Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Single Gene Links Susceptibility to Rare Infections with Predisposition to Autoimmune Disease


The mutations were familiar, but the patients’ conditions seemed baffling at first. A team lead by Rockefeller University researchers had linked variations in an immune gene to rare bacterial infections. Shortly afterward, Chinese scientists told them of three children in that country with mutated versions of the same gene. However, the Chinese children had no history of the severe bacterial infections. Instead, they had seizures and unusual calcium deposits deep in their brains.

This discrepancy led to the discovery of an immune protein with paradoxical roles: It both aids and tamps down aspects of an immune system response, according to research conducted in Jean-Laurent Casanova’s St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller in collaboration with scientists in China and elsewhere. The team’s report was published today (October 12) in Nature.

An unexpected link: Researchers found abnormal calcium deposits, a feature of certain autoinflammatory diseases, in the brains of all six patients who lack the immune protein ISG15. Above, the deposits appear as white spots in scans from two patients.

“It has turned out that mutations in a single gene eliminate 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,” Casanova says. “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, a former postdoc in the lab now an Assistant Professor at the Department of Microbiology at Icahn School of Medicine at Mount Sinai, linked a lack of ISG15 to an unusual vulnerability to infections by mycobacteria, a group of common bacteria that include the TB bug.

He and colleagues found three 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.

After this discovery, ISG15’s story continued to unfold. Bogunovic and his colleagues reported this link, and then scientists in China reached out saying they had also seen loss-of-function mutations in three patients, all from a single family. But none of these three had had unexplained mycobacterial infections, such as those caused by the vaccine.

“We asked, why were they patients?” Bogunovic recalls. “Our Chinese colleagues said these kids had seizures; in fact, one child had died from them. 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. Next we looked back at our first set of patients. None of them had ever had seizures, but we 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, runs amok, triggering harmful and unnecessary inflammation, leading to disease. When Bogunovic and his colleagues then looked for evidence something similar was happening to the 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. “However, with this knowledge, we hope they can monitor and properly treat this condition, just as they know now to avoid the BCG vaccine and other possible sources of mycobacterial infection,” Bogunovic says.

“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, as a result, the prospects for finding cures.”

Contact Information

Zach Veilleux

Zach Veilleux | newswise

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>