Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Infection-fighting protein could be key to autoimmune disease

12.01.2006


Scientists at the University of Michigan Medical School have discovered that a protein called cryopyrin responds to invading bacteria by triggering the activation of a powerful inflammatory molecule called IL-1beta, which signals the immune system to attack pathogens and induces fever to protect the body against infection.



The discovery could help scientists understand what causes autoimmune diseases like rheumatoid arthritis where the immune system attacks and destroys tissue in the patient’s body.

"IL-1beta is a master regulator of infection, and it’s known to be involved in the development of rheumatoid arthritis," says Gabriel Nunez, M.D., a professor of pathology in the U-M Medical School, who directed the research study. "So it’s likely that these findings will apply to other autoimmune diseases, as well."


In a study being published Jan. 11 as an Advance Online Publication in Nature, U-M scientists show, for the first time, that cryopyrin is activated by bacterial RNA and that it is essential to the cell’s ability to mount an effective defense against bacteria.

Found in the cytosol, or fluid inside cells, cryopyrin is a member of the NOD-LRR family of proteins, which protect cells against microbial infection. Defective cryopyrin is predicted to be associated with increased susceptibility to infection.

Small mutations in CIAS1 – the human gene for cryopyrin – are known to cause three rare autoinflammatory diseases: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease. People with these diseases produce uncontrolled amounts of IL-1beta and other inflammatory molecules. This causes them to have recurrent episodes of fever and to develop rashes – often when they are exposed to cold temperatures.

Based on previous research with cell lines, scientists suspected that cryopyrin was an important link between the immune system’s normal job of killing bacteria and the abnormal development of autoimmune diseases. But no one was sure exactly how cryopyrin was "turned on" in living animals or how it stimulated the immune response.

In previous research, the U-M team found that the single-point mutation in CIAS1 – which causes autoinflammatory syndromes in people – activates cryopyrin, even when there is no bacterial RNA present in the cell. "The mutation fools the cell into producing the activated form of cryopyrin, even when bacteria aren’t there," Nunez says.

To decipher cryopyrin’s signal, Thirumala-Devi Kanneganti, Ph.D., a U-M post-doctoral research fellow in pathology, studied immune cells called macrophages and several strains of laboratory mice. One of these strains was unable to produce cryopyrin, because the CIAS1 gene had been removed.

Kanneganti exposed the macrophages and mice to bacterial RNA and to small synthetic molecules called R837 (Imiquimod) and R848 (Resiquimod). These adjuvant molecules activate the pro-inflammatory response in mice and are used as anti-tumor agents and to treat genital warts caused by a virus in human patients.

"We found that cryopyrin was activated and the macrophages began secreting IL-1beta following stimulation with R837 or R848," Kanneganti says. "Since the structure of these molecules is very similar to DNA or RNA, we believe the natural ligand, or activating molecule, for cryopyrin could be DNA or RNA."

In previous research, other scientists discovered a signaling pathway in which molecules called toll-like receptors on the cell’s surface recognize invading bacteria and activate the immune response. But U-M scientists found that cryopyrin uses a different signaling pathway. Activated cryopyrin triggers an enzyme called caspase-1, which splits the immature form of IL-1beta to produce the active form of the molecule. Once IL-1beta is activated, it can be secreted out of the cell where it binds to the IL-1beta receptor on other cells to trigger an immune response.

"These two signaling pathways cooperate," Nunez explains. "The toll-like receptor pathway recognizes bacteria outside the cell, while cryopyrin recognizes bacteria that’s already in the cell. When a toll receptor on the membrane senses bacterial RNA, it activates a signaling pathway called NF-kappaB, which induces the production of IL-1beta. Cryopyrin does the same thing, but it works through caspase-1 to produce the active form of IL-1beta."

In her experiments, Kanneganti confirmed that the signaling pathway requires the presence of cryopyrin. Macrophages and mice that lacked the CIAS1 gene for cryopyrin were unable to generate an immune response when exposed to bacterial products.

The research was funded by the National Institute of Allergy and Infectious Diseases (NIAID). The University of Michigan has filed a patent application on this research technology.

Additional U-M collaborators on the study included Nesrin Ozoren, Mathilde Body-Malapel, Amal Amer, Jong-Hwan Park, Luigi Franchi and Joel Whitfield. Other collaborators were Winfried Barchet and Marco Colonna from the Washington University School of Medicine, Peter Vandenabeele from Belgium’s Ghent University, John Bertin, Anthony Coyle and Ethan P. Grant from Millennium Pharmaceuticals and Shizuo Akira from Japan’s Osaka University.

Citation: Nature DOI: 10.1038/nature04517

Sally Pobojewski | EurekAlert!
Further information:
http://www.umich.edu

More articles from Life Sciences:

nachricht Individual Receptors Caught at Work
19.10.2017 | Julius-Maximilians-Universität Würzburg

nachricht Rapid environmental change makes species more vulnerable to extinction
19.10.2017 | 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: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Rapid environmental change makes species more vulnerable to extinction

19.10.2017 | Life Sciences

Integrated lab-on-a-chip uses smartphone to quickly detect multiple pathogens

19.10.2017 | Interdisciplinary Research

Fossil coral reefs show sea level rose in bursts during last warming

19.10.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>