 2004). In contrastto IL-5, IL-4 induces apoptosis ineosinophils (Wedi et al., 1998).

Recent findings demonstrate that IL-4 and IL-13 have effects on keratino-cytes: both cytokines function via thesame receptor (Purwar et al., 2007b).

IL-13- or IL-4-stimulated keratinocytesattract CCR4 CD4 Th2 cells viaCCL22 (Purwar et al., 2006). Moreover,IL-13 induces the expression of MMP-9in keratinocytes (Purwar et al., 2007a),which may play a crucial role in atopicskin inflammation by facilitating themigration of leukocytes into the epi-dermis.

Some AD patients have a filaggrinloss-of-function mutation leading toreduced filaggrin expression in the skin(Brown and McLean, 2009). Recently it

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was shown that filaggrin expressionwas reduced in AD even in the absenceof a loss-of-function mutation (Howellet al., 2007). Keratinocytes differen-tiated in the presence of IL-4 and IL-13exhibited significantly reduced filag-

grin gene expression compared withmedium alone. Neutralization of IL-4and IL-13 may improve skin barrierintegrity (Howell et al., 2007). Thisindicates that the atopic immune re-sponse directly contributes to the skinbarrier defect in AD.

A new Th2-associated cytokine,IL-31, has been shown to be highlyexpressed in acute eczema (that is, inboth acute atopic and acute allergycontact dermatitis) (Neis et al., 2006).IL-31 is produced by T cells that

express CLA and localize to the skin(Bilsborough et al., 2006). It appears tobe a link between skin-infiltrating Tcells and pruritus in the skin, asdemonstrated in a mouse model (Ta-kaoka et al., 2006). In humans, IL-31 issignificantly overexpressed in itchingskin inflammation such as AD (Sonkolyet al ., 2006; Raap et al ., 2008).Staphylococcal superantigens and his-tamine induce IL-31 expression inatopic individuals (Gutzmer et al .,2009). These data suggest that IL-31

may be an itch-causing mediator inpatients with AD derived from skin-infiltrating T cells.

In chronic lichenified AD skin le-sions, fewer IL-4 and IL-13 mRNA-expressing cells are present, but greaternumbers of IL-5, GM-CSF, IL-12, andIFN-g mRNA-expressing cells are de-tected (Hamid et al., 1994). The rise inIL-5 expression during the transitionfrom acute to chronic AD probablyplays a role in the prolongation ofeosinophil survival and function (Wedi

et al ., 1999). Some of the othercytokines mentioned above supportthe function of macrophages and pro-mote the Th1-type inflammation morecharacteristic of chronic AD (Fisetet al ., 2006). Effects of IFN-g onkeratinocytes are discussed below.

In summary, T-cell cytokines havenumerous effects on skin inflammation,ranging from the induction of chemo-kines and downmodulation of barrier-associated molecules to the inductionof pruritus.

Th17 lymphocytes in ADRecently, a novel and unique subset ofIL-17-producing CD4 Th17 cells, dis-tinct from Th1 and Th2 cells, wasdiscovered. Th17 cells appear to beinvolved in protection against bacterial

pathogens. In addition, Th17 cells mayalso be crucial in the pathogenesis ofvarious chronic inflammatory diseasesthat were formerly categorized as Th1-mediated disorders. Whereas IL-17 mayplay an important role in the pathogen-esis of psoriasis and contact hypersensi-tivity, its role in AD is still underinvestigation (van Beelen et al., 2007).In skin biopsy specimens recovered fromacute and chronic skin lesions frompatients with AD, IL-17 mRNA waspreferentially associated with acute le-

sions (Toda et al., 2003). In a recentstudy, the percentage of Th17 cells wasshown to be higher in the peripheralblood of AD patients and associated withthe severity of AD. Immunohistochemi-cally, IL-17 cells infiltrated the papil-lary dermis of atopic eczema moremarkedly in acute lesions than in chroniclesions (Koga et al., 2008).

