Network of Myeloid DCs in AD

DCs as antigen-presenting cells are outposts of the immune system, which are located at the border zones of the body to the environment. Since they have been discovered over a century ago in 1868 by Paul Langerhans, they remained enigmatic and fascinated researchers all over the world (Jolles 2002). With the help of their dendrites, they form a sophisticated network within the epidermis and encounter foreign antigens. Subsequently, they internalize these antigens, secret cytokines, process them, migrate to the lymph nodes, and present the processed antigens to T cells. Obviously, their function of antigen uptake and presentation as well as T cell priming is of particular immunologic importance in diseases with an impaired epidermal skin barrier such as AD (Cork et al. 2006). This impaired skin barrier has been shown to result partially from genetic modifications in genes encoding important proteins of the epidermal differentiation complex such as Filaggrin or S100 (Weidinger et al. 2006; Palmer et al. 2006; Cookson 2004). Together with an increased water loss and shift of the pH, this contributes to the fatal "loss" of the skin barrier as a protective shield in AD patients, which allows foreign antigens to invade easily into the skin (Strid and Strobel 2005). As a basic principle, two different types of DCs are known to regulate the immune haemostasis in our body: First, the so-called myeloid DCs, which express the DC marker CD 1a. Myeloid DCs are

CD11c+CD123- and suspected to encounter a high number of immune reactions, which lead to immunity (Bonasio and von Andrian 2006).

The most prominent members of this class of DCs are the classical Langerhans cells (LCs), which are characterized by the Birbeck granules, electron-microscopically visible as tennis racket-shaped organelles originating from the accumulation of the C-type lectin Langerin (Villadangos and Heath 2005). LCs reside in both, healthy and inflamed skin and are constantly renewed under steady-state conditions. As a characteristic feature of AD, LCs are equipped with the high-affinity receptor for IgE (FceRI) on their cell surface, which enables them to take up allergens penetrating into the skin (Villadangos and Heath 2005). In vitro studies of LCs combined with Atopy-patch test results in which type I allergens applied to the skin induce an eczematous reaction within 24-48 h in sensitized individuals, provide evidence that LCs are in the foreground in the initial phase of AD (Novak et al. 2004b). LC are capable of taking up invading allergens and presenting these allergens to T cells (Kerschenlohr, Decard, Przy-billa, and Wollenberg 2003). In this step, primarily T cells of the Th2 type are primed by LCs in vitro, which are characterized by the production of IL-4, IL-5, and IL-13, typical for the initial phase of AD (Novak et al., 2004b). Other factors, such as the release of thymic stromal lymphopoietin (TSLP) by keratino-cytes, are suspected to aggravate this DC-mediated Th2-immune response (Wang et al. 2006). Further on, allergen challenge and concomitant IgE receptor cross linking on LCs or activation by microbial products such as staphylococcal enterotoxins lead to the release of different chemotactic mediators, which together with soluble factors contribute to the recruitment of other cell types such as inflammatory dendritic epidermal cells (IDECs) from their precursor cells from the blood into the skin (Gunther et al. 2005; Pivarcsi et al. 2004; Homey et al. 2006).

IDECs are only present at inflammatory epidermal sites and bear significantly high numbers of FceRI in combination with CD11b molecules and the mannose receptor (CD206) on their cell surface but are Langerin (CD207)-negative DCs (Wollenberg et al. 1995; Stary, Bangert et al. 2005). In time, kinetics acquired with the help of atopy patch tests, invasion of IDECs into the epidermis within 24-48 h after allergen application, and concomitant up-regulation of FceRI expression on LCs and IDECs in the developing skin lesions has been observed (Kerschenlohr et al. 2003), supporting the view of a two-step model directed by DC subtypes in AD (Figure 1) Due to their high ability to release distinct pro-inflammatory mediators after IgE receptor-mediated allergen challenge, it is assumed that IDECs are the main dendritic amplifiers of the epidermal allergic-inflammatory reaction in AD. Allergen challenge of IDECs in vitro leads, beside the release of proinflammatory cytokines and chemokines, to the production of IL-12 and IL-18, which might contribute to the alteration of the initial Th2-immune micromilieu to the predominance of interferon (IFN)-y-producing T cells in the skin, which seem to be a crucial step for the chronification of the skin lesions (Novak et al. 2004b; Grewe et al. 1995).

Filaggrin Gene Atopic Dermatitis

Figure 1 Network of Langerhans cells (LCs) and inflammatory dendritic epidermal cells (IDECs) in the epidermis of atopic dermatitis (AD) patients. (A) LC residing in the epidermis capture pathogens, secret cytokines/chemokines, process antigens, migrate to the lymph nodes, and present them to T cells. In the lymph node, LC prime large amounts of Th2 cells, which produce high amounts of Th2 cytokines such as IL-4, IL-5, and IL-13. (B) Allergen challenge and concomitant IgE receptor cross linking on LC or activation by microbial products lead to the release of different chemotactic mediators, which together with soluble factors contribute to the recruitment of IDECs into the skin. IDEC present at inflammatory epidermal sites and bear significantly high numbers of FcgRI on cell surface. Allergen challenge of IDEC in vitro leads to the production of IL-12 and IL-18 and release of pro-inflammatory cytokines and chemokines, which might contribute to the amplification of the allergic-inflammatory reaction and alteration of the initial Th2-immune micromilieu to the predominance of IFN-y-producing Th1 T cells in the skin, which seem to be a crucial step for the chronification of the skin lesions. MHC, major histocompatibility class; TCR, T cell receptor.

Figure 1 Network of Langerhans cells (LCs) and inflammatory dendritic epidermal cells (IDECs) in the epidermis of atopic dermatitis (AD) patients. (A) LC residing in the epidermis capture pathogens, secret cytokines/chemokines, process antigens, migrate to the lymph nodes, and present them to T cells. In the lymph node, LC prime large amounts of Th2 cells, which produce high amounts of Th2 cytokines such as IL-4, IL-5, and IL-13. (B) Allergen challenge and concomitant IgE receptor cross linking on LC or activation by microbial products lead to the release of different chemotactic mediators, which together with soluble factors contribute to the recruitment of IDECs into the skin. IDEC present at inflammatory epidermal sites and bear significantly high numbers of FcgRI on cell surface. Allergen challenge of IDEC in vitro leads to the production of IL-12 and IL-18 and release of pro-inflammatory cytokines and chemokines, which might contribute to the amplification of the allergic-inflammatory reaction and alteration of the initial Th2-immune micromilieu to the predominance of IFN-y-producing Th1 T cells in the skin, which seem to be a crucial step for the chronification of the skin lesions. MHC, major histocompatibility class; TCR, T cell receptor.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment