June 13, 2005 A new gene suspected to contribute to autoimmune diseases such as type 1 diabetes and lupus -- a condition in which the body's own immune system attacks organs such as the kidneys and skin -- has been discovered by Australian National University immunologists.
The researchers found that a mutation in the gene, which they have named Roquin, causes the body's infection fighters -- T-cells -- to attack their own tissue; the realisation opening the way to explore treatments that target the mutation.
Studies of the gene are underway in patients with lupus -- which affects one in 700 women of childbearing age -- and type 1 diabetes to determine whether the same or similar mutations observed in laboratory mice are present in humans.
"This could reveal other abnormalities that underpin autoimmunity, and open up opportunities for developing specific treatments and drugs," said lead researcher Dr Carola Vinuesa, from the John Curtin School of Medical Research (JCSMR) at ANU.
The discovery of Roquin was revealed in the latest edition of Nature magazine.
The researchers mirrored the spontaneous genetic variation that occurs naturally during population growth by introducing random changes in the mouse genome, generating novel models of autoimmune disease. After identifying signs of lupus, they worked backwards to find the altered gene responsible for the condition.
"Before this study, the existence and function of Roquin was not known. However, we now know that in the immune system of mammals, the protein Roquin usually suppresses the activity of forbidden T-cells that bind to parts of the body.
"We found that a single mutation in Roquin causes these T-cells to be abnormally activated, and results in autoimmunity affecting many different parts of the body," Dr Vinuesa said.
Autoimmune disease occurs when the immune system is activated to mount a response against normal tissue in the body, treating it as if it were a germ and damaging and destroying the tissue. For example, in type 1 diabetes, an immune response is mounted against the insulin-secreting cells of the pancreas; in lupus, virtually any part of the body can be attacked by the immune system.
According to Professor Christopher Goodnow, the Head of the Immunogenomics Laboratory at JCSMR and Director of the Australian Phenomics Facility, the discovery hinged upon identifying a single letter change in the DNA code of Roquin.
"It's one very small part of the genome that has proven a very big breakthrough. That single nucleotide change reduces the function of an autoimmunity gene and protein that was hithertoentirely unknown.
According to Professor Goodnow, the characteristics of the Roquin protein suggest that it might repress immune cells by silencing the communication channel between genes and cell functions.
"Roquin stops T-cells from displaying a stimulatory receptor, ICOS, that may cause the cells to attack normal body tissues. Therefore this gene seems critical in protecting us from autoimmunity -- but it only takes the mutation of one letter in that gene to cripple its function and lead to autoimmune disease.
"This finding immediately opens up research into testing the function of Roquin, examining variants that may explain autoimmune disease and working towards discovering drugs that might increase or decrease the activity of the newly-realised process."
The discovery was part of a research program into autoimmune diseases by the John Curtin School of Medical Research, the Australian Phenomics Facility, the ANU Medical School and Oxford University, Professor Goodnow said.
"The specific work described stems from a Wellcome Trust Programme between ANU and Oxford University, and its intersection with a separate Juvenile Diabetes Research Foundation and National Health and Medical Research Council special program in diabetes.
"These represent ambitious efforts to pioneer a new way to connect genes with immune system control mechanisms in diseases such as systemic lupus erythematosus and type 1 diabetes."
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