27 Dendritic Cells in Atopic Eczema

27 Dendritic Cells in Atopic Eczema

T. Kopp, G. Stingl

27.1

Introduction

Studies investigating the pathogenesis of atopic ecze- ma (AE) have revealed a central role for pathologic immune responses besides alterations of the vascular, the autonomous nervous, and the skin barrier systems.

In contrast to healthy individuals, AE patients appear to develop a T-cell-mediated delayed-type hypersensitivity reaction against certain environmen- tal and, perhaps, self-proteins resulting in an eczema- tous disease. Evidence supporting this concept comes (1) from the successful generation of allergen-specific T-cell clones out of the skin and peripheral blood of AE patients [1 – 4] and (2) from studies in which environ- mental antigens applied to tape-stripped skin of sensi- tized AE patients could elicit an eczematous reaction with macroscopic and microscopic similarities to lesio- nal skin of AE patients (atopy patch test) [5]. Our pre- sent understanding is that the acute cutaneous allergic inflammation is driven by T helper 2 (Th2) cells that secrete interleukin-4 (IL-4), IL-5, and IL-13. This leads to (1) upregulation of adhesion molecules on endothe- lial cells, (2) chemokine production, and thereby immune-cell recruitment (3) T-cell help for the IgE response, and (4) degranulation of eosinophils [6 – 9].

Dendritic cells (DC) and/or monocytes/macrophages, as major antigen-presenting cells, are likely to play a key role in determining the outcome of antigen encounter, probably not only during sensitization, but also in established allergic inflammation [10].

27.2

Antigen-Presenting Cell Subpopulations in Atopic Eczema Skin

27.2.1

Characterization of Antigen-Presenting Cells 27.2.1.1

Resident Indigenous Cutaneous Dendritic Cell Populations Normal human skin harbors two types of DC, i.e., Lan- gerhans cells (LC) in the epidermal compartment and dermal DC in the dermal compartment [11 – 13].

Langerhans Cells

Resident LC in normal human skin are immature cells with the capability to take up and process protein anti- gens for the initiation of primary and secondary immune responses. They are thus considered to form a large network of cutaneous immunosurveillance. More recently, LC were recognized to also possess immuno- regulatory properties as they are also able to promote T cell tolerance by the production of the immunoregula- tory enzyme indoleamine 2,3-dioxygenase [14].

In AE skin the LC population is not grossly changed.

There is an increase of dermal LC at the cost of their

epidermal counterparts. It is assumed that the shift in

the number of LC from the epidermis to the dermis

represents their migration to skin-draining lymph

nodes [15 – 17]. The initiation of LC migration and

maturation may be supported by GM-CSF and other

proinflammatory cytokines, which are produced by

keratinocytes in lesional skin [18 – 20]. As keratinocy-

tes from AE patients produce thymic stromal lympho-

poetin (TSLP), LC may become activated to preferen-

tially prime na¨ıve T-cells to become Th2 cells. This may

also lead to the selective attraction of Th2 effector cells

to lesional skin [21]. Moreover, it may result in an

Chapter 27

cells/mm epidermi s

CD1c⁺ BDCA-2⁺/CD123⁺

2 4

mDC pDC

NS AD

EPIDERMIS DERMIS

cells/m m

dermis 20 40 60 6

NS AD

CD1c⁺ BDCA-2⁺/CD123⁺

mDC pDC

80 impaired/biased immunosurveillance with a consecu- tive susceptibility to viral infections (e.g., herpes sim- plex virus) as a consequence of insufficient T1-mediat- ed immune responses.

Dermal Dendritic Cells

In normal human skin, dermal DC are primarily locat- ed in the upper reticular and papillar dermis [12]. They are marked by the surface expression of CD1c, HLA- DR, CD11c, CD11b, CD32, and intracytoplasmic factor XIIIa [13, 22]. CD1a is present on approximately 60 % and CD1b only on a small subpopulation of the CD1c

dermal DC [17].

In AE lesions the dermal DC population is almost doubled (Fig. 27.1). Phenotypically, the CD1c

dermal DC in AD and normal skin are very similar with the exception of a relative increase in cells coexpressing CD1b (approximately 50 %) in atopic lesions, a subpop- ulation closely resembling, or even identical to inflam- matory dendritic epidermal cells (IDEC, see below) [17].

27.2.1.2

Inflammatory Cutaneous Dendritic Cell Populations Inflammatory Dendritic Epidermal Cells

Different to normal human skin, anti-CD1a and anti- HLA-DR stainings cannot be applied for the identifica- tion of LC in inflamed AE skin, due to the presence of another epidermal non-LC DC population, namely the inflammatory dendritic epidermal cells (IDEC), which also bear these surface markers. These cells have been extensively characterized by flow cytometry. IDEC express CD1a

, CD1b

, CD11b

, CD11c

, and CD36

and are phenotypically distinct from LC

Fig. 27.1. Occurrence of mye- loid and plasmacytoid DC in AE skin

(CD1a

, LAG

, Langerin

, CD1b

, CD11b

, CD11c

) [16, 23, 24]. Electron microscopy studies revealed that IDEC lack Birbeck granules [25]. It is thus not surprising that IDEC are not reactive with anti- LAG and anti-Langerin antibodies. In contrast to LC, these cells bear the mannose receptor, a molecule important for pinocytosis of mannosylated protein antigens (e.g., glycoproteins from bacteria and fungi) [25].

Most importantly, IDEC are more abundant in AE skin than LC. They enter the epidermis only upon inflammation and they do express costimulatory mole- cules. Functional CD86 expression was reported on CD1a

cells in AD skin [26]. Subsequently it became clear that IDEC (CD1a

/HLADR

/CD11b

) and not LC (CD1a

/HLADR

/CD11b

) are the relevant cells expressing CD80 and CD86 [27]. In contrast to LC, with predominantly intracellular high affinity IgE receptor (Fc 5 RI), IDEC exhibit membrane expression of the Fc 5 RI and surface-bound IgE in patients with extrinsic AE [16, 24, 28]. Based on these features, IDEC are likely to be the DC type responsible for expanding allergen- specific T cells and, thus, the allergic tissue inflamma- tion.

Plasmacytoid Dendritic Cells

In 1983, Vollenweider and Lennert have described a

cell type with a morphology similar to that of plasma

cells in the paracortical areas of reactive lymph nodes

[29]. Today we know that these cells, which were later

found to express monocyte and T-cell markers

[30 – 33], represent immature DC termed plasmacytoid

DC [34]. Besides their plasma cell-like morphology,

they are characterized by coexpression of BDCA-2,

BDCA-4, CD123, CD4, CD45RA, MHC class II, and

CD68. They lack surface expression of other APC markers such as CD1a, CD1c, and CD14. A key feature of plasmacytoid DC is their ability to secrete large amounts of type I interferons in the presence of bacte- rial DNA and RNA virus by triggering Toll-like recep- tor (TLR) 9 and 7, respectively [35, 36]. When unstimu- lated, plasmacytoid DC may induce anergy in antigen- specific human CD4

T cell clones [37]. Upon activa- tion with bacterial DNA, viral DNA, IL-3 and CD40 ligand, IL-3 and TNF- [ , plasmacytoid DC develop den- drites, secrete IFN- [ and acquire the ability to activate na¨ıve and memory CD4

and CD8

T-cells [34, 35, 38, 39], although less efficiently than other DC. It thus appears to depend on both type and intensity of the stimulus whether plasmacytoid DC become immuno- stimulatory or tolerogenic.

Plasmacytoid DC have so far been detected in vari- ous human diseases including viral infections with adenovirus, herpes simplex, and varicella zoster viruses [40, 41], cancer [42], neuroborreliosis [43], allergic rhinitis [44], and in lesional skin of patients with lupus erythematosus [45], psoriasis [46], and allergic contact eczema [47].