Epicutaneous immunization withovalbumin, which causes allergic skininflammation with many characteristicsof the skin lesions of AD in a mouse

model, was found to drive IL-17expression. Epicutaneous, but not in-traperitoneal, immunization of micewith ovalbumin drove the generationof IL-17-producing T cells in both thespleen and the draining lymph nodesand increased serum IL-17 levels. DCstrafficking from skin to lymph nodesexpressed more IL-23 and inducedmore IL-17 secretion by naive T cells.This was inhibited by neutralizing IL-23in vitroand by intradermal injection ofanti-TGF-b-neutralizing antibody

in vivo. These data suggest that initialcutaneous exposure to protein antigensmay selectively induce the productionof IL-17 in AD (He et al., 2007).

Taking together these findings, Th17cells are present in the skin of AD. Therole of these cells in acute eczema for thecourse of AD remains to be elucidated.

T-reg cells in ADT-reg cells control the activation ofautoreactive and T-effector cells andare crucial for the maintenance of

peripheral tolerance to self-antigens.CD4 Foxp3 T-reg cells have beenreferred to as naturally occurring T-reg cells to distinguish them fromadaptive T-reg cells, which are gener-ated upon activation. A major popula-

tion of adaptive T-reg cells ischaracterized by the secretion of highlevels of IL-10 or transforming growthfactor (Akdis et al., 2005). Mutations inFOXP3, a nuclear factor expressed innatural T-reg cells and a subpopulationof adaptive T-reg cells, result in im-mune dysregulation polyendocrinopa-thy enteropathy X-linked syndromecharacterized by hyper-IgE, food al-lergy, and eczema (Torgerson andOchs, 2007), which suggests a possiblerole of T-reg cells in AD.

Increased numbers of peripheralblood CD4 CD25 T cells and anoverexpression of FOXP3 have beenfound in the blood of AD patientscompared with psoriasis patients andhealthy controls (Ou et al., 2004).Staphylococcal enterotoxin B inhibitsnatural T-reg cells in vitro (Ou et al.,2004). Superantigens have been shownto upregulate glucocorticoid-inducedTNF-receptor-related protein ligand onmonocytes, resulting in the prolifera-tion of natural T-reg cells and abroga-

tion of their immunosuppressiveactivity (Cardona et al., 2006).

In the skin, adaptive T-reg cells, but noFOXP3 natural T-reg cells, were de-tectable in AD in a series of biopsies fromeight AD patients (Verhagen et al., 2006).However, in recent studies, the numbersof FOXP3 natural T-reg cells weresimilar or higher in AD patients com-pared with healthy controls (Franz et al.,2007; Schnopp et al., 2008). It isnoteworthy that the number of naturalT-reg cells did not change significantly

after medium-dose UVA-1 radiation(Schnopp et al., 2007).

In summary, most recent studies haveidentified T-reg cells in the skin of ADpatients. It remains to be determinedwhether the differences in functionalactivities of T-reg cells shown in vitroare relevant for the course of AD in vivo.

DCsMyeloid DCs in ADDCs are specialized antigen-presentingcells found in lymphoid tissues and in



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peripheral organs such as the skin.Two major subtypes of DCs havebeen shown to play an importantrole in the pathophysiology of ADin humans: myeloid DCs and plasma-cytoid DCs (pDCs) (Novak et al .,

2007).Myeloid DCs can be further differ-

entiated into two subtypes thathave been found in lesional skin ofAD patients: LCs and inflammatorydendritic epidermal cells (IDECs).Both LCs and IDECs express thehigh-affinity receptor for IgE (FceRI)(Bieber, 2007), but they have differentfunctions in AD. LCs play a predomi-nant role in the initiation of theallergic immune response and primenaive T cells into T cells of the Th2 type

with high IL-4-producing capacity,which predominate in the initialphase of AD (Novak et al., 2004).Activated LCs can also present aller-gen-derived peptides to antigen-speci-fic T cells in the skin. The aggregationof FceRI on the surface of LCs inducesthe release of chemotactic factors (forexample, CCL2, CCL22, CCL17, or IL-16) and may facilitate allergen presen-tation to T cells (Maintz and Novak,2007).

IgE-bearing FceRI IDECs become

more prominent in chronic AD lesions.After allergen challenge, invasion ofhigh numbers of IDECs has beenshown, emphasizing their crucialrole in the development of eczema(Kerschenlohr et al., 2003). IDECs arealso found exclusively at inflammatorysites, suggesting an involvementin cell recruitment and IgE-mediatedantigen presentation to T cells. Incontrast to LCs, these cells promoteTh1 cytokine production from T cells.In this context it has been shown

that stimulation of FceRI on the surfaceof IDECs induces the release of IL-12and IL-18. This may contribute to theswitch from the initial Th2 immuneresponse in acute AD to the Th1polarization of T cells in the chronicphase (Novak et al., 2004).

