10:19am Friday 06 December 2019

Genetic Defect Links Rare Infections to Autoimmune Diseases

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 person’s 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 body’s 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 team next looked back at our first set of patients. None of them had ever had seizures, but researchers performed brain scans that found abnormal calcium deposits in a deep part of the brain involved in controlling movement — just like the deposits in brains of the Chinese children.

The researchers recognized the calcium deposits as a feature of a group of autoinflammatory diseases, including the neurodevelopmental disorder Aicardi-Goutieres syndrome. These are thought to occur when type 1 interferon, which normally helps fight viral infections, triggers harmful and unnecessary inflammation, leading to disease. When Bogunovic and his colleagues then looked for evidence something similar was happening to the all six patients, they found unusually high expression of genes stimulated by type 1 interferon.

Using cells from the patients, the researchers found that when they restored the ISG15 gene, the cells became able to resolve the inflammation. Further experiments performed in collaboration with Sandra Pellegrini at the Pasteur Institute in Paris, France, revealed the mechanics that linked a lack of ISG15 with an increase in type 1 interferon signaling: Under normal conditions, ISG15 prevents the degradation of another protein, USP18, which is responsible for turning down the dial on type 1 interferon. With no ISG15, and as a result, little USP18, interferon becomes too active.

The six children all showed elevated levels of autoantibodies, immune proteins that mistakenly attack the body itself, suggesting that in time they will likely develop autoimmune disease.

“With this knowledge, we hope they can monitor and properly treat this condition, just as we now know to avoid the BCG vaccine and other possible sources of mycobacterial infection in patients,” said Dr. Bogunovic. “Ultimately, ISG15 deficits may be included in genetic screening tests for infants to make early detection widely available. No treatments exist for many autoimmune disorders, but our work advances our understanding of them and the prospects for finding cures.”

About the Mount Sinai Health System
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community‐based facilities to tertiary and quaternary care.


The System includes approximately 6,600 primary and specialty care physicians, 12‐minority‐owned free‐standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.

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