Normal human skin is essentially devoid of plasma- cytoid DC [41, 47], whereas in AE substantial numbers of these cells are found in the dermis, but not the epi- dermis of lesional skin (Fig. 27.1) [46]. Proportions thereof express costimulatory molecules and matura- tion-defining markers as a sign of activation [17].

Their precise role in AE is not understood. It is quite clear that they play a role in innate immunity, but it is not known whether their pathogen-sensing capacity is better or worse in AE when compared to other diseases.

There is not yet an unanimous agreement on their anti- gen-presenting capacity. Whether they can process allergenic proteins and present the respective peptides is still a matter of debate. Due to their absence in nor- mal skin they are not likely to be critical initiators of immune responses to allergens in AD. In inflamed skin, however, they may act as components of both the innate and the adaptive immunity by (1) interacting with other DC, by (2) indirectly influencing the polari- zation of antigen-specific T cells, that have been expanded by other DC populations, or by (3) directly promoting Th1, Th2, or T regulatory responses [39, 48, 49]. Plasmacytoid DC may thus be responsible for modifying the strength, the duration, and the quality of the allergic skin reaction.

Macrophages

Further studies have demonstrated an increased num- ber of CD68

cells in both acute (atopy patch tests) and chronic AE lesions when compared to nonlesional AE skin. These cells have been generally assumed to be macrophages [50]. It is however likely that some of the CD68

cells represent myeloid and plasmacytoid DC, as these cells also express CD68.

27.2.2

Origin of Cutaneous Dendritic Cell Subsets and Selective Tissue Homing

27.2.2.1 Langerhans Cells

Clearly, LC are bone marrow-derived leukocytes [51 – 53]. In vitro studies have shown that they derive from hematopoietic stem cells. LC precursors can suc- cessfully be generated from CD34

hematopoietic stem cells after exposure to (1) GM-CSF and TNF- [ [54, 55]

and/or (2) TGF- q 1, GM-CSF, TNF- [ , and SCF [56].

They can however also be generated from CD14

DC precursors, in the presence of TGF- q 1 [57]. Moreover, the importance of TGF- q 1 to promote LC development in vivo was demonstrated in TGF- q 1-deficient mice which lack epidermal LC [58].

The epidermal localization of LC and their migration and lifespan differ under steady state conditions and under inflammation. It is quite clear that the number of LC in the epidermis is kept stable under both circum- stances. Excellent evidence now exists that, under steady state conditions, LC spend weeks to months in the epi- dermis before they migrate to lymph nodes where they quickly die [59]. In mice, Merad et al. have shown that in unperturbed skin this slow efflux is balanced by the division of LC within the epidermis [60]. In humans res- ident CD14

LC precursors may be responsible for their replacement [61]. If there is massive destruction of LC, as it occurs in cutaneous graft versus host disease, or, if there is skin inflammation with increased traffic of LC to lymph nodes, they are largely replaced via their blood- borne bone marrow-derived precursors [60, 62].

Although not directly investigated, the above-described mechanisms are likely to also apply for AE skin.

Molecules involved in skin homing of LC progenitors

include CLA [63], a fucosylated PSGL-1 moiety, which

has been shown to mediate skin homing of bone-mar-

row-derived DC in mice [64 – 66], and the chemokine

27.2 Antigen-Presenting Cell Subpopulations in Atopic Eczema Skin 277

receptor CCR6 which mediates selective migration to macrophage inflammatory protein-3 (MIP-3) [ (CCL20) [67], a chemokine weakly expressed in normal human skin, but strongly augmented in AE skin [68].

27.2.2.2

Inflammatory Myeloid and Plasmacytoid Dendritic Cells In the case of inflammatory DC a totally different situa- tion occurs. The question arises whether their rapid and massive appearance at the site of cutaneous inflamma- tion can be explained by a cutaneous or a systemic pre- cursor. This aspect has not been carefully investigated.

In this context it is noteworthy that only few Ki67

divid- ing cells occur in allergic contact dermatitis [47]. There- fore, it is unlikely that all of them derive from cutaneous progenitors. Alternatively, inflammatory myeloid and plasmacytoid cutaneous DC may derive from immature blood precursors, which have been attracted to the skin.

By their expression of CCR2, CCR5, and CXCR4, mye- loid DC may be attracted to AD skin in response to CCL2 and CCL5 expressed by AD keratinocytes [69], and to constitutively expressed CXCL12 [70, 71]. These cells may even derive from plasmacytoid DC, as the conver- sion of plasmacytoid DC to myeloid DC has recently been demonstrated in mice [72].

Plasmacytoid DC migrate in response to CXCL12 (CXCR4 ligand) and immobilized CXCL9, CXCL10, and CXCL11 (CXCR3 ligands) [41, 73]. Moreover, CXCL12- mediated migration is enhanced in the presence of CXCR3 ligands [74]. As IL-4 enhances TNF- [ and IFN-

* -induced expression of the latter chemokines in kera- tinocytes, CXCR3 ligands may well be involved in the recruitment of plasmacytoid DC to AD skin. Similar to LC, myeloid and plasmacytoid DC express CLA and may thus adhere to E-selectin upregulated on inflamed dermal microvascular endothelial cells [66, 75, 76].

27.3

Types of Antigen-Presenting Cells in Peripheral Blood

27.3.1 Monocytes

Analysis of the assembly of circulating monocyte pop- ulations revealed a significant increase in the popula- tion of CD14

CD64

CD16

monocytes at the expense of the CD14

CD64

CD16

subset during the exacerba-

tion phase of atopic eczema [77]. The contribution of these CD14

CD64

CD16

monocytes that also carry the Fc 5 RI to the development of atopic eczema has yet to be determined.

27.3.2

Monocyte-Derived Dendritic Cells

Monocyte-derived DC from atopic patients reportedly produce less bioactive IL-10 and IL-12 upon CD40 liga- tion when compared to healthy controls [78]. Their insufficiency of IL-12 production might contribute to the development of AD by preferentially skewing the T-helper cell response towards a T2 pattern. Interest- ingly, prostaglandin D

, which is produced by allergen- activated mast cells, has recently been demonstrated to affect the maturation of monocyte-derived DC and consequently the polarization of na¨ıve T-cells by favor- ing a T2 response in a model of allergen- and superan- tigen-pulsed DC-induced CD45RA

Th-cell differenti- ation [79]. Recent studies have identified surface expression of histamine H1 and H2 receptors on mono- cyte-derived DC. Stimulation through histamine was followed by inhibition of IL-12p70 production (immu- nomodulation) and F-actin polymerization (chemo- tactic effect). It is thus conceivable that histamine influ- ences the cutaneous cellular allergic inflammation in AE patients besides mediating immediate-type hyper- sensitivity reactions [80].

27.3.3

Myeloid and Plasmacytoid Dendritic Cells

Investigations of myeloid (MHC II

CD123

) and plas- macytoid (MHC II

CD123

) DC revealed a relative increase in the number of plasmacytoid DC in AE patients, when compared to healthy individuals [78].

This finding is in sharp contrast to the situation in sys- temic lupus erythematosus, where the number of plas- macytoid DC is decreased in peripheral blood [81]. It is not yet clear to which extent the higher proportion of plasmacytoid DC contributes to the observed insuffi- ciency of IL-12-production in AE [82].

