Introduction
Scientific objectives
Last updated 2006-01-19
The main objective is to utilize our unique position and pool of collected expertise in Aire and APS I to create increased understanding of the molecular mechanisms underlying loss of tolerance in this disease and in autoimmune disorders in general. New strategies for early and specific diagnosis of this monogenic autoimmune disease will be developed to enable early intervention in the disease process or even before the development of disease in at risk individuals.
In order to achieve this objective the consortium will:
-Establish a pan-European database and biobank for defined clinical phenotypes to facilitate standardised diagnostic and clinical practices for the care and monitoring of patients with APS 1.
- A database on European APS I patients and a dedicated website for clinicians and patients will be made.
-Elucidate why certain tissue-specific proteins are selected as targets by the immune system and why the immune system seems to specifically present and target protein sequences that are evolutionally conserved.
- Techniques for tetramer analysis of T cell responses against defined autoantigen derived peptides and MHC class I complexes will be established.
-Identify genes that can modify the intensity and/or the course of the disease process in animal models for the disease.
- Aire deficient mice on different genetic backgrounds and crosses will be generated.
-Determine the gene expression profile of cells that are competent or incompetent to express Aire and clarify the pathways involved in the function(s) of the Aire gene product in different cell types.
-Affymetrix mRNA expression profiles will be established of isolated thymic medullary epithelial cells compared to induced and non-induced monocytic cells compared to cells unable to express Aire.
-Elucidate the propensity for superficial mucocutaneous Candida infection that affect most APS I patients both at the T-cell level and at the level of innate immune system, e.g. alteration of antimicrobial peptides.
- Assess if autoimmunity against defensins or other antimicrobiological peptides accounts for the propensity to develop Candida infections in APS I patients.
It is important to stress the interdependencies between the different objectives. Most of the project time these will run in parallel and deliver and respond to outcomes that have not beforehand been anticipated to alter the design of coming experiments in all work packages.