Inflammatory Dendritic Epidermal Cells Research Articles

Immunological Pathomechanisms of Spongiotic Dermatitis in Skin Lesions of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic pruritic skin disease with a complex pathogenesis underlying its heterogeneous clinical phenotypes and endotypes. The skin manifestation of AD reflects the cytokine milieu of a type-2-dominant immunity axis induced by genetic predisposition, innate immunity dysregulation, epidermal barrier defects, and allergic inflammation. However, the detailed pathomechanism of eczematous dermatitis, which is the principal characteristic of AD, remains unclear. This review examines previous studies demonstrating research progress in this area and considers the immunological pathomechanism of “spongiotic dermatitis”, which is the histopathological hallmark of eczematous dermatitis. Studies in this field have revealed the importance of IgE-mediated delayed-type hypersensitivity, the Fas/Fas-ligand system, and cell-mediated cytotoxicity in inducing the apoptosis of keratinocytes in spongiotic dermatitis. Recent studies have demonstrated that, together with infiltrating CD4 T cells, IgE-expressing dendritic cells (i.e., inflammatory dendritic epidermal cells and Langerhans cells) that capture specific allergens (i.e., house dust mites) are present in the spongiotic epidermis of lichenified eczema in patients with IgE-allergic AD. These findings suggest that IgE-mediated delayed-type hypersensitivity plays a pivotal role in the pathogenesis of spongiotic dermatitis in the skin lesions of AD.

Immunohistopathological Analysis of Immunoglobulin E-Positive Epidermal Dendritic Cells with House Dust Mite Antigens in Naturally Occurring Skin Lesions of Adult and Elderly Patients with Atopic Dermatitis.

The immunopathogenic role of house dust mite (HDM) allergens in the development of skin lesions in atopic dermatitis (AD) has not yet been precisely clarified. We immunohistopathologically evaluated the localization of immunoglobulin E (IgE)-positive epidermal dendritic cells with HDM antigens in the skin lesions of patients with IgE-allergic AD. Using double-immunofluorescence and single-immunochemical staining methods, we analyzed biopsy specimens from the skin lesions of six patients with IgE-allergic AD and HDM allergy and 11 control subjects with inflammatory skin disorders. Inflammatory dendritic epidermal cells (IDECs; CD11c+ and CD206+ cells) were markedly observed in the central area of the spongiotic epidermis of skin lesions in all AD patients. Furthermore, IgE-positive IDECs with HDM antigens in the central areas of the spongiosis were found in four of the six (66.7%) AD patients. Langerhans cells (LCs; CD207+ cells) with HDM antigens were also observed in the peripheral areas of the spongiosis. Infiltration of CD4+ and CD8+ T cells in association with IgE-positive IDECs and LCs with HDM antigens was seen in the spongiotic epidermis. An IgE-mediated delayed-type hypersensitivity reaction, in combination with IgE-bearing dendritic cells, specific T cells, keratinocytes, and HDM antigens, may lead to spongiotic tissue formation in eczematous dermatitis in AD.

Vitamin D3-Induced Promotor Dissociation of PU.1 and YY1 Results in FcεRI Reduction on Dendritic Cells in Atopic Dermatitis.

Atopic dermatitis (AD) is a severe inflammatory skin disease. Langerhans cells and inflammatory dendritic epidermal cells (IDEC) are located in the epidermis of AD patients and contribute to the inflammatory processes. Both express robustly the high-affinity receptor for IgE, FcεRI, and thereby sense allergens. A beneficial role of vitamin D3 in AD is discussed to be important especially in patients with allergic sensitization. We hypothesized that vitamin D3 impacts FcεRI expression and addressed this in human ex vivo skin, in vitro Langerhans cells, and IDEC models generated from primary human precursor cells. We show in this article that biologically active vitamin D3 [1,25(OH)2-D3] significantly downregulated FcεRI at the protein and mRNA levels of the receptor's α-chain, analyzed by flow cytometry and quantitative RT-PCR. We also describe the expression of a functional vitamin D receptor in IDEC. 1,25(OH)2-D3-mediated FcεRI reduction was direct and resulted in impaired activation of IDEC upon FcεRI engagement as monitored by CD83 expression. FcεRI regulation by 1,25(OH)2-D3 was independent of maturation and expression levels of microRNA-155 and PU.1 (as upstream regulatory axis of FcεRI) and transcription factors Elf-1 and YY1. However, 1,25(OH)2-D3 induced dissociation of PU.1 and YY1 from the FCER1A promotor, evaluated by chromatin immunoprecipitation. We show that vitamin D3 directly reduces FcεRI expression on dendritic cells by inhibiting transcription factor binding to its promotor and subsequently impairs IgE-mediated signaling. Thus, vitamin D3 as an individualized therapeutic supplement for those AD patients with allergic sensitization interferes with IgE-mediated inflammatory processes in AD patients.

JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis

Janus kinase (JAK) inhibitors are a new class of therapeutic compounds for dermatological diseases. In atopic dermatitis (AD), data of clinical phase III trials show rapid improvement of pruritus and significant reduction of inflammation within the first weeks with a favorable safety profile. However, their mode of action in AD is not fully understood. In our study, we investigate the effect of different JAK inhibitors on cell differentiation, phenotype, and function of inflammatory dendritic epidermal cells (IDECs). We analyzed the JAK expression in IDEC from exvivo skin and invitro generated IDECs using flow cytometry and PCR. Further, we studied invitro the effect of different JAK inhibitors on IDEC cell differentiation, phenotype, and maturation. IDECs express JAK1 and JAK2 exvivo and invitro. We found that JAK1 and JAK2 were upregulated during the differentiation from monocytes to IDECs. Conversely, JAK2 inhibition by ruxolitinib (JAK1/2 inhibitor) or BMS-911543 (JAK2 inhibitor) abrogated the differentiation from monocytes into IDECs. Differentiated IDECs can redifferentiate into a more monocyte-like phenotype in the presence of ruxolitinib or BMS-911543. Furthermore, we showed that concomitant inhibition of JAK1/2 rather than blocking JAK1 or JAK2 alone, impaired maturation and the release of proinflammatory cytokines on lipopolysaccharide stimulation. Our results suggest that inhibition of JAK1/2 impairs IDEC differentiation and function. We provide new insight into the mode of action of JAK inhibitors in AD and highlight the role of JAK1/2 inhibitors for the treatment of patients with AD.

Langerhans and inflammatory dendritic epidermal cells in atopic dermatitis are tolerized toward TLR2 activation.

The skin of atopic dermatitis (AD) patients presents a significant dysbalance of the microbiome with a high colonization by Staphylococcus aureus (S.aureus), which positively correlates with the severity of the disease. Understanding the role of epidermal dendritic cells (DC) as link between the innate and the adaptive immune systems in AD. Comparative phenotypic and functional analysis of TLR2 on Langerhans cells (LC) and inflammatory dendritic epidermal cells (IDEC) in organotypic models as well as freshly isolated cells from healthy and AD skin. In situ analysis of freshly isolated LC and IDEC from AD skin revealed decreased TLR2 expression compared to LC from healthy skin. In contrast to IDEC, LC from AD skin failed to display any evidence for insitu activation. Exposure to TLR2 ligand Pam3Cys resulted in maturation and increased migratory activity of LC from normal skin. LC and IDEC from AD were unresponsive to TLR2 ligand in that they failed to mature and displayed a high spontaneous migratory activity. Keratinocytes from both healthy and AD skin expressed similar levels of TLR2. The production of IL-6 and IL-10 was impaired by Pam3Cys in supernatants from AD skin. IL-18 was significantly higher in supernatants from AD skin and not influenced by TLR2 ligation, when compared to healthy skin. Our results suggest that TLR2-mediated sensing of S.aureus-derived signals is strongly impaired in LC from AD skin. This phenomenon may partlycontribute to the immune deviation in AD and the lack of S.aureus clearance.

Uncovering the Mysteries of Langerhans Cells, Inflammatory Dendritic Epidermal Cells, and Monocyte-Derived Langerhans Cell-Like Cells in the Epidermis.

