Target the Gene That Suppresses Autoimmune Diseases, Australian Scientists Say

by Gopalan on Nov 11 2007 12:39 PM

Target the Gene That Suppresses Autoimmune Diseases, Australian Scientists Say
Research on treatment of autoimmune diseases should focus on the gene Roquin, say Australian researchers.
It was in 2005 Dr Carola Vinuesa and Professor Chris Goodnow from The Australian National University discovered that such pathologies were linked to the gene Roquin, which can undergo a specific mutation that results in it instructing T cells to react against the self. Now the researchers lead an international team that reports in the journal Nature on exactly how a healthy Roquin gene prevents abnormal T-cell behaviour.

The immune system is the body's front line of defence against disease-causing invaders such as bacteria, viruses and parasites.

However, sometimes this formidable defender can turn against us - mistakenly attacking and damaging the body's own tissues. This case of mistaken identity is the cause of common autoimmune diseases such as type one diabetes, rheumatoid arthritis and lupus.

The two researchers found that Roquin gene played a vital role in preventing the immune system from attacking friendly cells. It suppresses the production of antibodies that target the body's tissues, to keep us safe from our own molecular weaponry.

Antibodies are proteins normally produced by the body in response to infection or immunisation. They bind to pathogens, neutralising them or preparing them for destruction by other immune cells.

B-cells are the antibody factories of the immune system. When they recognise a potential pathogen they begin to multiply and produce antibodies to bind to their target. To do this however, they need assistance from helper T-cells that have also recognised the same potential pathogen.

Roquin specifically stops self-reactive T-cells from providing this assistance to B-cells, preventing the production of antibodies that might target healthy tissue. T-cells that react to invading pathogens are not suppressed by Roquin, allowing the immune system to mount a powerful defence against foreign threats without accidentally attacking friendly cells.

When a mutation causes Roquin to stop working, the immune system loses one of its safeguards against autoimmune diseases like lupus and diabetes.

“Our findings hinge on the fact that the activities of a normal Roquin gene are orchestrated by parts of the genome until very recently considered to be "junk DNA",” said Dr Vinuesa from the John Curtin School of Medical Research (JCSMR) at ANU.

The discovery centres on a form of RNA, or Ribo Nucleic Acid. Most RNAs are thought of as messengers that carry information from a cell’s DNA blueprint so it can be written into proteins, the building-blocks of cells and tissues. But not all RNAs act as a messenger. Some small, non-protein-coding forms of the material, called microRNAs, actually induce the decay of messenger RNAs.

“This decay leads to reduction of the expression of proteins such as one called ICOS, that we have now shown can result in autoimmunity when it is over-expressed,” said Dr Di Yu from JCSMR, who performed most of the experiments leading to the discovery. “This is the first time that microRNAs have been linked to protection from autoimmune diseases.”

Once considered to be genetic junk, microRNAs are now thought to regulate up to 30 per cent of the genome, and have been recently shown to play an important role in the development of cancer and other diseases. “More and more scientists are beginning to think of genes as ‘RNA factories’,” said JCSMR’s Professor Chris Goodnow, who is also the Director of the Australian Phenomics Facility at ANU. “We’re learning more and more about how RNAs regulate critical processes related to cell development and the evolution of complex structures like the brain.”

The researchers said their work opened up the possibility of using RNA interference, or the microRNAs themselves, in the treatment of autoimmune diseases.