In summary, both resident andinfiltrating myeloid DC populationsare crucial in AD. The expression ofFc receptors for IgE on these cells maybe of importance for facilitated allergenpresentation in AD.

pDCsActivated pDCs are able to produceantiviral type I interferons. pDCs in theperipheral blood of patients with ADhave been shown to bear the trimericvariant of FceRI on their cell surface,

which is occupied by IgE molecules.pDCs can take up allergens by FceRI-IgE, process them, and promote Th2-type immune responses (Novak et al.,2007). Increased numbers of pDCshave been found in the peripheralblood of AD patients, but only lownumbers of pDCs are detectable in skinlesions in AD, in contrast to otherinflammatory skin diseases (Wollen-berg et al., 2002).

The lack of pDCs in the skin hasbeen shown to contribute to the high

susceptibility of AD patients to viralskin infections, such as herpes simplex-induced eczema herpeticum.

KERATINOCYTET-CELLINTERACTIONSThere is growing evidence supportingkeratinocytes as enhancer cells of theinflammatory response in AD (Witt-mann and Werfel, 2006; Holgate,2007). Keratinocytes play a role ininnate immunity by expressing Toll-likereceptors and producing antimicrobial

peptides in response to invading mi-crobes (McGirt and Beck, 2006; DeBenedetto et al., 2009).

Keratinocytes secrete a unique pro-file of chemokines and cytokines afterexposure to proinflammatory cytokines(Figure 1A and B). Keratinocyte-derivedthymic stromal lymphopoietin (TSLP)may be of particular importance in AD(Soumelis and Liu, 2004; Homey et al.,2006): This protein is not detected innormal skin or in nonlesional skin inpatients with AD, but it is highly

expressed in lesions in both acute andchronic AD. TSLP instructs human DCsto create a Th2-permissive microenvir-onment by inducing the expression ofOX40L, which triggers the differentia-tion of inflammatory Th2 cells (Itoet al., 2005). Recently it was shownthat TSLP, synergistically with IL-1 andTNFa, stimulates the production ofhigh levels of Th2 cytokines by humanmast cells. In that study, TSLP wasshown to be released by primaryepithelial cells in response to microbial

products, physical injury, or inflamma-tory cytokines (Allakhverdi et al .,2007). Moreover, a recent paper de-monstrated a strong link between TSLPand skin barrier disruption (Demehriet al., 2008).

The general role of chemokines inthe initiation and perpetuation of ADhas been reviewed by Homey et al.(2006). Keratinocytes stimulated withproinflammatory cytokines have beenidentified as an important cellularsource of chemokines, which attract Tcells of different subtypes (Wittmannand Werfel, 2006). For example,CXCR3 ligands such as CXCL10 pre-ferentially attract Th1 cells (Albanesiet al., 2001). CCL22 and CCL17 pre-ferentially attract Th2 cells by binding

to CCR4 (Purwar et al., 2006). CCL2 iseffective on both Th1 and Th2 subsets.CCL27, which is constitutively ex-pressed by keratinocytes, binds toCCR10 expressed on most skin-hominglymphocytes (Homey et al., 2002).

Keratinocytes are also importantcellular sources of cytokines such asthe T-cell growth factor IL-15 in theskin (Han et al., 1999) (Figure 1B). IL-15 has been implicated in the patho-genesis of different skin diseases byvirtue of its action on the maintenance

of T cellspossibly intraepithelialT cells.

Keratinocytes respond to both Th1and Th2 cytokines from T cells (Figure1C). Among them, IFN-g is one of themost potent keratinocyte-activatingfactors. It induces surface molecules(for example, ICAM-1, MHC class I andII, CD40, and Fas), chemokines (forexample, CCL2, CCL3, CCL4, CCL5,CCL18, CCL22, and CXCL10) andcytokines (for example, IL-1, IL-6, IL-18, and TGF-b) in keratinocytes. Many

other molecules, such as matrix metal-loproteinases, growth factors, enzymes,and transcription factors/pathwaymolecules, are also upregulated.(Homey et al., 2006; Wittmann andWerfel, 2006). Pastore et al. (1998,2000) observed differences in the re-sponsiveness to cytokines of keratino-cytes from AD patients as comparedwith healthy controls or psoriasis pa-tients (Giustizieri et al., 2001).