The identity of Langerhans cells (LCs) has been called into question of late due to the increasing evidence that LCs originate from macrophage lineage instead of dendritic cell (DC) lineage as previously thought. For many years, LCs have been assumed to be DCs due to its migratory capabilities. However, recent studies have demonstrated that LCs are from macrophage lineage of the adult fetal liver (FL) progenitor. Bona fide LCs are now considered tissue-resident macrophages as they originate from the FL as shown by fate mapping models. In recent years, studies have shown that there are three types of antigen-presenting cells present in the epidermis, such as LCs, monocyte-derived LC-like cells, and inflammatory dendritic epidermal cells (IDECs). Of these, LC-like cells have been characterized in both human and mouse studies, while IDECs have only been described in human studies. This has shed a new light on the area of epidermal macrophages, suggesting that there might be a misidentification and misclassification of LCs. IDECs and LC-like cells have been shown to be present in both steady state and inflammatory state, but they are present in more significant amounts under inflammatory conditions such as atopic dermatitis, ultra violet injury, and psoriasis. In this review, we discuss what is already known and discuss the possible roles of LCs, LC-like cells, and IDECs during inflammation. Most intriguingly, we discuss the possibility of LCs having a dual identity as both a macrophage and a DC. This is shown as LCs are the only tissue-resident macrophage to have shown migratory property-like DCs.

Human skin dendritic cell fate is differentially regulated by the monocyte identity factor Kruppel-like factor 4 during steady state and inflammation

BackgroundLangerhans cell (LC) networks play key roles in immunity and tolerance at body surfaces. LCs are established prenatally and can be replenished from blood monocytes. Unlike skin-resident dermal DCs (dDCs)/interstitial-type DCs and inflammatory dendritic epidermal cells appearing in dermatitis/eczema lesions, LCs lack key monocyte-affiliated markers. Inversely, LCs express various epithelial genes critical for their long-term peripheral tissue residency.ObjectiveDendritic cells (DCs) are functionally involved in inflammatory diseases; however, the mechanisms remained poorly understood.MethodsIn vitro differentiation models of human DCs, gene profiling, gene transduction, and immunohistology were used to identify molecules involved in DC subset specification.ResultsHere we identified the monocyte/macrophage lineage identity transcription factor Kruppel-like factor 4 (KLF4) to be inhibited during LC differentiation from human blood monocytes. Conversely, KLF4 is maintained or induced during dermal DC and monocyte-derived dendritic cell/inflammatory dendritic epidermal cell differentiation. We showed that in monocytic cells KLF4 has to be repressed to allow their differentiation into LCs. Moreover, respective KLF4 levels in DC subsets positively correlate with proinflammatory characteristics. We identified epithelial Notch signaling to repress KLF4 in monocytes undergoing LC commitment. Loss of KLF4 in monocytes transcriptionally derepresses Runt-related transcription factor 3 in response to TGF-β1, thereby allowing LC differentiation marked by a low cytokine expression profile.ConclusionMonocyte differentiation into LCs depends on activation of Notch signaling and the concomitant loss of KLF4.

Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis

The stratum corneum and tight junctions (TJs) form physical barriers in the epidermis. Dendrites of activated Langerhans cells (LCs) extend beyond the TJs to capture external antigens in mice. LCs and inflammatory dendritic epidermal cells (IDECs) are observed in the skin of patients with atopic dermatitis (AD). We sought to investigate the characteristics of LCs and IDECs and the distribution of their antigen capture receptors in relation to TJs in normal and AD skin. We characterized the interactions of LCs and IDECs with TJs and the expression patterns of langerin and FcεRI by using whole-mount epidermal sheets from healthy subjects and patients with AD, ichthyosis vulgaris, and psoriasis vulgaris. As in mouse skin, activated LCs penetrate TJs in human skin. The number of LCs with TJ penetration increased approximately 5-fold in erythematous lesional skin of patients with AD but not in nonlesional skin of patients with AD or lesions of patients with ichthyosis vulgaris or psoriasis. Incontrast, IDECs localized in the lower part of the epidermis, and their dendrites extended horizontally without penetration through TJs. Although langerin accumulated on the tips of dendrites of activated LCs, FcεRI was expressed diffusely on the cell surfaces on LCs and IDECs in lesional skin from patients with AD. These findings highlight interesting differences between LCs and IDECs in epidermis of patients with AD, where LCs, but not IDECs, extend dendrites through the TJs, likely to capture antigens from outside the TJ barrier with a polarized distribution of langerin but not FcεRI. These behavioral differences between skin dendritic cells might reflect an important pathophysiology of AD.

Systemic sensitization with the protein allergen ovalbumin augments local sensitization in atopic dermatitis

Mouse models of atopic dermatitis based on epicutaneous sensitization have shed light on the role of epicutaneous allergen entry in the development of respiratory and gastrointestinal allergy. However, the contribution of non-cutaneous modes of sensitization to skin diseases has not been evaluated. We assessed if systemic ovalbumin administration, in conjunction with local sensitization, could prime for a robust inflammatory response. Furthermore, we attempted to elucidate important aspects of disease pathogenesis previously unaddressed in mouse models. Mice that underwent intraperitoneal ovalbumin sensitization prior to epicutaneous challenge demonstrated an acute (Th2-polarized) atopic dermatitis-like phenotype upon local challenge. The inflammatory response was strikingly more robust than in mice that underwent epicutaneous sensitization alone. The lesional infiltrate contained a dendritic cell population that corresponded phenotypically with inflammatory dendritic epidermal cells of significance in human disease. Finally, in accordance with observations in human atopic dermatitis, there was an increase in cluster of differentiation (CD) 103 (αE subunit)-expressing CD4+ T lymphocytes. However, the absence of CD103 on approximately 50% of infiltrating cells argues against a primary role for the αEβ7 integrin in tissue homing. In conclusion, we present a mouse model of atopic dermatitis that reveals novel insights into the pathogenesis of this complex disease.

IL‐27 acts as a priming signal for IL‐23 but not IL‐12 production on human antigen‐presenting cells

IL-27 belongs to the IL-12 family of cytokines and has been described not only to support T-cell polarization along the Th1 lineage, but also to induce important anti-inflammatory responses in later phases of inflammation. We and others have previously shown that the cytokine IL-27 has an important impact on the chronic manifestation of inflammatory skin diseases. Thus, the aim of this study was to specify the effects of IL-27 on the human antigen-presenting cell (APC) subtype inflammatory dendritic epidermal cells (IDEC), which are known to play an important role in eczema. IDEC and blood-derived human macrophages were generated from human peripheral blood and stimulated with IL-27. Functional responses of the cells were analysed by intracellular cytokine staining, ELISA and FlowCytomix. IL-27 was found to be the only IL-12 family member that acts on human APC as a priming signal for IL-23 but not IL-12 production. We confirmed for macrophages that IL-27 limits lipopolysaccharide-induced IL-10 production and detected the same tendency for IDEC. Furthermore, we showed that this also applies to CD40L-induced IL-10 expression in both investigated human APC subsets. We demonstrate that IL-27 exerts pro-inflammatory effects on human APC in particular in the context of a range of bacterial-derived TLR ligands. Hence, our study builds upon the idea that IL-27 exerts a pro-inflammatory effect on innate immune and tissue-resident cells and may drive eczematous reaction - in particular in the context of bacterial superinfection - towards a chronic phase.

News from dendritic cells in atopic dermatitis

Dendritic cells are essential for the generation of innate and adaptive immune responses, which makes them stay on center stage when studying the immuno pathogenesis of atopic dermatitis. This review will discuss recent findings on the role of dendritic cells subsets in atopic dermatitis and will report novel findings on how the microenvironment conditions dendritic cells to fuel atopic dermatitis. Several microenvironmental factors characteristic for atopic dermatitis and with direct relevance for the disease have been defined. We now increasingly understand how thymic stromal lymphopoietin and histamine contribute to the disease by modulating the function of dendritic cells. We have learned much about the pathogenesis of atopic dermatitis by the studies on inflammatory dendritic epidermal cells. However, the current analysis on the functional and phenotypic heterogeneity of dendritic cells in eczematous skin lesions may lead to the definition of additional dendritic cell types relevant in the pathogenesis of atopic dermatitis. In this respect, it appears interesting to further discuss the parallels and differences in atopic dermatitis and psoriasis. Understanding the heterogeneity of dendritic cells and their functional alteration by local factors in the inflamed skin will provide essential clues to the immunopathogenesis of atopic dermatitis.