In a recent study in Dermatophagoides pteronyssi-

nus (Dpt)-sensitized individuals and healthy controls,

Charbonnier et al. showed that coculture of na¨ıve CD4

T cells from healthy donors with Der p 1-pulsed mye-

loid DC from patients with allergic rhinitis favors a Th1

profile, and coculture with Der p 1-pulsed plasmacyto-

CD1c Fc RI Merge

CD1c IgE Merge

id DC a Th2 profile, whereas neither DC type, when derived from healthy donors, induces such a polariza- tion. However, Der p1-pulsed myeloid DC stimulated allogeneic CD4 T-cells to secrete IL-10. The authors concluded that the balance between the development of tolerance versus allergy might be controlled by mye- loid DC through their IL-10 secretion and that plasma- cytoid DC might contribute to the development of Th2 responses in allergic donors [83]. It is conceivable that similar mechanisms are operative in AD.

27.4

IgE-Facilitated Amplification of the Immune Response

On mast cells and basophils of atopic and nonatopic individuals, Fc 5 RI is a tetrameric structure with a heavily glycosylated [ chain (Fc 5 R1 [ ), two * chains (Fc 5 R1 * ), and one q chain (Fc 5 R1 q ) [84]. It is constitu- tively expressed on their surface and its ligation with allergen-specific IgE leads to the immediate release of allergic mediators [85, 86]. Fc 5 RI is also present on the surface of DC in lesional skin and in the blood from AE patients, whereas little, if any, is detectable on the cellu- lar surface in healthy individuals [16, 24]. Different to the tetrameric Fc 5 RI complex on mast cells and baso- phils, DC from AE individuals display a trimeric Fc 5 RI

Fig. 27.2. Detection of Fc 5 RI and cell-bound IgE on CD1c

myeloid DC in AD lesions

composed of one [ chain and two * chains. As the Fc 5 RI * chain is present on DC from AE patients, but downregulated in healthy donors, it was suggested to be the mandatory component responsible for surface expression of the high affinity IgE receptor [87].

Lesional skin from AE patients harbors large amounts of IgE

LC, IDEC, dermal DC, and macro- phages, whereas the epidermis of healthy individuals is devoid of IgE

DC [88, 89]. Evidence for a potentially important role of Fc 5 RI-mediated IgE binding in the pathogenesis of AE was derived from studies by Klubal et al., who showed that Fc 5 RI expressed on epidermal LC and dermal DC as well as on mast cells is the pre- dominant IgE-binding structure in diseased atopic skin [90]. In peripheral blood, DC and, to a lesser extent monocytes, were found to carry Fc 5 RI-bound, allergen-specific IgE [16, 91, 92]. This was more evi- dent in patients with „allergic“ AE, when compared to those with „nonallergic“ AE [93], possibly as a result of IgE and IL-4-mediated enhanced Fc 5 RI expression on APC [94 – 96]. Upon internalization via Fc 5 RI, the IgE- bound allergen is processed and delivered into a cathepsin S-dependent pathway of MHC class II pre- sentation [97], which consequently results in a greatly enhanced antigen-specific T cell response [92, 98].

Another consequence of IgE crosslinking on DC is the increased production of Interleukin 16, a chemoattrac- tant for dendritic cells, CD4

T cells and eosinophils

27.4 IgE-Facilitated Amplification of the Immune Response 279

IgE

CD123 MHCII

CD123 MH CII

Fc RI Merge

Merge

[99]. As the spectrum of cutaneous DC is larger than previously thought, Fc 5 RI expression and IgE-binding properties are not only restricted to DC from the mye- loid lineage, but also occur on plasmacytoid DC (Figs. 27.2, 27.3) [17, 100]. The preferential uptake and

Fig. 27.3. Detection of Fc 5 RI

and cell-bound IgE on

CD123

/MHCII

plasmacy-

toid DC in AE lesions

presentation of IgE-bound allergens by the Fc 5 RI on

cutaneous DC may thus amplify the cutaneous allergic

inflammation and thereby contribute to the chronicity

of the disease. Interestingly, Fc 5 RI aggregation on plas-

macytoid DC impaired their surface expression of

MHC I and II, induced the production of IL-10 and enhanced the apoptosis of plasmacytoid DC, suggest- ing that Fc 5 RI mediates different functions in distinct DC subsets [100].

Based on the above studies, IgE might be a promis- ing therapeutic target in AE. IgE immunomodulators currently available are omalizumab (Xolair), a recom- binant humanized monoclonal anti-IgE antibody that has demonstrated efficacy in allergic respiratory dis- eases [101, 102] and TNX-901, a humanized IgG1 monoclonal antibody against IgE that proved to be effective in peanut allergy [103]. Only one trial has yet been performed in AE patients. It showed a substantial downregulation of cell-bound IgE and Fc 5 RI density on DC in blood and skin after 16-weeks treatment with omalizumab [104]. The anti-IgE therapy did, however, not effect the clinical outcome, possibly as a result of too short a treatment period or too small a study popu- lation (n = 20).

27.5

Role of Dendritic Cells in Initiating, Maintaining, and/or Silencing the Allergic Tissue Inflammation

Central and peripheral tolerance, both of which are regulated and maintained by DC [105, 106], are the mechanisms in charge for controlling adaptive immu- nity. Central tolerance permits elimination of T cells with a receptor, which recognizes components ex- pressed by thymic DC. Environmental antigens and some self antigens may, however, not access the thy- mus. Upon activation, these T cells may thus lead to reactions against environmental and self antigens.

Hence, peripheral tolerance occurs in lymphoid organs by silencing T cells either via deletion or expansion of regulatory T cells.

The skin is continuously exposed to a large array of environmental proteins and pathogens. As a defense mechanism, a complex cutaneous immune system including a network of epidermal LC has evolved, which in most cases is able to distinguish between potentially dangerous and harmless antigens. In con- trast to healthy individuals responding to environmen- tal allergens with immune tolerance [107], AE patients exhibit a misdirected immunological response, possi- bly based on a dysregulated balance between „sensitiz- ing“ and „tolerizing“ DC.

27.5.1

Sensitization Phase

Due to a genetic predisposition [108], patients with

„allergic AE“ develop a T2-mediated delayed-type hypersensitivity reaction against certain environmen- tal and, perhaps, self proteins. DC and/or macrophages are considered to be fundamental for the development of cutaneous immune responses to normally harmless proteins, as these cells are able to initiate primary and secondary immune responses. Upon allergen uptake and maturation, DC upregulate surface expression of adhesion molecules (CD54), costimulatory molecules (e.g., CD80, CD86, CD40) and the chemokine receptor CCR7, which enables them to migrate to regional lymph nodes and prime na¨ıve T cells [109 – 111]. As DC express many pattern-recognition receptors, they are susceptible to TLR ligands including microbial stimuli as well as endogenous ligands such as fibronec- tin, heparan sulfate and heat shock proteins released in response to tissue injury [112 – 114]. By their suscepti- bility of TLR ligands DC may markedly change the type of T cell response induced [36].

Epithelial cells have been identified to trigger the immune cascade leading to T2-type allergic inflamma- tion. By the production of TSLP they activate DC to migrate to lymph nodes and to prime na¨ıve T cells to preferentially produce IL-4, IL-5, IL-13, while down- regulating IL-10 and IFN- * [21]. TSLP also induces DC to secrete the T2 attracting chemokine TARC/CCL17 [21].

27.5.2 Effector Phase

It is quite clear that allergen-specific T2 cells, which

mainly belong to the T-helper phenotype, are impor-

tant in the acute eczematous skin response. This

assumption is based on the observations that (1)

eczematous skin lesions can be provoked by epicutane-

ous application of allergens (atopy patch test) in some

AE patients [115], and that (2) allergen-specific T-cells,

isolated from such lesions as well as from peripheral

blood, predominantly produce Th2 cytokines [1, 2, 4,

116]. According to recent experiments in transgenic

mice the newly identified Th2 cytokine IL-31 may well

contribute to the development of the eczematous reac-

tion besides IL-4, IL-5, and IL-13 [117]. During chronic

inflammation the Th2-dominated response is switched

27.5 Role of Dendritic Cells in Initiating, Maintaining, and/or Silencing the Allergic Tissue Inflammation 281

to a Th1 cytokine pattern, presumably through IL-12 secretion by eosinophils and other resident cells in skin [118 – 122].