It has been shown that IFN-g in-duces Fas on keratinocytes, which



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renders them susceptible to apoptosisinduction by infiltrating FasL T cells(Trautmann et al., 2000). This has beeninterpreted as an important event ineczema, mainly in AD. There is furtherevidence that cleavage of E-cadherinand sustained desmosomal cadherin

contacts between keratinocytes thatare undergoing apoptosis result inspongioform morphology in the epider-mis. This morphology is regarded as ahallmark of eczematous lesions (Traut-mann et al., 2001). Suppression ofkeratinocyte activation and apoptosis

thus remains a potential target for thetreatment of AD (Akdis et al., 2006).

Both CXCR3 CD4 and CCR4CD4 T cells migrate in response toIFN-g-treated human primary keratino-cytes (Purwar et al., 2006). It is inter-

esting to note that IFN-g also inducesCCL22 production in human keratino-cytes. Many IFN-g-inducible moleculesare reinforced by IL-4 or IL-13 inhuman keratinocytes, such as CD54,CCL2, CCL5, and CXCL10 (Albanesiet al., 2000; Purwar et al., 2006).

Keratinocytes have been shown toexpress the IL-1 and IL-33 receptor,ST2, in the acute phase of eczema inAD. A significant genetic associationbetween AD and a single-nucleotidepolymorphism has been found in the

distal promoter region of the ST2 gene(Shimizu et al., 2005). This polymorph-ism is associated with an upregulationof the transcriptional activity of the ST2gene. The ligand of ST2, IL-33, inducesthe expression of IL-4, IL-5, and IL-13in vivo, which may explain higher IgEserum levels found in patients with theST2 polymorphism in AD.

Taken together, these observationssuggest that keratinocytes are importantregulatory and effector cells in skindiseases involving the epidermis as a

particular feature.

EOSINOPHILSEosinophils play an important role inAD, characterized by activated eosino-phils in the peripheral blood and in thelesional skin (Leiferman et al., 1985;Kapp, 1993; Simon et al ., 2004).Increased numbers of circulating eosi-nophils are frequently observed inpatients with AD. Inhibition of eosino-phil apoptosis in AD, probablymediated by IL-5 and GM-CSF, appears

to be a relevant mechanism for theeosinophil accumulation observed inAD (Wedi et al., 1999). Interestingly,acute psychosocial stress leads tofurther increases in eosinophil countsand IL-5 T cells in the peripheralblood (Schmid-Ott et al., 2001a, b).

Eosinophils are recruited to tissuesites mainly by chemokines (for exam-ple, eotaxin and RANTES (regulated onactivation, normal T-cell expressed andsecreted)). A survey on the chemokinereceptor repertoire of human peripheral

T cellCCL2/MCP-1

CCL18/PARC

CXCL10/IP-10

CCL5/RANTES

CCL22/MDC

CCL27/CTACK

IL-1 IL-27

IL-8IL-18

IFN- IL-4

IL-13

Keratinocytes attract T cellsby chemokine production

a

b

c

Keratinocytes

Keratinocytes stimulate skin-infiltratingT cells via cytokines

T cells stimulate keratinocytesvia cytokines

IL-23

Figure 1. KeratinocyteT-cell interactions. (a) Keratinocytes attract T cells by chemokine production. (b)

Keratinocytes stimulate skin-infiltrating T cells via cytokines. (c) T cells stimulate keratinocytes via

cytokines.



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blood eosinophils draws a confusingpicture of receptors (Homey et al.,2006). However, the expression ofCCR3 on eosinophils seems to be ofparticular importance; a number offindings suggest that CCR3-driven path-

ways are essential for the recruitment ofeosinophils to sites of atopic skininflammation (Hoechstetter et al .,2000). In the skin lesions of AD,CCR3 ligands are candidates that med-iate the influx of eosinophils into theskin (Gombert et al., 2005).

