Die Rolle FcepsilonRl+ epidermaler dendritischer Zellen bei der Steuerung der kutanen Entzündungsreaktion im atopischen Ekzem
Zusammenfassung der Projektergebnisse
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-ß1 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-ß production of skin cells was analyzed. Tacrolimus and TGF-b1 act synergistically on the generation of LCs and the expression of CD40, CD80, CD86, CD83, and MHC II; stabilize TGF-ß 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-ß1 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. Based on the current disease concept, it is believed that deficient skin barrier in AD impacts on overactivation of DCs within the epidermis of AD. Therefore, identification of factors increasing the risk for impaired epidermal skin barrier as well as repetitive microbial infections represents a major issue in AD research. During the epidermal differentiation process, there is increasing expression of keratin proteins, which form the intermediate filament cytoskeleton on epithelial cells. Similarly, expression of desmosomal proteins increases as keratinocytes differentiate upwards and outwards in the epidermis, firmly anchoring the keratin network to cell membranes. Filaggrin, which consolidates the keratin filaments into dense bundles at the granular layer-stratum corneum boundary, represents an integral part of the epidermis and is crucial for the development of the cornified envelope to engineer and maintain the barrier function of the uppermost layer of the skin. We were able to identify inherited risk factors for impaired skin barrier and atopic sensitizations in the filaggrin-gen associated with AD in a subgroup of patients. Further on, we could show that polymorphisms in the Toll-like receptor (TLR)9 gene with AD might attenuate TLR9 mediated signaling in AD in response to stimulation with TLR-ligands. Finally, we could show that a deficiency to initiate strong IFN and CXCL10 production in response to stimulation with inactivated Herpes simplex virus (HSV) might predispose a subgroup of AD patients to recurrent virus infections of the skin.
Projektbezogene Publikationen (Auswahl)
- Different expression of adhesion molecules and tetraspanins of monocytes of patients with atopic eczema. Allergy 2006; 61(12):1419-22
Jockers JJ, Novak N
- Clinical improvement and immunological changes in atopic dermatitis patients undergoing subcutaneous immunotherapy with a house dust mite allergoid: a pilot study. Clin Exp Allergy 2007; 37(9):1277-85
Bussmann C, Maintz L, Hart J, Allam JP, Vrtala S, Chen KW, Bieber T, Thomas WR, Valenta R, Zuberbier T, Sager A, Novak N
- Filaggrin Mutations Strongly Predispose to Early-Onset and Extrinsic Atopic Dermatitis. J Invest Dermatol 2007; 127(3): 724-726
Weidinger S, Rodriguez E, Stahl C, Wagenpfeil S, Klopp N, Illig T, Novak N
- Putative association of a TLR9 promoter polymorphism with atopic eczema. Allergy 2007; 62(7):766-72
Novak N, Yu CF, Bussmann C, Maintz L, Peng WM, Hart J, Hagemann T, Diaz-Lacava A, Baurecht HJ, Klopp N, Wagenpfeil S, Behrendt H, Bieber T, Ring J, Illig T, Weidinger S
- Risk factors of atopic dermatitis patients for eczema herpeticum. J Invest Dermatol 2007; 127(5):1261-3
Peng WM, Jenneck C, Bussmann C, Bogdanow M, Hart J, Leung DY, Bieber T, Novak N
- Tacrolimus and TGF-ß act synergistically on the generation of Langerhans cells. J Allergy Clin Immunol 2008; 122(1):126-132
Kwiek B, Peng WM, Allam JP, Langner A, Bieber T, Novak N