Dendritic cells in infectious disease, hypersensitivity, and autoimmunity

Dendritic cells are thought to direct subsequent T lymphocyte-driven adaptive immune responses (Th1/Th2) following interaction with either endogenous or exogenous antigens. These cells have an integral role in the pathogenesis of countless infectious diseases, but their role is most vividly illustrated in human immunodeficiency virus/acquired immunodeficiency syndrome and tuberculosis. Dendritic cells can arise from either myeloid or lymphoid progenitors, but the former is more common. Of particular importance are myeloid-related dendritic cells, plasmacytoid dendritic cells, infiltrating inflammatory dendritic epidermal cells, and Langerhans cells. Myeloid-related dendritic cells resemble typical monocytes, but produce cytokines that favor the cell-mediated immune response. Plasmacytoid dendritic cells resemble plasma cells, but have additional antigen-processing capabilities, and their major role is to produce interferon alpha and beta in response to viral infections. Inflammatory dendritic epidermal cells express the highest concentration of costimulatory molecules known in any cell lineage. Langerhans cells are the chief dendritic cells of the skin, and play a pivotal role in hypersensitivity and autoimmune patholo- gies, such as atopic dermatitis and psoriasis. Lastly, reduced glutathione has been implicated in modulation of the cytokine profiles of professional antigen-presenting cells, and holds promise as a future immunotherapeutic agent. This review discusses in detail the origin, characteristics, and overall functions of different types of dendritic cells. Furthermore, we have also highlighted the role of dendritic cells in infectious diseases and autoimmune diseases, with special reference to human immunodeficiency virus, tuberculosis, atopic dermatitis, and psoriasis.

Treatment with topical tacrolimus favors chronic actinic dermatitis: A clinical and immunopathological study

Background: Previous studies have demonstrated the efficacy and safety of tacrolimus ointment in the treatment of atopic dermatitis (AD); however, few have investigated the effect of tacrolimus on chronic actinic dermatitis (CAD).Objectives: To investigate the efficacy and safety of tacrolimus ointment on CAD and its mechanism of treatment.Methods: Forty adult patients with CAD were treated with 0.1% tacrolimus ointment. Skin biopsies were performed on 15 patients before and after treatment. The specimens were subjected to immunohistochemical staining with a panel of monoclonal antibodies to CD1a, CD11b, and CC chemokine receptor 7.Results: Among all the 40 patients, two (5%) were clinically cured and 23 (57.5%) achieved excellent results, making a total effective rate of 62.5%; 14 (35%) were improved; and one (2.5%) case was withdrawn due to intolerable itching at the locally applied areas. CD1a, CD11b and CCR7 expression were all significantly down-regulated after topical treatment with tacrolimus.Conclusions: Treatment with topical tacrolimus is effective and safe for chronic actinic dermatitis, probably due to suppression of the function of Langerhans' cells and inflammatory dendritic epidermal cells and their relevant cytokines.

Cytokine-Producing Dendritic Cells in the Pathogenesis of Inflammatory Skin Diseases

Inflammatory skin diseases can be examined from many viewpoints. In this review, we consider three distinct cutaneous inflammatory diseases from the point of view of their major lesional dendritic cell (DC) subpopulations. The DC populations considered are Langerhans cells, myeloid DCs, and plasmacytoid DCs (pDCs), with specific attention to the presence and role of the inflammatory counterparts of these cells. From such a "dendritic cell-centric" focus, psoriasis, atopic dermatitis (AD), and cutaneous lupus erythematosus (CLE) are explored. In psoriasis, there is a specific population of myeloid "inflammatory" DCs that appears to play an important pathogenic role, while pDCs have been recently implicated in the initiation of psoriatic lesions. In AD, Langerhans cells may be important during initiation, while "inflammatory dendritic epidermal cells" (IDECs) appear to be abundant in lesional epidermis and dermis and contribute to maintenance of AD. These IDECs may actually be analogous to the myeloid inflammatory DCs found in the epidermal and dermal compartments of the skin in psoriasis, although they express distinct surface markers and induce different T cell polarities as a result of different cytokine milieu in which they develop. CLE has been recently characterized as a type I IFN-mediated disease, and pDCs are integral to the pathogenesis of this disease. Thus, these DC subpopulations and their products will be reviewed in the context of these three cutaneous diseases to provide clinico-pathophysiological correlations between the lesional DCs, their products, and the skin diseases.