The interaction of eosinophilsurface molecules with endothelialcell vascular cell adhesion molecule 1and intercellular adhesion molecule 1are important for eosinophil extravasa-tion and activation. Activated eosino-

phils are capable of releasing a varietyof potent cytotoxic granule proteinsand chemical mediators contributingto tissue inflammation (Elsner andKapp, 1999), as shown by the deposi-tion of eosinophil products in theinflamed skin (Bruijnzeel-Koomenet al., 1992).

Eosinophils play a relevant role inneuroimmunologic interactionsen-hanced levels of brain-derived growthfactor can be detected in the sera andplasma of patients with AD. Brain-

derived growth factor has been shownto reduce eosinophil apoptosis whileenhancing chemotaxis of eosinophilsin vitro (Raap et al., 2006).

In summary, eosinophils infiltratethe skin of AD patients and aggravatethe inflammatory response.

DEFECTS IN THE INNATE IMMUNERESPONSE IN ADMost patients with AD are colonizedwith Staphylococcus aureus and ex-perience exacerbation of their skin

disease after infection with this organ-ism (De Benedetto et al., 2009). Inpatients with AD with bacterial infec-tion, treatment with anti-staphylococ-cal antiseptics and antibiotics canresult in the improvement of skinlesions (Breuer et al., 2002). BindingofS. aureus to skin is enhanced by ADskin inflammation. This is supported byclinical studies demonstrating thattreatment with topical corticosteroidsor tacrolimus reduces S. aureus countsin AD.

Recent evidence suggests that adeficiency of the antimicrobial pep-tides dermcidin, cathelicidin LL-37,human b-defensin (HBD)-2, and HBD-3 contributes to the susceptibility ofatopic patients to skin infections

(McGirt and Beck, 2006). Defensinsare broad-spectrum antibiotics that killbacterial and fungal pathogens. LL-37has been shown to display antimicro-bial activity against viral pathogens inaddition to bactericidal and fungicidalactions (Howell et al ., 2006). Theexpression of antimicrobial peptidesby keratinocytes is increased in re-sponse to inflammatory cytokines.However, IL-4 and IL-13 have beenshown to downregulate the expressionofb-defensins and of LL-37 in the skin

in AD (Ong et al., 2002; Nomura et al.,2003; Howell et al., 2006). This canpredispose to S. aureus colonizationand to severe eczema herpeticatum.

Recently it was shown that mono-cytes from AD patients are functionallydefective in their ability to produceproinflammatory cytokines on Toll-likereceptor 2 stimuli (Hasannejad et al.,2007; Niebuhr et al., 2009). Moreover,Toll-like receptor 2 with a single-nucleotide polymorphism was foundin higher frequency in patients with

severe AD compared with controlgroups (Ahmad-Nejad et al., 2004).Cells with this polymorphic Toll-likereceptor 2 show altered responses topeptidoglycans and lipoteichoic acidfrom staphylococcal cell walls, whichmay further contribute to the innateimmune defect in AD (Niebuhr et al.,2008 and Mrabet-Dahbi et al., 2008).

Patients with the head and neckvariant of AD are frequently colonizedwith Malassezia species (Scheyniuset al., 2002). Malassezia sympodialis

cells produce, express, and releaseallergens to a greater extent whencultured at the higher pH resemblingthe high pH in the skin of AD. This wasparticularly true of the major allergenMala s 12, suggesting that the skinbarrier in AD patients provides anenvironment that can enhance therelease of allergens from M. sympodia-lis, which can in turn contribute to theinflammation (Selander et al., 2006).

Together, these findings indicatethat a number of constitutive and

acquired defects of innate immunitymay explain the predisposition of theskin in AD to bacterial, viral, or fungalinfection or colonization.

IgE IMMUNOREACTIVITY

In approximately 80% of adult patientswith AD, the disease is associatedwith increased serum IgE levels(4150kUl1), sensitization to aeroal-lergens and food allergens, and/orconcomitant food allergy, allergic rhi-nitis, and asthma (Werfel and Kapp,1998; Leung et al ., 2004). Recentepidemiologic data suggest a contribu-tory role for IgE-mediated immunologicprocesses in the onset and course ofAD, especially in patients with severedisease. (Williams and Flohr, 2006).

