AIRE-TOP2A

The Role of Topoisomerase 2a in Aire-mediated Induction of Immunologic Tolerance

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

T lymphocytes are the body's immunological weapons, capable of killing invading pathogens. A European study is investigating how these cells can turn against self and attack the body's own organs causing autoimmunity.

Descrizione progetto (Article)

Central to a functional immune system is the education of T cells to distinguish foreign from self antigens.

This is facilitated through a process in the thymus known as negative selection, where T cells that can recognise self antigens are eliminated.

When this process goes wrong, it leads to severe cases of autoimmunity such as diabetes.Emerging evidence suggests that the negative selection process does not educate T cells against blood-circulating antigens only but also against antigens encountered in parenchymal tissues such as the brain.

This occurs through a specialised cell population in the thymus known as medullary thymic epithelial cells (mTECs), which express thousands of genes even those restricted to parenchymal organs (peripheral-tissue-antigen (PTA) genes).

PTA gene regulation has been recently attributed to the Autoimmune regulator (Aire) protein.Scientists in the EU-funded 'The Role of Topoisomerase 2a in Aire-mediated Induction of Immunologic Tolerance' (AIRE-TOP2A) project have set out to understand the molecular mechanisms behind Aire-mediated regulation.

In particular, they are looking into the interacting molecular partners of Aire.Analysis so far has revealed a number of transcriptional control elements that directly interact with Aire to form a multi-molecular complex.

Results indicate that Aire impacts its partner topoisomerase-2a, an enzyme that usually cuts DNA to facilitate excessive winding during DNA replication.

This Aire-mediated mechanism on topoisomerase-2a resembles the action of the anti-cancer drug etoposide to induce DNA double-strand breaks.These findings have encouraged researchers to further dissect this mechanism and address the requirement for the Aire-Topoisomerase-2a association in PTA gene expression in the thymus.

Additionally, the study will explore whether etoposide treatment could restore the immunological tolerance in patients with a mutated AIRE gene suffering from the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

Taken together, these approaches are expected to provide fundamental knowledge on the mechanisms of negative selection of T cells.

Furthermore, the outcome of the AIRE-TOP2A study has clinical extrapolations as it will shed light onto the health issue of autoimmunity.