However, the role of cutaneous DC subsets in con- trolling this effector T cell response is not well investi- gated. Both myeloid and plasmacytoid DC express skin-specific homing receptors and may thus enter the skin following a chemokine gradient [66, 76]. Their migration from the blood to the skin requires several steps involving attachment and rolling through selec- tin-carbohydrate interactions, activation through che- moattractant-receptor interactions, and firm adhesion through integrin-immunoglobulin family interactions [123]. The vast majority of myeloid and plasmacytoid blood DC express CLA and an array of chemokine receptors, which enable them to roll over E-selectin and enter the epidermis to target their ligands [41, 66, 70, 71, 75, 76]. Upon arrival in lesional skin cutaneous DC may receive survival and maturation signals from keratinocytes, which produce GM-CSF, TNF- [ , and IL- 1 [ [18, 20].

Whether and how cutaneous DC subsets are involved in maintaining or silencing the allergic tissue inflammation remains to be determined. We do know that a rapid accumulation of inflammatory myeloid and plasmacytoid DC occurs in AE skin and atopy patch test reactions [17, 124] and that the infiltrating T- cells are in close apposition to DC, suggesting the exis- tence of an operative immunological synapse in skin lesions, a phenomenon previously described for Th2- mediated airway inflammation [125]. By their secre- tion of the chemokines TARC/CCL17 and MDC/CCL22, DC may selectively attract CCR4

Th2 memory cells [126]. The attracted Th2 cells are likely to mediate their effector functions upon activation with DC. Moreover, as allergens can be presented more efficiently via IgE and its corresponding high affinity receptor on antigen presenting cells (APC) than in the conventional man- ner [92, 97], IgE-facilitated antigen presentation may contribute to continuous T cell activation and, conse- quently, to the chronicity of the disease.

27.6

Effects of Topical Calcineurin Inhibitors

Topical corticosteroids and calcineurin inhibitors such as tacrolimus (FK 506) and pimecrolimus (ASM 981) are well established as anti-inflammatory treatment

modalities in AE [127 – 129]. The latter preparations recently became available. They are effective and safe in adults and children [317 – 319], and, as maintenance therapy, reduce the number of flare-ups and the requirements for topical glucocorticoids [120]. They may interfere with the immunopathology of AE by influencing T-cells, mast cells, basophils, eosinophils, and dendritic cells [130 – 144]. Within the DC popula- tion both calcineurin inhibitors selectively deplete IDEC, but not LC from the epidermis; however, in con- trast to T-cells, this depletion is not apoptosis-induced [135, 143, 145]. This is in sharp contrast to the cortico- steroid q -methasone-17-valerate, which depletes both LC and IDEC [135]. According to two studies tacroli- mus and pimecrolimus differ in their effect on the immunophenotype of epidermal DC. Tacrolimus was shown to downregulate DC costimulatory molecule, and Fc 5 RI expression, and may thus hamper their immunostimulatory capacity [142, 146], whereas only marginal effects were reported by pimecrolimus treat- ment [135, 145, 147].

References

1. Lanzavecchia A, Santini P, Maggi E, Del Prete G, Falagiani P, Romagniani S, Ferrarini M (1983) In vitro selective expan- sions of allergen specific T-cells from atopic individuals.

Clin Exp Immunol 52:21

2. Zimmerman B, Underdown BJ, Ellis J, James O (1986) Cloned helper T cell for IgE: characterization of T cells cloned from an atopic donor with a high serum IgE. J Aller- gy Clin Immunol 77:70

3. Van der Heijden FL, Wierenga EA, Bos JD, Kapsenberg ML (1991) High frequency of IL-4-producing CD4+ allergen- specific T lymphocytes in atopic dermatitis lesional skin. J Invest Dermatol 97:389

4. Rawle FC, Mitchell EB, Platts-Mills TA (1984) T cell responses to the major allergen from the house dust mite Dermatophagoides pteronyssinus, Antigen P1: comparison of patients with asthma, atopic dermatitis, and perennial rhinitis. J Immunol 133:195

5. Langeveld-Wildschut EG, Riedl H, Thepen T, Bihari IC, Bruijnzeel PL, Bruijnzeel-Koomen CA (2000) Modulation of the atopy patch test reaction by topical corticosteroids and tar. J Allergy Clin Immunol 106:737

6. Bochner BS, Schleimer RP (1994) The role of adhesion mol- ecules in human eosinophil and basophil recruitment. J Allergy Clin Immunol 94:427

7. Chuluyan HE, Issekutz AC (1993) VLA-4 integrin can medi- ate CD11/CD18-independent transendothelial migration of human monocytes. J Clin Invest 92:2768

8. Springer TA (1994) Traffic signals for lymphocyte recircula- tion and leukocyte emigration: the multistep paradigm.

Cell 76:301

9. Kita H, Weiler DA, Abu-Ghazaleh R, Sanderson CJ, Gleich GJ (1992) Release of granule proteins from eosinophils cultured with IL-5. J Immunol 149:629

10. Leung DYM, Eichenfield LF, Boguniewicz M (2003) Atopic dermatitis (Atopic eczema). In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, Fitzpatrick TB (eds) Dermatology in general medicine, Vol. 1. McGraw- Hill, p. 1180

11. Stingl G, Wolff-Schreiner EC, Pichler WJ, Gschnait F, Knapp W, Wolff K (1977) Epidermal Langerhans cells bear Fc and C3 receptors. Nature 268:245

12. Cerio R, Griffiths CE, Cooper KD, Nickoloff BJ, Heading- ton JT (1989) Characterization of factor XIIIa positive der- mal dendritic cells in normal and inflamed skin. Br J Der- matol 121:421

13. Meunier L, Gonzalez-Ramos A, Cooper KD (1993) Hetero- geneous populations of class II MHC+ cells in human der- mal cell suspensions. Identification of a small subset responsible for potent dermal antigen-presenting cell activity with features analogous to Langerhans cells. J Immunol 151:4067

14. von Bubnoff D, Bausinger H, Matz H, Koch S, Hacker G, Takikawa O, Bieber T, Hanau D, de la Salle H (2004) Human epidermal langerhans cells express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. J Invest Dermatol 123:298

15. Rocha C, de Maubeuge J, Sarfati M, Song M, Delespesse G (1984) Characterization of cellular infiltrates in skin lesions of atopic eczema by means of monoclonal anti- bodies. Dermatologica 169:330

16. Wollenberg A, Kraft S, Hanau D, Bieber T (1996) Immuno- morphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epi- dermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol 106:446

17. Stary G, Bangert C, Kopp T, Stingl G Dendritic cells in atopic dermatitis: Expression of Fc 5 RI on two distinct inflammation-associated subsets. (in prep)

18. Pastore S, Corinti S, La-Placa M, Didona B, Girolomoni G (1998) Interferon-gamma promotes exaggerated cytokine production in keratinocytes cultured from patients with atopic dermatitis. J Allergy Clin Immunol 101:538 19. Albanesi C, Scarponi C, Cavani A, Federici M, Nasorri F,

Girolomoni G (2000) Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon- gamma- and interleukin-4-induced activation of human keratinocytes. J Invest Dermatol 115:81

20. Pastore S, Fanales-Belasio E, Albanesi C, Chinni LM, Gian- netti A, Girolomoni G (1997) Granulocyte macrophage colony-stimulating factor is overproduced by keratinocy- tes in atopic dermatitis. Implications for sustained den- dritic cell activation in the skin. J Clin Invest 99:3009 21. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G,

Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, et al.