However, 20% of adult patientswith eczematous skin lesions clinicallyand histologically indistinguishablefrom AD lack sensitization and otherclinical manifestations of the atopicdiseases. This subtype of AD often hasa late onset (420 years of age) and alack of IgE sensitization to inhalant orfood allergens (Werfel and Kapp, 1999;Novak and Bieber, 2003). In children, atransient form of AD with low IgEserum levels and without any detect-able sensitization has been observed; it

develops into the extrinsic variant ofAD with increasing IgE serum levelsand development of sensitization toaeroallergens and food allergens laterin life (Novembre et al., 2001).

Despite the clinical similarity,AD patients with IgE-mediated allergyexhibit higher tissue eosinophilia,enhanced lesional cytokine expression,and higher surface expression of theFceRI on epidermal DCs comparedwith non-allergic eczema patients.

Specific IgE may play a critical role

in cutaneous inflammation in theactivation of mast cells and DCs viahigh-affinity Fc receptors (Bieber,2007). IgE-mediated histamine releasefrom cutaneous mast cells may aggra-vate AD through the itchscratch cycle.Moreover, increased cutaneous inflam-mation, mediated via histamine recep-tors, on T-lymphocytes (Jutel et al.,2001; Gutzmer et al., 2009), antigen-presenting cells (Gutzmer et al., 2005;Gutzmer et al., 2005; Dijkstra et al.,2007), and keratinocytes (Giustizieri



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et al., 2004) is probable. IgE-facilitatedallergen presentation by DCs andactivation of DCs via high-affinity Fcreceptors in the skin are discussedabove (Bieber, 2007).

Despite many in vitro and ex vivo

findings, the importance of IgE to theclinical severity of AD is difficult toevaluate. In a recent study of adultpatients with AD, it became clear thatpatients with greater IgE-mediated sensi-tization suffer from more severe disease(Salt et al., 2007). In proof-of-concepttrials, somebut not allpatients trea-ted with anti-IgE antibodies improved interms of eczema severity (Lane et al.,2006; Vigo et al., 2006; Belloni et al.,2007; Forman and Garrett, 2007). How-ever, extremely high total IgE serum

levels in AD present a major problem fortreatment with anti-IgE. A controlledstudy with anti-IgE is therefore required(Beck and Saini, 2006).

In summary, specific IgE not only isrelevant to immediate reactions butmay contribute to delayed eczematousskin reactions in AD as well.

ALLERGEN-SPECIFIC T CELLSPrimary T-cell immunodeficiency dis-orders are frequently associated withhigh serum IgE levels and eczematous

skin lesions, which clear after success-ful bone marrow transplantation (Akdiset al., 2006). In animal models of AD,the eczematous rash does not occur inthe absence of T cells (Spergel et al.,1999).

FOOD ALLERGENSFood allergy and AD may occur in thesame patient. In addition to typicalimmediate types of allergic reactions(that is, noneczematous reactions),which are observed in AD patients,

foods can provoke flares of AD; this hasbeen demonstrated in placebo-con-trolled food challenge studies (Werfeland Breuer, 2004). The serum levels offood-specific IgE can be predictive forthe outcome of oral provocation testswith foods, as observed in cohortstudies with children with AD whohad immediate reactions to foods(Sampson, 2001; Mehl et al., 2005).Specific T cells have been shown to beinvolved in the late eczematous re-sponse to food; higher proliferative

responses to food proteins and specificT-cell clones can be generated frompatients with food-induced eczema(Reekers et al., 1996; Werfel et al.,1997a; van Reijsen et al., 1998). Inaddition, milk-induced eczema has

been reported to be associated with ahigher rate of CLA lymphocytesupon in vitro stimulation with casein(Abernathy-Carver et al., 1995).

A murine model of food-induced ADconfirmed the important role of food-specific T cells in eczema. C3H/HeJmice were orally sensitized to cowsmilk or peanuts and then subjected tolow-grade allergen exposure. An ecze-matous eruption developed in approxi-mately one-third of mice after low-gradeexposure to milk or peanut proteins.

Histologic examination of the lesionalskin revealed spongiosis and a cellularinfiltrate consisting of CD4 lympho-cytes, eosinophils, and mast cells. IL-5and IL-13 mRNA expression was ele-vated only in the skin of mice with theeczematous eruption (Li et al., 2001).

