When Dr. Jakub Abramson was a 14-year-old boy in the former Czechoslovakia, he asked his father what was the best place to do science. His father took the question seriously and, after some consideration, answered “the Weizmann Institute of
Science.” Since that day, says Abramson, he knew he was bound for the Institute. “It’s just that the science I was interested in back then involved blowing things up,” he says.
Today, Abramson is more interested in exploding the common wisdom about autoimmune diseases. His lab at the Weizmann Institute has produced two new papers – one of them showing that an autoimmune disease so rare that most people have never heard of it has a more common form that could affect one in 1,000 people or more. Abramson’s lab worked together with that of Dr. Eystein S. Husebye in Norway. Husebye, a leading endocrinologist, had a patient whose symptoms pointed to the rare disease, which is recessive – caused by mutations in both copies of a particular gene called AIRE. But genetic testing showed that the patient had only one mutated copy of the AIRE gene. This surprising finding led the team to also check the patient’s family members, uncovering evidence for a milder disease associated with just one mutation. Subsequent studies led by the Norwegian and Weizmann scientists helped to elucidate the mode of action of these dominant mutations, as well as to demonstrate that they are significantly over-represented in patients suffering from various autoimmune syndromes.
This finding suggests that several autoimmune disorders for which the genetic cause was unknown may actually be caused by a specific mutation in one copy of the AIRE gene.
AIRE stands for AutoImmune REgulator. One mutation can cause a range of different symptoms because the autoimmune attack can affect pretty much any organ in the body. Abramson began investigating this gene in his postdoctoral research at Harvard Medical School, and his current research has led him to believe that it may be the key to various (but not all) autoimmune diseases for which the genetic factor has remained elusive.
The AIRE gene is only expressed in one organ – the thymus – and in one relatively rare type of cell, called mTEC. But every one of the immune system T cells must pass inspection by an mTEC before it is allowed out of the thymus and into the body. “Of course, the thymus does not have a brain,” says Abramson, “but the mTEC is a library of sorts – containing a comprehensive repository of self-antigens. That is, almost every one of the body’s genes is expressed in this cell. The process is one of negative selection – any T cell that is attracted to a self-antigen in the mTEC library gets eliminated in the thymus. So a slip-up at this stage could open the door to all sorts of autoimmune diseases.”
In the other paper, Abramson and his team identified a gene that regulates the AIRE master regulator. This gene, called Sirtuin 1 (Sirt1), is expressed in massive quantities in the mTEC cells – its levels are hundreds of times the norm – where it operates as an “on” switch for AIRE. This gene, interestingly enough, has previously been described as controlling diverse biological processes, including fertility, metabolism, stress responses and aging.
“We have uncovered yet another critical function for Sirt1 – the establishment of immunological self-tolerance in the thymus,” says Abramson. “We hope that this finding will provide an important basis for diagnosing all sorts of autoimmune syndromes for which the genetic cause is unknown. In the future, this may be very instrumental in designing new, 'personalized' strategies for treating these disorders. Indeed there is evidence that specific Sirt1 mutations are found in certain patients suffering from type1 diabetes." Whether Sirt1 mutations are also associated with other types of autoimmune disorders is currently under investigation by the Abramson-Husebye teams in follow up studies.