(2002) Human epithelial cells trigger dendritic cell medi- ated allergic inflammation by producing TSLP. Nat Immu- nol 3:673 – 680

22. Nestle FO, Zheng XG, Thompson CB, Turka LA, Nickoloff BJ (1993) Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and

functionally distinctive subsets [published erratum ap- pears in J Immunol 1994 Jan 1;152(1):376]. J Immunol 151:

6535

23. Wollenberg A, Wen S, Bieber T (1999) Phenotyping of epi- dermal dendritic cells: clinical applications of a flow cyto- metric micromethod. Cytometry 37:147

24. Wollenberg A, Bieber T (2002) Antigen-presenting cells.

In: Bieber T, Leung DY (eds) Atopic dermatitis. Marcel Dekker AG, Basel, p 267

25. Wollenberg A, Mommaas M, Oppel T, Schottdorf EM, Gunther S, Moderer M (2002) Expression and function of the mannose receptor CD206 on epidermal dendritic cells in inflammatory skin diseases. J Invest Dermatol 118:327 26. Ohki O, Yokozeki H, Katayama I, Umeda T, Azuma M,

Okumura K, Nishioka K (1997) Functional CD86 (B7-2/

B70) is predominantly expressed on Langerhans cells in atopic dermatitis. Br J Dermatol 136:838

27. Schuller E, Teichmann B, Haberstok J, Moderer M, Bieber T, Wollenberg A (2001) In situ expression of the costimula- tory molecules CD80 and CD86 on langerhans cells and inflammatory dendritic epidermal cells (IDEC) in atopic dermatitis. Arch Dermatol Res 293:448

28. Wollenberg A, Wen S, Bieber T (1995) Langerhans cell phe- notyping: a new tool for differential diagnosis of inflam- matory skin diseases [letter]. Lancet 346:1626

29. Vollenweider R, Lennert K (1983) Plasmacytoid T-cell clusters in non-specific lymphadenitis. Virchows Arch B Cell Pathol Incl Mol Pathol 44:1

30. Prasthofer EF, Prchal JT, Grizzle WE, Grossi CE (1985) Plasmacytoid T-cell lymphoma associated with chronic myeloproliferative disorder. Am J Surg Pathol 9:380 31. Facchetti F, De Wolf-Peeters C, van den Oord JJ, Desmet VJ

(1989) Plasmacytoid monocytes (so-called plasmacytoid T cells) in Hodgkin’s disease. J Pathol 158:57

32. Facchetti F, de Wolf-Peeters C, van den Oord JJ, de Vos R, Desmet VJ (1989) Plasmacytoid monocytes (so-called plasmacytoid T-cells) in Kikuchi’s lymphadenitis. An immunohistologic study. Am J Clin Pathol 92:42 33. Facchetti F, De Wolf-Peeters C, De Vos R, van den Oord JJ,

Pulford KA, Desmet VJ (1989) Plasmacytoid monocytes (so-called plasmacytoid T cells) in granulomatous lymph- adenitis. Hum Pathol 20:588

34. Kohrgruber N, Halanek N, Groger M, Winter D, Rappers- berger K, Schmitt-Egenolf M, Stingl G, Maurer D (1999) Survival, maturation, and function of CD11c- and CD11c+

peripheral blood dendritic cells are differentially regulat- ed by cytokines. J Immunol 163:3250

35. Colonna M, Trinchieri G, Liu YJ (2004) Plasmacytoid den- dritic cells in immunity. Nat Immunol 5:1219

36. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987 37. Kuwana M (2002) Induction of anergic and regulatory T

cells by plasmacytoid dendritic cells and other dendritic cell subsets. Hum Immunol 63:1156

38. Cella M, Facchetti F, Lanzavecchia A, Colonna M (2000) Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization. Nat Immunol 1:305

39. Rissoan MC, Soumelis V, Kadowaki N, Grouard G, Briere F, de Waal Malefyt R, Liu YJ (1999) Reciprocal control of T

References 283

helper cell and dendritic cell differentiation [see com- ments]. Science 283:1183

40. Zou W, Borvak J, Wei S, Isaeva T, Curiel DT, Curiel TJ (2001) Reciprocal regulation of plasmacytoid dendritic cells and monocytes during viral infection. Eur J Immunol 31:3833

41. Kohrgruber N, Groger M, Meraner P, Kriehuber E, Petzel- bauer P, Brandt S, Stingl G, Rot A, Maurer D (2004) Plas- macytoid dendritic cell recruitment by immobilized CXCR3 ligands. J Immunol 173:6592

42. Zou W, Machelon V, Coulomb-L-Hermin A, Borvak J, Nome F, Isaeva T, Wei S, Krzysiek R, Durand-Gasselin I, Gordon A, et al. (2001) Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med 7:1339

43. Pashenkov M, Teleshova N, Kouwenhoven M, Smirnova T, Jin YP, Kostulas V, Huang YM, Pinegin B, Boiko A, Link H (2002) Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections. J Neuroimmunol 122:106 44. Jahnsen FL, Lund-Johansen F, Dunne J, Farkas L, Haye R, Brandtzaeg P (2000) Experimentally induced recruitment of plasmacytoid (CD123high) dendritic cells in human nasal allergy. J Immunol 165:4062

45. Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahn- sen FL (2001) Plasmacytoid dendritic cells (natural inter- feron- alpha/beta-producing cells) accumulate in cutane- ous lupus erythematosus lesions. Am J Pathol 159:237 46. Wollenberg A, Wagner M, Gunther S, Towarowski A, Tuma

E, Moderer M, Rothenfusser S, Wetzel S, Endres S, Hart- mann G (2002) Plasmacytoid dendritic cells: a new cutane- ous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol 119:1096

47. Bangert C, Friedl J, Stary G, Stingl G, Kopp T (2003) Immu- nopathologic features of allergic contact dermatitis in man: participation of plasmacytoid dendritic cells in the pathogenesis of the disease? J Invest Dermatol (in press) 48. Farkas L, Kvale EO, Johansen FE, Jahnsen FL, Lund-Johan-

sen F (2004) Plasmacytoid dendritic cells activate aller- gen-specific TH2 memory cells: modulation by CpG oligo- deoxynucleotides. J Allergy Clin Immunol 114:436 49. Gilliet M, Liu YJ (2002) Human plasmacytoid-derived

dendritic cells and the induction of T-regulatory cells.

Hum Immunol 63:1149

50. Kiekens RC, Thepen T, Oosting AJ, Bihari IC, Van-De-Win- kel JG, Bruijnzeel-Koomen CA, Knol EF (2001) Heteroge- neity within tissue-specific macrophage and dendritic cell populations during cutaneous inflammation in atopic der- matitis. Br J Dermatol 145:957

51. Caughman SW, Sharrow SO, Shimada S, Stephany D, Mizu- ochi T, Rosenberg AS, Katz SI, Singer A (1986) Ia+ murine epidermal Langerhans cells are deficient in surface expres- sion of the class I major histocompatibility complex. Proc Natl Acad Sci 83:7438

52. Lenz A, Heufler C, Rammensee HG, Glassl H, Koch F, Romani N, Schuler G (1989) Murine epidermal Langer- hans cells express significant amounts of class I major his- tocompatibility complex antigens. Proc Natl Acad Sci 86:7527

53. Volc-Platzer B, Stingl G, Wolff K, Hinterberg W, Schnedl W (1984) Cytogenetic identification of allogeneic epidermal

Langerhans cells in a bone-marrow-graft recipient. N Engl J Med 310:1123

54. Caux C, Dezutter-Dambuyant C, Schmitt D, Banchereau J (1992) GM-CSF and TNF-alpha cooperate in the genera- tion of dendritic Langerhans cells. Nature 360:258 55. Strunk D, Rappersberger K, Egger C, Strobl H, Kromer E,

