Discovery unlocks sectrets of Down syndrome immune defects

Scientists at the Monash Institute of Reproduction and Development's Centre for Functional Genomics and Human Disease have identified a transcription factor gene on chromosome 21 that may help to explain the immune system defects common to Down syndrome patients.

Individuals with Down syndrome, caused by an extra copy of chromosome 21, have a variety of problems affecting most of the major organ systems of the body, including immune system defects that lead to a compromised immune system and increased susceptibility to immune diseases, as well as an increase in the incidence of some cancers, including leukaemia.

Many of the problems associated with Down syndrome are thought to be due to overexpression of the 250 genes on chromosome 21.

Using a mouse model over-expressing the Ets2 gene, the Monash IRD researchers have started to unravel how this transcription factor contributes to Down syndrome, and other diseases.

Dr Paul Hertzog, who along with Dr Ernst Wolvetang and Dr Trevor Wilson is involved in the project, said that the mouse had changes in the thymus, brain and skeletal system. But when the mouse was examined closely, the researchers found that the underlying phenomenon at work was an increased rate of apoptosis, or programmed cell death.

"The mice with extra Ets2 have an increase in the death of their immune cells, similar to what occurs in people with Down syndrome. The increase of Ets2 activates a pathway in cells of the thymus that causes the immune cells to destruct. In the mouse model, the size of the thymus is visibly reduced," said Wolvetang.

But the scientists have also discovered that the action of Ets2 is dependent on another gene, which plays a major role in many cancers, the p53 gene. According to Hertzog, Ets2 has long been suspected of playing a role in the development of certain cancers, but conflicting reports of its involvement in apoptosis had confused the issue.

By crossing the mouse with overexpressed Ets2 with a p53 knockout mouse, the researchers were able to show that cell death was prevented, confirming the interaction of the two genes, and giving clues to the mechanism involved.

"This finding is exciting because we are now looking at the factor Ets2 as a target for treatment. If we are able to inhibit the cooperation between Ets2 and p53 we might be able to stop the destruction of the thymus and the immune cells in people with Down Syndrome, and improve their response to infection and quality of life," Hertzog said.

"An interesting sideline is that the discovery probably explains the controversy about the function of Ets2 in cancer."

Hertzog said the researchers were now focused on teasing out the details of the interaction. In addition to possible benefits to patients with Down syndrome, modulation of Ets2 expression may also have therapeutic benefits for other immune disorders including cancer, inflammatory diseases and even neurodegenerative disorders.

The Centre for Functional Genomics and Human Disease is part of the CRC for Chronic Inflammatory Disease, along with the University of Melbourne, the University of Queensland and AstraZeneca.

Reference: EJ Wolvetang, TJ Wilson, E Sanij, J Busciglio, T Hatzistavrou, A Seth, PJ Hertzog, and I Kola. "ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway" Hum Mol Genet 2003 12: 247-255.