Human Inflammatory Dendritic Epidermal Cells Express a Functional Histamine H4 Receptor

Expression of histamine H(4) receptor (H(4)R) on leukocytes suggests an immunomodulatory role of this receptor. Here we investigated the expression and function of H(4)R on human inflammatory dendritic epidermal cells (IDECs). H(4)R is expressed by IDEC of the skin. On monocyte-derived IDECs (Mo-IDECs), H(4)R is also expressed and upregulated by IFN-gamma. Functionally, histamine and H(4)R agonists clobenpropit and 4-methylhistamine downregulated the production of the Th2-linked chemokine CCL2 and the Th1 cytokine IL-12 on Mo-IDEC, whereas agonists for the other histamine receptors did not. An H(4)R-selective antagonist (JNJ7777120) blocked the effect of H(4)R agonists. Downregulation of CCL2 also led to a decreased migration of monocytes. Thus, IDEC express a functionally active H(4)R, which upon stimulation leads to downregulation of CCL2 and IL-12. This might have implications for the treatment of atopic dermatitis, since H(4)R agonists may have beneficial effects in downregulating inflammation.

Topical Application of Cream-emulsified CD86 siRNA Ameliorates Allergic Skin Disease by Targeting Cutaneous Dendritic Cells

Induction of the co-stimulatory molecule CD86 on dendritic cells (DCs) in the peripheral tissues is a critical event in triggering antigen-specific immune responses. In this study, we propose a new small interfering RNA (siRNA)-based therapy using cream-emulsified CD86 siRNA, targeting DCs for murine contact hypersensitivity (CH) and atopic dermatitis (AD)-like disease. Topical application of CD86 siRNA efficiently inhibited CH and markedly decreased the numbers of infiltrating CD86(+) or major histocompatibility complex (MHC) class II(+) cells in murine ear skin. The total number of cells, the percentage of hapten-carrying DCs, and their CD86 expression in the regional lymph nodes (RLNs) also significantly decreased. These results suggest that the silencing of CD86 in local DCs inhibits the recruitment and migration of DCs into the skin and RLNs, respectively, resulting in reduced antigen-specific local inflammation. The therapeutic efficacy of the CD86 siRNA was confirmed in AD-prone NC/Nga mice. Treatment produced marked amelioration in the clinical manifestations of AD and reduced the antigen-specific production of interleukin-4 (IL-4) and serum immunoglobulin E (IgE) and IgG1. Our results suggest that the targeting of cutaneous DCs by CD86 siRNA may be a promising strategy in the treatment of allergic skin disease.

Tacrolimus and TGF-β act synergistically on the generation of Langerhans cells

The proportion of dendritic cell subpopulations in the skin is important for the severity of atopic dermatitis because topical treatment with tacrolimus leads to rapid depletion of inflammatory dendritic epidermal cells, whereas Langerhans cells (LCs) predominate in cured sites. The effects of tacrolimus and TGF-beta1 on LC differentiation and the idea of tacrolimus skewing the differentiation of epidermal precursors to LCs were evaluated. The presence of LC markers, MHC, and costimulatory molecules and stimulatory capacity toward T cells of monocyte-derived LCs were analyzed. Skin samples of patients with atopic dermatitis were assessed by means of immunofluorescence microscopy before and after tacrolimus treatment. TGF-beta production of skin cells was analyzed. Tacrolimus and TGF-beta1 act synergistically on the generation of LCs and the expression of CD40, CD80, CD86, CD83, and MHC II; stabilize TGF-beta receptor II expression; and decrease the stimulatory capacity of LCs toward T cells. In vivo the number of epidermal LCs in tacrolimus-treated skin increased. The synergism between TGF-beta1 and tacrolimus leads to the generation of LCs, reduced expression of costimulatory and MHC II molecules, and reduced stimulatory activity. Shifting the balance of the dendritic cell population to LCs might be of major importance for the therapeutic effect of tacrolimus.