Patients sensitized to pollen aller-gens often develop an IgE-response tocross-reactive food allergens. Con-sumption of birch pollen-related foodssuch as hazelnuts, carrots, apples, andcelery (that is, foods that are cross-

reactive to birch pollen allergens,mainly the major allergen Bet v1) maylead to an exacerbation of eczema in asubpopulation of patients with ADsensitized to birch pollen antigens. Abirch pollen-specific T-cell responsecould be detected in lesional skin ofthese responding patients (Reekerset al., 1999): Birch pollen-related foodmay also induce allergic symptoms in asubgroup of children with AD (Breueret al., 2004). Recently, Bohle et al.(2006) showed that T-cell cross-reac-

tivity between Bet v1 and related foodallergens can occur independent of IgEcross-reactivity in vitro and in vivo. Inpatients with AD, the resulting immunereaction that manifested as late ecze-matous skin reactions to cooked foodwas shown to elicit T cell- but not IgE-mediated responses.

In summary, T-cell responses andspecific IgE to food allergens mayexplain flare-ups of eczema upon oralfood challenges in sensitized patientswith AD.

AEROALLERGENSPruritus and skin lesions can develop afterintranasal or bronchial inhalation chal-lenge with aeroallergens in patients withAD. Epicutaneous application of aero-allergens (house dust mites, weeds, ani-

mal danders, and molds) onasymptomatic skin of patients with ADelicits eczematous reactions in a sub-group of patients with AD. The so-calledatopy patch test has been used in recentyears as a model for studying allergen-induced changes in the skin of ADpatients (Darsow et al., 2004; Turjanmaaet al., 2006). Aeroallergen-specific T cellswere first isolated from skin sites fromatopy patch test lesions (Sager et al.,1992; Van Reijsen et al., 1992). Similartechniques were applied later to isolate

aeroallergen-specific T cells from sponta-neous lesional skin (Werfel et al., 1996).

A combination of effective measuresto control house dust mites has beenreported to improve AD, but theclinical effect varied in different clin-ical studies (Tan et al., 1996; Holmet al., 2001; Oosting et al., 2002).

Specific immunotherapy directly ad-dresses an adaptive mechanism inhypersensitivity reactions. A recentmeta-analysis of specific immunother-apy studies revealed positive effects of

subcutaneous immunotherapy in themajority of studies performed to dateon AD (Bussmann et al., 2006). In thelargest cohort study, subcutaneous im-munotherapy with mite allergens waseffective in moderate to severe AD(Werfel et al ., 2006). In contrast,sublingual immunotherapy with miteallergens, which has recently beenstudied in children with AD, waseffective only in patients with mildeczema (Pajno et al., 2007). Duringspecific immunotherapy of AD, the

level of the tolerogenic cytokine IL-10increased in the sera of patients,whereas the levels of CCL17 and IL-16 decreased (Bussmann et al., 2007).

In summary, evidence of the clinicalrole of adaptive immune responses toaeroallergens for AD come from atopypatch tests and therapy studies onspecific immunotherapy.

MICROBIAL ALLERGENSS. aureuscan exacerbate AD by secret-ing exotoxins. Some of them function



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as superantigens, which stimulate acti-vation of T cells and MHC antigen-presenting cells, macrophages, or ker-atinocytes. Major effects elicited bysuperantigens are summarized inFigure 2A. Some patients with AD

produce specific IgE antibodies directedagainst staphylococcal superantigens(Figure 2B), to an extent that correlateswith skin disease severity (Bunikowskiet al., 1999; Breuer et al., 2000).

Superantigens have been shown topenetrate into the dermis (Skov et al.,2000), and higher doses have beenshown to induce cutaneous inflamma-tion when applied to the skin in patchtests (Strange et al., 1996). Low dosesthat do not induce visible clinicalinflammation are still able to amplify

aeroallergen-induced patch test re-sponses (Langer et al., 2007).

