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Newswise (NEW YORK - Oct. 15) A team led by researchers at The Rockefeller University and the Icahn School of Medicine at Mount Sinai has explained the function of key immune protein and solved an international medical mystery, according to a letter published this week in the journal Nature.

In previous work, the research team lead had linked small changes in a key gene with a reduced ability to fight off a set of rare bacterial infections. Shortly afterward, a team of Chinese scientists reached out to say they had found three Chinese children with mutated versions of the same gene. Strangely, the Chinese children had no history of the severe bacterial infections, but instead had seizures and unusual calcium deposits in their brains.

The disconnect led to the discovery of an immune protein with two seemingly opposing roles: amplifying and tamping down aspects of an immune system response, according the study, published on Sunday, Oct. 12. The roles explained how the protein, or lack of it, could weaken response to an infectious disease in one instance, but contribute to the attack by the immune system on a persons own tissues (autoimmune disease) in another.

It has turned out that mutations in a single gene eliminates the immune protein ISG15, giving rise to two different problems: an inability to resolve harmful inflammation, which can lead to autoimmune disease, and susceptibility to infections caused by the tuberculosis bacterium and its cousins, said Jean-Laurent Casanova of the St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller. By identifying the source of this genetic disorder, we have taken a first step toward finding treatments for those facing the autoimmune disease and severe TB-related infections it may produce.

When under attack, the immune system releases signaling proteins known as interferons, which further activate the bodys defenses. In previous research, Dusan Bogunovic, PhD, Assistant Professor at the Department of Microbiology at Icahn School of Medicine at Mount Sinai and study author, had linked a lack of ISG15 to an unusual vulnerability to infections by mycobacteria, a group of common bacteria that include the tuberculosis bug.

He and colleagues had previously found children, one from Turkey, two from Iran, who became severely ill after receiving the anti-tuberculosis BCG vaccine. Normally, ISG15 protects against infection by mycobacteria by prompting the release of type 2 interferon, but all three children had two copies of a defective form of the ISG15 gene, and became infected by a TB-related component of the vaccine.

When Bogunovic and his colleagues reported this link publically, scientists in China reached out saying they had also seen loss-of-function mutations in three patients, all from a single Chinese family. But none of these three had had unexplained mycobacterial infections, such as those caused by the vaccine.

We asked why these children were patients; our Chinese colleagues said these kids had seizures, said Dr. Bogunovic. When we looked into their BCG vaccination history, we found these children, who were born at home in a remote village, never received their shots, so they never became sick.

The rest is here:

Genetic Defect Links Rare Infections to Autoimmune Diseases