Elbe A, Maurer D, Stingl G (1996) Generation of human dendritic cells/Langerhans cells from circulating CD34+

hematopoietic progenitor cells. Blood 87:1292

56. Strobl H, Riedl E, Scheinecker C, Bello-Fernandez C, Pickl WF, Rappersberger K, Majdic O, Knapp W (1996) TGF- beta 1 promotes in vitro development of dendritic cells from CD34+ hemopoietic progenitors. J Immunol 157:

1499

57. Jaksits S, Kriehuber E, Charbonnier AS, Rappersberger K, Stingl G, Maurer D (1999) CD34+ cell-derived CD14+ pre- cursor cells develop into Langerhans cells in a TGF-beta 1-dependent manner. J Immunol 163:4869

58. Borkowski TA, Letterio JJ, Farr AG, Udey MC (1996) A role for endogenous transforming growth factor beta 1 in Lan- gerhans cell biology: the skin of transforming growth fac- tor beta 1 null mice is devoid of epidermal Langerhans cells. J Exp Med 184:2417

59. Kamath AT, Henri S, Battye F, Tough DF, Shortman K (2002) Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood 100:1734 60. Merad M, Manz MG, Karsunky H, Wagers A, Peters W,

Charo I, Weissman IL, Cyster JG, Engleman EG (2002) Langerhans cells renew in the skin throughout life under steady-state conditions. 3:1135

61. Larregina AT, Morelli AE, Spencer LA, Logar AJ, Watkins SC, Thomson AW, Falo Jr LD (2001) Dermal-resident CD14+ cells differentiate into Langerhans cells. Nat Immu- nol 2:1151

62. Merad M, Hoffmann P, Ranheim E, Slaymaker S, Manz MG, Lira SA, Charo I, Cook DN, Weissman IL, Strober S, Engleman EG (2004) Depletion of host Langerhans cells before transplantation of donor alloreactive T cells pre- vents skin graft-versus-host disease. Nat Med 10:510 63. Strunk D, Egger C, Leitner G, Hanau D, Stingl G (1997) A

skin homing molecule defines the langerhans cell progeni- tor in human peripheral blood. J Exp Med 185:1131 64. Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS (1997)

Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 389:978 65. Pendl GG, Robert C, Steinert M, Thanos R, Eytner R, Bor- ges E, Wild MK, Lowe JB, Fuhlbrigge RC, Kupper TS, Vest- weber D, Grabbe S (2002) Immature mouse dendritic cells enter inflamed tissue, a process that requires E- and P- selectin, but not P-selectin glycoprotein ligand 1. Blood 99:946

66. Robert C, Fuhlbrigge RC, Kieffer JD, Ayehunie S, Hynes RO, Cheng G, Grabbe S, von Andrian UH, Kupper TS (1999) Interaction of dendritic cells with skin endotheli- um: A new perspective on immunosurveillance. J Exp Med 189:627

67. Charbonnier AS, Kohrgruber N, Kriehuber E, Stingl G, Rot

A, Maurer D (1999) Macrophage inflammatory protein

3alpha is involved in the constitutive trafficking of epider-

mal langerhans cells. J Exp Med 190:1755

68. Nakayama T, Fujisawa R, Yamada H, Horikawa T, Kawasa- ki H, Hieshima K, Izawa D, Fujiie S, Tezuka T, Yoshie O (2001) Inducible expression of a CC chemokine liver- and activation-regulated chemokine (LARC)/macrophage inflammatory protein (MIP)-3 alpha/CCL20 by epidermal keratinocytes and its role in atopic dermatitis. Int Immu- nol 13:95

69. Giustizieri ML, Mascia F, Frezzolini A, De Pita O, Chinni LM, Giannetti A, Girolomoni G, Pastore S (2001) Keratino- cytes from patients with atopic dermatitis and psoriasis show a distinct chemokine production profile in response to T cell-derived cytokines. J Allergy Clin Immunol 107:

871

70. Pablos JL, Amara A, Bouloc A, Santiago B, Caruz A, Galin- do M, Delaunay T, Virelizier JL, Arenzana Seisdedos F (1999) Stromal-cell derived factor is expressed by dendrit- ic cells and endothelium in human skin. Am J Pathol 155:1577

71. Penna G, Vulcano M, Sozzani S, Adorini L (2002) Differen- tial migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells. Hum Immunol 63:1164

72. Zuniga EI, McGavern DB, Pruneda-Paz JL, Teng C, Olds- tone MB (2004) Bone marrow plasmacytoid dendritic cells can differentiate into myeloid dendritic cells upon virus infection. Nat Immunol 5:1227

73. Penna G, Sozzani S, Adorini L (2001) Cutting edge: selec- tive usage of chemokine receptors by plasmacytoid den- dritic cells. J Immunol 167:1862

74. Vanbervliet B, Bendriss-Vermare N, Massacrier C, Homey B, de-Bouteiller O, Briere F, Trinchieri G, Caux C (2003) The inducible CXCR3 ligands control plasmacytoid den- dritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12. J Exp Med 198:823

75. Groves RW, Allen MH, Barker JN, Haskard DO, MacDo- nald DM (1991) Endothelial leucocyte adhesion molecule- 1 (ELAM-1) expression in cutaneous inflammation. Br J Dermatol 124:117

76. Schaekel K, Kannagi R, Kniep B, Goto Y, Mitsuoka C, Zwir- ner J, Soruri A, von Kietzell M, Rieber E (2002) 6-Sulfo Lac- NAc, a novel carbohydrate modification of PSGL-1, defines an inflammatory type of human dendritic cells. Immunity 17:289

77. Novak N, Allam P, Geiger E, Bieber T (2002) Characteriza- tion of monocyte subtypes in the allergic form of atopic eczema/dermatitis syndrome. Allergy 57:931

78. Reider N, Reider D, Ebner S, Holzmann S, Herold M, Fritsch P, Romani N (2002) Dendritic cells contribute to the development of atopy by an insufficiency in IL-12 pro- duction. J Allergy Clin Immunol 109:89

79. Gosset P, Bureau F, Angeli V, Pichavant M, Faveeuw C, Ton- nel AB, Trottein F (2003) Prostaglandin D2 affects the mat- uration of human monocyte-derived dendritic cells: con- sequence on the polarization of naive Th cells. J Immunol 170:4943

80. Gutzmer R, Langer K, Lisewski M, Mommert S, Rieckborn D, Kapp A, Werfel T (2002) Expression and function of his- tamine receptors 1 and 2 on human monocyte-derived dendritic cells. J Allergy Clin Immunol 109:524

81. Gill MA, Blanco P, Arce E, Pascual V, Banchereau J, Palucka AK (2002) Blood dendritic cells and DC-poietins in sys- temic lupus erythematosus. Hum Immunol 63:1172 82. Grouard G, Rissoan MC, Filgueira L, Durand I, Banchere-

au J, Liu YJ (1997) The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J Exp Med 185:1101

83. Charbonnier AS, Hammad H, Gosset P, Stewart GA, Alkan S, Tonnel AB, Pestel J (2003) Der p 1-pulsed myeloid and plasmacytoid dendritic cells from house dust mite-sensi- tized allergic patients dysregulate the T cell response. J Leukoc Biol 73:91

84. Kinet JP (1999) The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. Annu Rev Immunol 17:

931

85. Yamaguchi M, Sayama K, Yano K, Lantz CS, Noben Trauth N, Ra C, Costa JJ, Galli SJ (1999) IgE enhances Fc epsilon receptor I expression and IgE-dependent release of hista- mine and lipid mediators from human umbilical cord blood-derived mast cells: synergistic effect of IL-4 and IgE on human mast cell Fc epsilon receptor I expression and mediator release. J Immunol 162:5455

