Dendritic cell (DC) subpopulations throughout the body often occur at the interface with the environment. They reside in the skin, the airways and the gut and because of their function as antigen presenting cells (APC) they have a wide range of features in common. As primary sentinels of the immune system APC traffic from the blood to the peripheral tissue to capture foreign antigens (1, 2). Thereafter, they migrate to the draining lymphoid organs in order to prime naïve T-cells and gear their development into Th1 or Th2 effector cells. In the human immune system, two functionally different subsets of DC have been found: myeloid DC, which preferentially drive naïve T-cell differentiation toward Th1 cells and are therefore called DC1 and plasmacytoid DC which represent the type 2 DC, namely plasmacytoid dendritic cells (pDC) and have a Th2 polarizing profile (1, 2). The oldest members of the DC1 system are the classical epidermal Langerhans cells (LC), which are characterized by their primary ultrastructural marker, the tennis-racket shaped Birbeck granules in combination with their surface expression of CD1a (3). The LC reside in the basal and suprabasal layers of the epidermis and are present even in normal, uninflamed skin. Marker and functional studies have provided strong support for a concept in which LC represent a resident population of the human epidermis (4). Their primary function in uninflamed skin is to maintain a state of tolerance against invading antigens and allergens under immunological steady state condition (5). By contrast, in response to arriving danger signals such as inflammation multiple changes occur. Among these is the release of monocyte-chemoattractant protein (MCP)-chemokines by skin cells which induce the recruitment of LC progenitors from the bone marrow. Other factors initiate LC migration to the peripheral lymphnode. Altogether, this leads to the break down of tolerance and the rapid induction of an immune response at this site. In this manner in the acute phase of allergic and inflammatory diseases, LC precursors and other DC subtypes are immediately recruited by chemotactic signals to the site of inflammation. Compelling evidence is now available that in the exacerbation state of Atopic Dermatitis (AD) (6), the so-called ‘Inflammatory Dendritic Epidermal Cells’ (IDEC) are recruited from monocytes of the peripheral blood into the inflammatory skin lesions (7–12). A hallmark of both, epidermal LC and IDEC in the skin lesions of AD patients is the elevated expression of the high affinity receptor for immunoglobulin (IgE) (FcɛRI) (Table 1) (13–17). Evidence suggests that allergens, which penetrate the epidermis due to the reduced skin barrier of AD patients, are taken up by FcɛRI-bound IgE molecules of epidermal DC, are internalized and processed in major histocompatibility class (MHC) II containing compartments within these cells (Fig. 1). This mechanism is referred to as antigen focusing and leads to a more efficient antigen presentation toward T-cells (12–18). Furthermore, mRNA for IL-16, the natural soluble ligand of the CD4 molecule that induces chemotactic response of CD4+ cells, monocytes and eosinophils is enhanced in active AD (18, 19). Recent findings suggest that LC are a major cellular source for the production of Interleukin (IL)-16 in AD, which can be induced by the aggregation of FcɛRI on LC of atopic donors in vitro. It is therefore likely that IL-16 plays a major role in the initiation phase of AD (18, 19). Based on recent evidence thymic stromal lymphopoetin (TSLP), which is an IL-7 like cytokine, is produced in high amounts by keratinocytes in AD and seems to contribute to the initiation of the allergic cascade and the induction of LC migration into the lymph nodes (20). The TSLP stimulated DC prime naïve T-cells to produce soluble factors such as IL-5, IL-13 and tumor-necrosis-factor (TNF)-α and initiate the production of chemokines by DC such as macrophage-derived chemokine (MDC) or thymus and activation-regulated chemokine (TARC), which attract T-cells of the Th2 type (20).
Figure 1. The role of antigen-presenting cells in the skin. Allergens invading the skin because of the reduced epidermal skin barrier are taken up by FcɛRI-bearing dendritic cells, internalized and efficiently presented to T-cells. KC, keratinocytes; LC, Langerhans cells; Eo, eosinophils; Mo, monocytes; Tn, naïve T-cells; Tm, memory T-cells; TLSP, thymic stromal lymphopoetin; MDC, macrophage derived chemokine; TARC, thymus and activation regulated chemokine; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α.
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Indeed, precedence for a major role of IDEC in the exacerbation of AD arises from the finding that after successful topical treatment and clinical improvement of the skin lesions the number of IDEC decreases below the detectable level (22). This indicates that IDEC represent promising cellular targets for successful treatment strategies aimed at effectively breaking down the recurrent exacerbation of this chronic-inflammatory skin disorder.
It is of special notice that pDC, which are involved in anti-viral defense by the production of large amounts of IFN-α and IFN-β are present only in low amounts in the epidermis of AD patients in contrast to other inflammatory skin diseases such as Psoriasis vulgaris, Contact Dermatitis or Lupus erythematodes (23–25). The lack of this DC subset in AD might be one reason for the high predisposition of these patients for viral infections such as eczema herpeticatum, which represents a frequent complication of AD (23).