Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Immune system’s attack dogs kept on genetic leash

13.02.2004


Loss of restraint may contribute to lupus, other autoimmune disorders



When they’re not busy battling invaders, some of the cells that act as the attack dogs of the mouse immune system have to be kept on a genetic leash to prevent them from mounting inappropriate attacks on the mouse’s own tissues, researchers from Washington University School of Medicine in St. Louis have found.

The findings, reported in this week’s issue of Science, are the first scientific proof of a theory that could open up a significant new front in the battle to control autoimmune diseases like lupus, multiple sclerosis and diabetes.


"We used to think of mature immune cells like T cells and B cells as metabolically inactive when waiting for infections or other signals that trigger an attack," says Stanford Peng, M.D., Ph.D., assistant professor of internal medicine and of pathology and immunology. "We’re now thinking these resting cells actually are very metabolically active, and they are kept in a quiescent state by genes actively working to shut down activating proteins."

In the new study, Peng and colleagues showed for the first time that a gene, Foxj1, helps keep immune attack cells inactive. If malfunctions in this gene and others contribute to human autoimmune diseases, researchers may be able to develop new treatments that restore the genes’ functions and ease patients’ symptoms.

"Our efforts to develop new treatments have been focused on pathological targets in autoimmune diseases -- genes that are overused or are used inappropriately, leading to immune system attacks on self," Peng explains. "Another concept we should keep in mind is that the loss of one of these regulatory genes that keep the immune system in check also may be a primary contributing factor."

Peng notes, though, that errors in regulatory genes are unlikely to be the sole cause of a particular autoimmune disorder.

"You probably need multiple malfunctions in different genes to cause a severe autoimmune syndrome," he explains.

The Lupus Foundation of America estimates about 1.5 million Americans have lupus, which can cause arthritis, prolonged fatigue, skin rashes, kidney damage, anemia and breathing pain.

Many key symptoms of human lupus spontaneously appeared in lines of mice being bred for other purposes by various scientists in the 1960s and 1970s. Peng and colleagues compared the activity levels of different genes in cells from normal mice and from the mice that develop lupus. They measured how often cells used the genes to make messenger RNA, which is like an order slip for production of a copy of the gene’s protein.

"Although Foxj1 had never previously been shown to have an immune system role, cells of the mice with lupus were clearly making less RNA from this gene, and this is typically reflective of reduced activity on the part of the gene’s protein," Peng says.

When Peng’s group disabled the gene in the immune systems of normal mice, they developed a lupus-like syndrome, with inflammation in the salivary glands, lungs, kidneys and several other organs.

The protein made from the gene already was known to be a transcription factor -- a protein that promotes or suppresses the creation of proteins made from other genes. Peng found that lack of the Foxj1 protein increased activity of another transcription factor, NF-B.

"This protein belongs to a family of transcription factors heavily implicated in various types of inflammation," Peng says. "So our thinking is that without the protein, more NF-B is activated, possibly triggering the inappropriate activation of immune cells."

Peng speculates that other Fox gene family members may play an intrinsic role in keeping immune cells quiet or in preparing them to battle invaders.

"There’s not a lot known yet about the family of Fox genes," Peng says. "One member, Foxp3, has been linked to the development of regulatory T cells that suppress the activation of other immune cells. But that’s an external limit on cell activation. Foxj1 is the first gene to limit activity instrinsically, or from within the cell itself."

Peng continues to investigate the basic biochemistry of the gene, which also has been identified in humans. He hopes to look for signs of malfunction in the gene in humans with lupus and other autoimmune disorders.

"This may be relevant to other diseases beyond lupus," Peng says. "In diabetes, for example, it’s known that T cells, one of the cell types affected by this gene, attack the pancreas. In multiple sclerosis, T cells appear to attack the brain. So this gene may have a much more general role to play."


Lin L, Spoor MS, Gerth AJ, Brody SL, Peng SL. Modulation of Th1 activation and inflammation by the NF-B repressor Foxj1. Science, Feb. 13, 2004.

Funding from the Lupus Research Institute, the Arthritis Foundation, the National Institutes of Health, the Siteman Cancer Center, the Diabetes Research and Training Center and the Digestive Diseases Research Core Center of the Washington University School of Medicine supported this research.

Michael C. Purdy | WUSTL
Further information:
http://aladdin.wustl.edu/medadmin/PAnews.nsf/news/48AC43D9D7D4AC4486256E370075894A?OpenDocument

More articles from Life Sciences:

nachricht Bioenergy cropland expansion could be as bad for biodiversity as climate change
11.12.2018 | Senckenberg Forschungsinstitut und Naturmuseen

nachricht How glial cells develop in the brain from neural precursor cells
11.12.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Topological material switched off and on for the first time

Key advance for future topological transistors

Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...

Im Focus: Researchers develop method to transfer entire 2D circuits to any smooth surface

What if a sensor sensing a thing could be part of the thing itself? Rice University engineers believe they have a two-dimensional solution to do just that.

Rice engineers led by materials scientists Pulickel Ajayan and Jun Lou have developed a method to make atom-flat sensors that seamlessly integrate with devices...

Im Focus: Three components on one chip

Scientists at the University of Stuttgart and the Karlsruhe Institute of Technology (KIT) succeed in important further development on the way to quantum Computers.

Quantum computers one day should be able to solve certain computing problems much faster than a classical computer. One of the most promising approaches is...

Im Focus: Substitute for rare earth metal oxides

New Project SNAPSTER: Novel luminescent materials by encapsulating phosphorescent metal clusters with organic liquid crystals

Nowadays energy conversion in lighting and optoelectronic devices requires the use of rare earth oxides.

Im Focus: A bit of a stretch... material that thickens as it's pulled

Scientists have discovered the first synthetic material that becomes thicker - at the molecular level - as it is stretched.

Researchers led by Dr Devesh Mistry from the University of Leeds discovered a new non-porous material that has unique and inherent "auxetic" stretching...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

Expert Panel on the Future of HPC in Engineering

03.12.2018 | Event News

 
Latest News

Electronic evidence of non-Fermi liquid behaviors in an iron-based superconductor

11.12.2018 | Physics and Astronomy

Topological material switched off and on for the first time

11.12.2018 | Materials Sciences

NIST's antenna evaluation method could help boost 5G network capacity and cut costs

11.12.2018 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>