86. MacGlashan D, Schroeder JT (2000) Functional conse- quences of FcepsilonRIalpha up-regulation by IgE in human basophils. J Leukoc Biol 68:479

87. Novak N, Tepel C, Koch S, Brix K, Bieber T, Kraft S (2003) Evidence for a differential expression of the FcepsilonRI- gamma chain in dendritic cells of atopic and nonatopic donors. J Clin Invest 111:1047

88. Barker JN, Alegre VA, MacDonald DM (1988) Surface- bound immunoglobulin E on antigen-presenting cells in cutaneous tissue of atopic dermatitis. J Invest Dermatol 90:117

89. Leung DY, Schneeberger EE, Siraganian RP, Geha RS, Bhan AK (1987) The presence of IgE on macrophages and den- dritic cells infiltrating into the skin lesion of atopic derma- titis. Clin Immunol Immunopath 42:328

90. Klubal R, Osterhoff B, Wang B, Kinet JP, Maurer D, Stingl G (1997) The high-affinity receptor for IgE is the predomi- nant IgE-binding structure in lesional skin of atopic der- matitis patients. J Invest Dermatol 108:336

91. Maurer D, Fiebiger E, Reininger B, Wolff-Winiski B, Jouvin MH, Kilgus O, Kinet JP, Stingl G (1994) Expression of func- tional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals. J Exp Med 179:745 92. Maurer D, Ebner C, Reininger B, Fiebiger E, Kraft D, Kinet

JP, Stingl G (1995) The high affinity IgE receptor (Fc epsi- lon RI) mediates IgE-dependent allergen presentation. J Immunol 154:6285

93. Oppel T, Schuller E, Gunther S, Moderer M, Haberstok J, Bieber T, Wollenberg A (2000) Phenotyping of epidermal dendritic cells allows the differentiation between extrinsic and intrinsic forms of atopic dermatitis. Br J Dermatol 143:1193

94. Reischl IG, Corvaia N, Effenberger F, Wolff-Winiski B, Kromer E, Mudde GC (1996) Function and regulation of Fc epsilon RI expression on monocytes from non-atopic donors. Clin Exp Allergy 26:630

95. Reischl IG, Dubois GR, Peiritsch S, Brown KS, Wheat L, Woisetschlager M, Mudde GC (2000) Regulation of Fc

References 285

epsilonRI expression on human monocytic cells by ligand and IL-4. Clin Exp Allergy 30:1033

96. Gosset P, Lamblin-Degros C, Tillie-Leblond I, Charbon- nier AS, Joseph M, Wallaert B, Kochan JP, Tonnel AB (2001) Modulation of high-affinity IgE receptor expres- sion in blood monocytes: opposite effect of IL-4 and glu- cocorticoids. J Allergy Clin Immunol 107:114

97. Maurer D, Fiebiger E, Reininger B, Ebner C, Petzelbauer P, Shi GP, Chapman HA, Stingl G (1998) Fc epsilon receptor I on dendritic cells delivers IgE-bound multivalent anti- gens into a cathepsin S-dependent pathway of MHC class II presentation. J Immunol 161:2731

98. Maurer D, Fiebiger S, Ebner C, Reininger B, Fischer GF, Wichlas S, Jouvin MH, Schmitt-Egenolf M, Kraft D, Kinet JP, Stingl G (1996) Peripheral blood dendritic cells express Fc epsilon RI as a complex composed of Fc epsi- lon RI alpha- and Fc epsilon RI gamma-chains and can use this receptor for IgE-mediated allergen presentation.

J Immunol 157:607

99. Reich K, Heine A, Hugo S, Blaschke V, Middel P, Kaser A, Tilg H, Blaschke S, Gutgesell C, Neumann C (2001) Engagement of the Fc epsilon RI stimulates the produc- tion of IL-16 in Langerhans cell-like dendritic cells. J Immunol 167:6321

100. Novak N, Allam JP, Hagemann T, Jenneck C, Laffer S, Valenta R, Kochan J, Bieber T (2004) Characterization of FcepsilonRI-bearing CD123 blood dendritic cell antigen- 2 plasmacytoid dendritic cells in atopic dermatitis. J Allergy Clin Immunol 114:364

101. Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, van As A, Gupta N (2001) Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 108:184

102. Kuehr J, Brauburger J, Zielen S, Schauer U, Kamin W, Von Berg A, Leupold W, Bergmann KC, Rolinck-Werninghaus C, Grave M, Hultsch T, Wahn U (2002) Efficacy of combi- nation treatment with anti-IgE plus specific immuno- therapy in polysensitized children and adolescents with seasonal allergic rhinitis. J Allergy Clin Immunol 109:274 103. Leung DY, Sampson HA, Yunginger JW, Burks Jr. AW, Schneider LC, Wortel CH, Davis FM, Hyun JD, Shanahan Jr WR (2003) Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med 348:986

104. Hayek B, P. M. Heil LM MD HT, Stingl G Omalizumab- induced downregulation of IgE/FceRI on dendritic cells in patients with atopic dermatitis. (in prep)

105. Steinman RM, Turley S, Mellman I, Inaba K (2000) The induction of tolerance by dendritic cells that have cap- tured apoptotic cells. J Exp Med 191:411

106. Steinman RM, Nussenzweig MC (2002) Avoiding horror autotoxicus: the importance of dendritic cells in periph- eral T cell tolerance. Proc Natl Acad Sci 99:351

107. Ebner C, Schenk S, Najafian N, Siemann U, Steiner R, Fischer GW, Hoffmann K, Szepfalusi Z, Scheiner O, Kraft D (1995) Nonallergic individuals recognize the same T cell epitopes of Bet v 1, the major birch pollen allergen, as atopic patients. J Immunol 154:1932

108. Uehara M, Kimura C (1993) Descendant family history of atopic dermatitis. Acta Dermato-Venereologica 73:62

109. Forster R, Schubel A, Breitfeld D, Kremmer E, Renner Muller I, Wolf E, Lipp M (1999) CCR7 coordinates the pri- mary immune response by establishing functional micro- environments in secondary lymphoid organs. Cell 99:23 110. Lanzavecchia A, Sallusto F (2001) The instructive role of

dendritic cells on T cell responses: lineages, plasticity and kinetics. Curr Opin Immunol 13:291

111. Martin Fontecha A, Sebastiani S, Hopken UE, Uguccioni M, Lipp M, Lanzavecchia A, Sallusto F (2003) Regulation of dendritic cell migration to the draining lymph node:

impact on T lymphocyte traffic and priming. J Exp Med 198:615

112. Johnson GB, Brunn GJ, Kodaira Y, Platt JL (2002) Recep- tor-mediated monitoring of tissue well-being via detec- tion of soluble heparan sulfate by Toll-like receptor 4. J Immunol 168:5233

113. Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J, Chow JC, Strauss 3rd JF (2001) The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem 276:10229

114. Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H (2002) HSP70 as endogenous stimu- lus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 277:15107

115. Clark RA, Adinoff AD (1989) The relationship between positive aeroallergen patch test reactions and aeroaller- gen exacerbations of atopic dermatitis. Clin Immunol Immunopath 53:S132

116. van-der-Heijden FL, Wierenga EA, Bos JD, Kapsenberg ML (1991) High frequency of IL-4-producing CD4+ aller- gen-specific T lymphocytes in atopic dermatitis lesional skin. J Invest Dermatol 97:389

117. Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, Haugen HS, Maurer M, Harder B, Johnston J, et al. 2004. Interleukin 31, a cyto- kine produced by activated T cells, induces dermatitis in mice. Nat Immunol 5:752