Current Aspects of Innate and Adaptive Immunity in Atopic Dermatitis

Atopic dermatitis (AD) is a highly pruritic, chronic, multifactorial skin disease predisposing to bacterial and viral infections based on abnormalities of the innate and acquired immune system. The innate system quickly mobilizes an inflexible, standardized first-line response against different pathogens. Epidermal barrier dysfunction results in increased protein allergen penetration through the epidermis and predisposes to secondary skin infections. Two loss-of-function mutations in the epidermal filaggrin gene are associated with AD. Langerhans cells and inflammatory dendritic epidermal cells (IDEC) express high affinity IgE receptors, which are functional in IgE-mediated antigen presentation. Inducible antimicrobial peptides including the antiviral cathelicidin and the antibacterial beta-defensins show defective upregulation in lesional AD skin. The desmosomal protein nectin-1 is unmasked in AD lesions, thus becoming a relevant herpes simplex virus (HSV) entry receptor. Type I IFN-producing plasmacytoid dendritic cells are decreased and dysfunctional in AD skin, predisposing the patients to viral skin infections. Molluscum contagiosum virus produces a unique IL-18 binding protein to evade antiviral defense mechanisms. Innate and adaptive immunity do not simply coexist but are linked to one another in a complex network of skin immunobiology.

Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis

Atopic dermatitis (AD) and psoriasis represent contrasting poles of the T(H)1 versus T(H)2 paradigm. Both diseases have been associated with increased numbers of dendritic cells (DCs) in the skin, but the similarities and differences in DC populations need to be established. We aimed to characterize the specific DC subsets, as well as chemokine and cytokine environment in chronic AD compared with psoriasis. Skin biopsies were obtained from patients with acute exacerbation of chronic AD (n = 18), psoriasis (n = 15), and healthy volunteers (n = 15) for microarray analysis, RT-PCR, immunohistochemistry, and double-label immunofluorescence. Myeloid DCs upregulate CCL17 and CCL18 in AD, as opposed to TNF-alpha and inducible nitric oxide synthase (iNOS) in psoriasis. In our study, we identified cells phenotypically identical to the inflammatory dendritic epidermal cells in the dermis in both diseases, although to a lesser extent in psoriasis. We found substantially higher numbers of dermal CCL22 producing plasmacytoid DCs in AD. The thymic stromal lymphopoietin receptor showed significantly higher expression in AD, whereas the thymic stromal lymphopoietin ligand was upregulated more in psoriasis. There are major differences in myeloid and plasmacytoid subsets of cutaneous DCs and the chemokine/cytokine environment between AD and psoriasis. Distinct subsets within the CD11c(+) population may influence polarization through the production of regulatory mediators, including iNOS, TNF, CCL17, and CCL18. Plasmacytoid DCs may also influence T(H)2 polarization, having a more important role in AD than previously appreciated. Dermal inflammatory dendritic cells in AD and TNF and iNOS-producing DCs in psoriasis, and/or their regulatory products, may be potential targets for future therapeutic interventions.

The pro- and anti-inflammatory properties of human antigen-presenting cells expressing the high affinity receptor for IgE (Fc εRI)

Almost 20 years after the first description of IgE on the surface of epidermal Langerhans cells (LC) and the subsequent characterization of the trimeric Fc εRI on human antigen-presenting cells (APC), we have gained profound insights into the receptor responsible for this binding. Fc εRI may act as a pro-inflammatory structure on some APC such as inflammatory dendritic epidermal cells (IDEC) in the skin of patients with atopic dermatitis while it can also be an important instrument in mechanisms leading to tolerance on other APC such as LC of the oral mucosa. By virtue of Fc εRI, APC can initiate inflammation by secretion of a wide spectrum of pro-inflammatory cytokines and chemokines. Fc εRI+DC can induce either Th2 or Th1 profile in T-cells. In contrast, the production of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as well as IL-10 and TGF ß may contribute to the tolerogenic properties of DC.