       Links
       Contact
       Terms - Privacy

Division of Immunopathology
Department of Pathophysiology and Allergy Research
Center of Pathophysiology, Infectiology & Immunology

Medical University of Vienna

Vienna General Hospital, AKH, 3Q
Waehringer Guertel 18-20
A-1090 Vienna, Austria

T-cell autoreactivity-A pathogenetic principle in atopic dermatitis? [Stingl]

Project summary 2005 - 2006

The Achilles heel in the clinical management of AD is the chronic relapsing course of the disease and the lack of a specific therapy. New insights into the pathogenesis of AD are urgently needed to allow the development of new disease-specific therapeutic interventions. This study is designed to elucidate the role of T cell autoreactivity in the pathogenesis of AD.
The hypothesis that autoreactive T cells play a role in the pathogenesis of AD gained support from studies describing the occurrence of autoreactive IgE antibodies to different human proteins in a large number of AD patients. We propose that IgE autoantibodies are indicative of a T cell autoimmune response providing incidental B cell help. We further propose that an autoantigen can be presented more efficiently via IgE and its corresponding high affinity receptor on antigen presenting cells (APC) than in the conventional manner, similarily to what has been described for IgE-bound environmental antigens. The project focuses on the search and, if successful, on the characterization of autoreactive T cells with the aim to investigate their pathogenetic relevance in AD. We plan to investigate i) the APC-based restriction elements and the T cell recognition structures for autoantigens; ii) the activation requirements of autoreactive T cells and the role of APC-bound FceRI in the presentation of IgE-autoantigen complexes; iii) the quality of autoreactive T cells (immunophenotype, cytokine expression pattern, effector or regulatory functions in vitro and in vivo, the signals governing migration and homing properties of autoreactive T cells; iv) strategies to down-regulate autoreactive T cell responses. The longterm goals are 1) the development of strategies aimed at silencing (anergy, suppression, deletion) autoreactive T cells and 2) the identification of autoantigen peptide epitopes that drive AD and the development of specific inhibitory peptides to these moieties
Background: Atopic dermatitis (AD) is a high prevalence chronic relapsing inflammatory skin disease. It is frequently associated with IgE-mediated type I reactions to exogenous antigens. Increasing evidence indicates that IgE-mediated type I reactions in AD are not only driven by exogenous antigens but also by endogenous antigens.
Hypothesis: We propose that IgE autoantibodies present in AD patients are indicative of a T-cell autoimmune response providing incidental B-cell help.
Aim of the study: Characterization of autoreactive T-cells with the aim to investigate their pathogenetic relevance in inducing skin inflammation.
Experimental design: Autoantigen-specific T - cell cultures, lines, and clones will be obtained and phenotypically and functionally characterized. In a complementary approach, gene expression monitoring will be applied to identify patterns possibly linked to autoreactivity. The in vivo relevance of autoantigen-specific T - cells will be tested in the human skin explant/SCID mouse transfer system. Whether autoreactive T – cells are able to elicit eczematous reactions in clinically well-characterized patients will be evaluated using appropriate skin tests.
Long term goal: The longterm goals are 1) the development of strategies aimed at silencing (anergy, suppression, deletion) autoreactive T – cells and 2) the identification of autoantigen peptide epitopes that drive AD and the development of specific inhibitory peptides to these moieties.