118. Grewe M, Bruijnzeel-Koomen CA, Schopf E, Thepen T, Langeveld Wildschut AG, Ruzicka T, Krutmann J (1998) A role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis. Immunol Today 19:359

119. Thepen T, Langeveld Wildschut EG, Bihari IC, van- Wichen DF, van-Reijsen FC, Mudde GC, Bruijnzeel-Koo- men CA (1996) Biphasic response against aeroallergen in atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: an immunocyto- chemical study. J Allergy Clin Immunol 97:828

120. Muller G, Saloga J, Germann T, Bellinghausen I, Moha- madzadeh M, Knop J, Enk AH (1994) Identification and induction of human keratinocyte-derived IL-12. J Clin Invest 94:1799

121. Kang K, Kubin M, Cooper KD, Lessin SR, Trinchieri G, Rook AH (1996) IL-12 synthesis by human Langerhans cells. J Immunol 156:1402

122. Grewe M, Czech W, Morita A, Werfel T, Klammer M, Kapp A, Ruzicka T, Schopf E, Krutmann J (1998) Human eosin- ophils produce biologically active IL-12: implications for control of T cell responses. J Immunol 161:415

123. de-la-Rosa G, Longo N, Rodriguez-Fernandez JL, Puig-

Kroger A, Pineda A, Corbi AL, Sanchez-Mateos P (2003)

Migration of human blood dendritic cells across endo- thelial cell monolayers: adhesion molecules and chemo- kines involved in subset-specific transmigration. J Leu- koc Biol 73:639

124. Kerschenlohr K, Decard S, Przybilla B, Wollenberg A (2003) Atopy patch test reactions show a rapid influx of inflammatory dendritic epidermal cells in patients with extrinsic atopic dermatitis and patients with intrinsic atopic dermatitis. J Allergy Clin Immunol 111:869 125. Julia V, Hessel EM, Malherbe L, Glaichenhaus N, O’Garra

A, Coffman RL (2002) A restricted subset of dendritic cells captures airborne antigens and remains able to acti- vate specific T cells long after antigen exposure. Immuni- ty 16:271

126. Hammad H, Smits HH, Ratajczak C, Nithiananthan A, Wierenga EA, Stewart GA, Jacquet A, Tonnel AB, Pestel J (2003) Monocyte-derived dendritic cells exposed to Der p 1 allergen enhance the recruitment of Th2 cells: major involvement of the chemokines TARC/CCL17 and MDC/

CCL22. Eur Cytokine Netw 14:219

127. Ruzicka T, Bieber T, Schopf E, Rubins A, Dobozy A, Bos JD, Jablonska S, Ahmed I, Thestrup-Pedersen K, Daniel F, Finzi A, Reitamo S (1997) A short-term trial of tacrolimus ointment for atopic dermatitis. European Tacrolimus Multicenter Atopic Dermatitis Study Group. New Engl J Med 337:816

128. Luger T, Van-Leent EJ, Graeber M, Hedgecock S, Thur- ston M, Kandra A, Berth-Jones J, Bjerke J, Christophers E, Knop J, et al. 2001. SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 144:788

129. Hanifin JM, Ling MR, Langley R, Breneman D, Rafal E (2001) Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy. J Am Acad Dermatol 44:S28

130. Goto T, Kino T, Hatanaka H, Nishiyama M, Okuhara M, Kohsaka M, Aoki H, Imanaka H (1987) Discovery of FK- 506, a novel immunosuppressant isolated from Strepto- myces tsukubaensis. Transplant Proc 19:4

131. Grassberger M, Baumruker T, Enz A, Hiestand P, Hultsch T, Kalthoff F, Schuler W, Schulz M, Werner FJ, Winiski A, Wolff B, Zenke G (1999) A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol 141:264

132. Tocci MJ, Matkovich DA, A. Collier K, Kwok P, Dumont F, Lin S, Degudicibus S, Siekierka JJ, Chin J, Hutchinson NI (1989) The immunosuppressant FK506 selectively inhib- its expression of early T cell activation genes. J Immunol 143:718

133. Reitamo S (2001) Tacrolimus: a new topical immuno- modulatory therapy for atopic dermatitis. J Allergy Clin Immunol 107:445

134. Hashimoto Y, Matsuoka N, Kawakami A, Tsuboi M, Nakashima T, Eguchi K, Tomioka T, Kanematsu T (2001) Novel immunosuppressive effect of FK506 by augmenta- tion of T cell apoptosis. Clin Exp Immunol 125:19 135. Hoetzenecker W, Ecker R, Kopp T, Stuetz A, Stingl G,

Elbe-Buerger A Pimecrolimus leads to an apoptosis- induced depletion of T cells but not Langerhans cells in patients with atopic dermatitis: results from a random- ized, double-blind, vehicle-controlled clinical trial. (sub- mitted)

136. de-Paulis A, Cirillo R, Ciccarelli A, Condorelli M, Marone G (1991) FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human Fc epsilon RI+

cells. J Immunol 146:2374

137. de-Paulis A, Stellato C, Cirillo R, Ciccarelli A, Oriente A, Marone G (1992) Anti-inflammatory effect of FK-506 on human skin mast cells. J Invest Dermatol 99:723 138. Hatfield SM, Roehm NW (1992) Cyclosporine and FK506

inhibition of murine mast cell cytokine production. J Pharmacol Exp Ther 260:680

139. Hatfield SM, Mynderse JS, Roehm NW (1992) Rapamycin and FK506 differentially inhibit mast cell cytokine pro- duction and cytokine-induced proliferation and act as reciprocal antagonists. J Pharmacol Exp Ther 261:970 140. Hultsch T, Muller KD, Meingassner JG, Grassberger M,

Schopf RE, Knop J (1998) Ascomycin macrolactam deriv- ative SDZ ASM 981 inhibits the release of granule-associ- ated mediators and of newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin-dependent man- ner. Arch Dermatol Res 290:501

141. Zuberbier T, Chong S, Guhl S, Welker P, Henz BM, Gras- sberger M (1999) SDZ ASM 981 inhibits anti-IgE stimu- lated mediator release inhuman dermalbmast cells (abstract). J Invest Dermatol 112:608

142. Wollenberg A, Sharma S, von Bubnoff D, Geiger E, Haber- stok J, Bieber T (2001) Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epi- dermal antigen-presenting dendritic cells in atopic der- matitis. J Allergy Clin Immunol 107:519

143. Schuller E, Oppel T, Bornhovd E, Wetzel S, Wollenberg A (2004) Tacrolimus ointment causes inflammatory den- dritic epidermal cell depletion but no Langerhans cell apoptosis in patients with atopic dermatitis. J Allergy Clin Immunol 114:137

144. Simon D, Vassina E, Yousefi S, Kozlowski E, Braathen LR, Simon HU (2004) Reduced dermal infiltration of cyto- kine-expressing inflammatory cells in atopic dermatitis after short-term topical tacrolimus treatment. J Allergy Clin Immunol 114:887

145. Hoetzenecker W, Meingassner JG, Ecker R, Stingl G, Stu- etz A, Elbe-Burger A (2004) Corticosteroids but not pimecrolimus affect viability, maturation and immune function of murine epidermal Langerhans cells. J Invest Dermatol 122:673

146. Panhans-Gross A, Novak N, Kraft S, Bieber T (2001) Human epidermal Langerhans’ cells are targets for the immunosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 107:345

147. Kalthoff FS, Chung J, Musser P, Stuetz A (2003) Pimecroli- mus does not affect the differentiation, maturation and function of human monocyte-derived dendritic cells, in contrast to corticosteroids. Clin Exp Immunol 133:350

References 287