There is increasing evidence that theopportunistic yeast Malassezia speciesis a contributing factor in AD. Severalstudies have demonstrated the pre-sence of specific serum IgE, a positiveskin prick test response, and a positivepatch test response against Malasseziaspecies in adults with AD (Scheyniuset al., 2002). IgE sensitization to Ma-lassezia species is specific for patientswith AD; it is not seen in patients with

asthma or allergic rhinitis (Scalabrinet al ., 1999; Schmid-Grendelmeieret al., 2006).

Within non-allergic patients withatopic eczema, some exhibit IgEsensitization against microbial anti-gens, such as S. aureus enterotoxinsand Candida albicansor M. sympodia-lis antigens (Novak et al., 2003). The

presence of specific IgE to Malasseziaantigens in the non-allergic variant ofAD was confirmed in a recent study(Casagrande et al., 2006). In a largercohort, however, it was found thatantimicrobial IgE antibodies were un-common in patients with AD with lowIgE levels (Reefer et al., 2007).

In summary, microbial allergensmay worsen the skin condition in AD.

SELF-ALLERGENSAutoimmunity to human proteins may

also contribute to the pathophysiologyof AD. IgE against autoantigens hasbeen shown to stimulate type 1 hyper-sensitivity reactions and DCs (Valenta,2009). Autoallergens induce the prolif-eration of CLA autoreactive T cells inthe blood, and T-cell clones specific forautoallergens can be generated fromthe skin of patients with AD (Heratiza-deh et al., submitted). Interestingly,autoallergen-specific IgE was found asearly as in infancy in AD (Mothes et al.,2005). Cross-reactivity between in-

haled allergens and autoantigens maylead to autoimmunity: For example, IgEagainst manganese superoxide dismu-

tase (MnSOD) from the skin-colonizingyeast M. sympodialiscross-reacts withhuman MnSOD. Patients with ADsensitized to human MnSOD havebeen shown to also be sensitizedagainst the M. sympodialis MnSOD

(Schmid-Grendelmeier et al., 2005).Lens epithelium-derived growth fac-

tor/dense fine speckles 70 kDa protein(LEDGF/DFS70) is another definedautoantigen in patients with AD. Auto-antibodies to this protein have beenfound in Japan in approximately 30%of AD patients. It is located predomi-nantly in the nucleus of the basalepidermal cells and translocates intothe cytoplasm during differentiation.Once in the cytoplasm, LEDGF/DFS70accumulates in the keratohyalin gran-

ules in the granular layer (Sugiura et al.,2007).

The role of self-allergens remains tobe elucidated in more detail in futurestudies. The concept of AD as anautoimmune disease has therapeuticimplications and may explain thechronicity of the disease in autoaller-gic patients.

CONCLUSIONImmunological responses to definedallergens, inflammatory reactions to

microbial agents, and a complex inter-play of cells and mediators belongingto the skin immune system contributeto the clinical appearance of AD.Allergens may reach the skin from thebloodstream or through the epidermis,as depicted in Figure 3. Specific IgE,which is bound to Fc receptors on DCs(LC, IDECs, dermal DCs) and oncutaneous mast cells, may facilitateallergen presentation to specific T cells(Th2 cells in the acute phase, Th1 cellsin the chronic phase). Figure 3 high-

lights only some key mediators of ADthe Th2 cytokine IL-4 and histamine inthe acute phase and Th1-related cyto-kines IL-12 and IL-18 in the chronicphase. A number of other mediators arecurrently being investigated, with IL-17and IL-31 representing extensivelystudied cytokines with regard to AD atpresent. More knowledge of thesefactors may contribute to the develop-ment of specific approaches for phase-dependent therapies in this chronicrelapsing skin disease.

T cell

T cell

TCR

TCR Specific

IgE

Induction

of

specific IgEIL-2IL-4

IL-13

MHC II

MHC II

Exotoxin

Induction of T-cell proliferation

Induction of IL-2, IL-5, IL-13 and

IFNproduction by T cells

Induction of CLA expression on T cells

Reversal of suppressive activity of

regulatory T cells (Treg)

Release of cytokines (e.g. IL-12)from MHC+ APC

Release of proinflammatory cytokinesfrom activated MHCII+ positive cells

Exotoxin

APC

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

induce strong effects on both T cells and antigen-presenting cells, as summarized in the gray box.

Exotoxins can also function as allergens in atopic dermatitis (depicted in the lower part of the figure)

inducing specific IgE and specific Th2 responses.



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