AIP IN AUTOIMMUNITY · AIP (Aire-Interacting Protein) regulates autoantigen expression
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2007-03-01 → 2010-02-28
- EU contribution
- €204,966
- Participants
- 2
- Scheme
- OIF
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Results in brief
Final Activity Report Summary - AIP IN AUTOIMMUNITY (AIP (Aire-Interacting Protein) regulates autoantigen expression)
Dysfunction of the immune system, due to breakdown of self-tolerance, is the cause of development of autoimmune diseases, and has serious, disabling and even fatal consequences. An increase of the mechanisms of immune tolerance to exogenous would also be beneficial in the context of organ transplantation, allergy and gene therapy. Thus, the knowledge of immunological mechanisms involved in tolerance represents a major challenge to improve both the understanding and treatment of autoimmune diseases but also those processes. The main objective of this project was to better understand the mechanisms of action of Aire gene in the central and peripheral tolerance. This work allowed us a better understanding of the involvement of the interaction of two types of cells (Aire expressing epithelial cells and dendritic cells) in deletion process of autoreactive T cells. We also showed that Aire expression is restricted to the thymus and not expressed in dendritic cells. In addition, Aire-deficient mouse only present a mild autoimmune phenotype and does not entirely mimic the human form of the disease. Interestingly, we found that Aire-deficient mice have more aggressive CD8 T cells than the normal mice. Although the mouse model has enabled substantial progress in this area, it seemed useful to develop a new animal model for which the physiopathology might be closer to those observed in mice. Thus, we are currently working on a new animal model in Aire-deficiency: in rats. We analysed the interactions between thymic epithelial cells that express Aire and thymic dendritic cells, two cell populations playing a major role in T cell tolerance. Indeed, we found that rat dendritic cell subsets were able to specifically kill thymic epithelial cells expressing Aire. Interestingly this killing activity was never found in mouse which supports the use of a rat model. We will also use this model to study the involvement of Aire in alloreactivity.
Data: CORDIS, © European Union
Project objective
APECED patients suffer from tissue-specific destructive autoimmunity, affecting principally endocrine organs. They indicate a profound defect in immune maturation, especially in the mechanisms leading to tolerance against self-antigens, which occur during negative selection in the thymus. AIRE, the mutated gene in APECED and necessary for maintenance of T-cell tolerance, is responsible for intrathymic expression of peripheral autoantigens. Indeed, AIRE has an activity of transcriptional regulator. However the exact mechanism how AIRE influences the transcription of autoantigens remains elusive. The knowledge about AIRE functional targets and partners will have a significant input to the understanding of AIRE in these processes and immune tolerance in general.Recently Hamish's group has discovered a new protein involved in epigenetic processes, which they are calling AIP (AIRE interacting protein). Only few things are known on this new and exiting molecule. Its expression and sub-cellular localization mirrors A IRE in the thymus in vivo and it also interact with AIRE in vitro. We purpose to analyse the role of AIP by multidisciplinary approach (genetic and immunology). Using uniqueness resources such as transgenics and KO technologies, we will study the general autoimmune phenomena in AIP KO mice. Then we will investigate the role of AIP in control of thymic selection and also the role of AIP in control of peripheral tolerance by cross presentation of self-antigens.
Original text from CORDIS.
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Data: CORDIS, © European Union