In a functional immune system, T cells serve as potent immunologic weapons, attacking foreign invaders, while tolerating the body’s own components. Unfortunately, these beneficial weapons can occasionally turn against self and attack the body’s own organs, resulting in autoimmunity. One of the most common reasons for this phenomenon is that the body fails to properly educate T cells on how to distinguish between self and non-self (foreign invader). These mis-educated cells then remain in the body where they can potentially cause autoimmunity by attacking its own organs. Recently a rare cell population of the thymic stroma, called the medullary epithelial cells (MECs), was shown to play a very fundamental role in this process. Namely, these cells have the amazing capacity to express essentially all body antigens, and in particular those, whose expression was previously thought to be restricted only to peripheral organs (e.g. pancreas). Hence, expression and a subsequent presentation of these peripheral-tissue-antigens (PTAs) to the differentiating thymocytes help to purge self-reactive T cells that could potentially cause autoimmunity. Many of these ectopic transcripts are regulated by the product of a single gene, the Autoimmune regulator (Aire), as mice with a mutation in this locus express only a fraction of the PTA repertoire and develop a multiorgan autoimmunity. Recently, we provided very significant insights into the Aire’s mode of action, by identification of its molecular partners. The research proposed herein is a direct continuation of these groundbreaking findings and specifically focuses on one of the most important and promising Aire-interacting partners – Topoisomerase 2a (TOP2a). The major objectives are to verify TOP2a significance under in vivo conditions, further delineate its mode of action, as well as to test whether its specific modulator – Etoposide could revert the onset of autoimmunity in Aire-deficient animals.
Field of science
- /medical and health sciences/basic medicine/immunology
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