Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps research scientists find key culprits in lupus

02.07.2009
The more than 1.5 million Americans with systemic lupus erythematosus (or lupus) suffer from a variety of symptoms that flare and subside, often including painful or swollen joints, extreme fatigue, skin rashes, fever, and kidney problems. Researchers at The Scripps Research Institute have now identified the main trigger for the development of this disease.

Lupus is one of several autoimmune diseases in which the immune system turns against parts of the body, destroying the very cells and tissues it is meant to protect.

In a study published in the Early Edition of the Proceedings of the National Academy of Sciences (PNAS) the week of June 29, 2009, Scripps Research Professor of Immunology and Microbial Science Dwight Kono and colleagues demonstrate that three proteins, called Toll-like receptors (TLRs), are necessary for this autodestruction to occur. TLRs may thus provide effective targets for the development of new treatments for lupus, as well as other autoimmune diseases.

The Double-Edged Sword of Immunity

In response to infection, a healthy immune system produces antibodies—proteins that fight and destroy invading pathogens such as viruses, bacteria, and other foreign substances. But in lupus something goes awry with the chain of events leading to antibody production. As a result, the immune system produces "autoantibodies" against some of the body's own molecules, cells and tissues.

TLRs are proteins found in immune cells that normally help stimulate the initial response of the immune system to foreign pathogens. Humans have 10 different types of TLRs. Some of them sit on the surface of immune cells and seek out molecules that appear on the coating of bacteria and viruses. Other TLRs—TLR 3, TLR7, (TLR 8 in humans, but not mice), and TLR 9—reside inside immune cells, in a compartment known as the endolysosome, where bits of foreign substances usually end up.

When bacteria or viruses enter the body, some are engulfed by immune cells and degraded in the endolysosome. Inside this compartment, resident TLRs come across the bacterial and viral debris. These TLRs specifically detect the genetic material of pathogens—viral DNA, viral RNA, and bacterial DNA—and stimulate immune cells to produce antibodies against these molecules.

But the production of antibodies against foreign DNA and RNA seems to be particularly prone to error. The most common types of autoantibodies found in lupus patients are ones to the body's own genetic material—the DNA and RNA that resides inside the cell's command center, or nucleus. As a result, doctors often test for the presence of "antinuclear" antibodies to diagnose lupus.

"That's the Achilles heel," says Kono. "These endolysosomal TLRs are needed for viral and bacterial immunity, but they open the possibility of self reactivity."

Toll-Like Receptors and Lupus

Scientists don't quite know how antinuclear antibodies develop, but have suspected for some time that TLRs might be involved. By engineering mice that lack either TLR 7 or TLR9, scientists have gathered evidence that these TLRs may play a role in the disease.

"Earlier studies had strongly suggested that endolysosomal TLRs were important, but if you eliminate one or the other you do not get a huge effect," says Kono. "So we asked, 'What happens if you get rid of all the endolysosomal nucleic acid-sensing TLRs at once?'"

To answer this question, Kono and colleagues took advantage of strains of laboratory mice prone to lupus. These mice spontaneously develop many of the same signs and symptoms as humans with the disease. The next step was to eliminate TLR 3, TLR 7, and TLR 9 in these lupus-prone mice.

But how do you get rid of three proteins at once? Kono and colleagues knew that these TLRs need to be transported to the endolysosome to function. They also knew that one particular protein, called UNC-93B, produced by a gene called Unc93b1, serves as an essential "taxi" service. The UNC-93B protein attaches itself to TLR 3, TLR 7, and TLR 9 and facilitates their transport from the compartment in the cell where they are made to the endolysosome.

Using geneticists' tools of the trade, Kono and colleagues, engineered lupus-prone mice with an inactive Unc93b1 gene. Compared to lupus-prone mice with a functioning Unc93b1 gene, the mice with the Unc93b1 mutation produced fewer antinuclear antibodies and had fewer and less severe symptoms of lupus.

As a further test, Kono and colleagues treated the mutant mice with a substance that stimulates TLR 4—as TLR 4 stimulation is known to promote the production of autoantibodies. But even with TLR 4 stimulation, the mice lacking functioning TLR 3, TLR 7, and TLR 9 did not develop lupus.

"It seems like these three TLRs are absolutely required for optimal autoantibody production," says Kono. "This is an important finding that builds on results obtained by other groups."

The results "suggest that the three endosomal TLRs, or UNC-93B itself, might be good targets for therapy," says Kono, adding that more tests will be needed before these findings are translated into treatments for patients. "We are definitely getting closer to understanding the etiology of this autoimmune disease."

In addition to Kono, other co-authors of the article "Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus," include M. Katarina Haraldsson, Brian R. Lawson, K. Michael Pollard, Yi Ting Koh, Xin Du, Carrie N. Arnold, Roberto Baccala, Bruce Beutler, and Argyrios N. Theofilopoulos of The Scripps Research Institute, and Gregg J. Silverman of the University of California, San Diego.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California with a second campus located in Jupiter, Florida. Research at Scripps Florida focuses on basic biomedical science, drug discovery, and technology development.

Keith McKeown | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Health and Medicine:

nachricht One gene closer to regenerative therapy for muscular disorders
01.06.2017 | Cincinnati Children's Hospital Medical Center

nachricht The gut microbiota plays a key role in treatment with classic diabetes medication
01.06.2017 | University of Gothenburg

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

Im Focus: Optoelectronic Inline Measurement – Accurate to the Nanometer

Germany counts high-precision manufacturing processes among its advantages as a location. It’s not just the aerospace and automotive industries that require almost waste-free, high-precision manufacturing to provide an efficient way of testing the shape and orientation tolerances of products. Since current inline measurement technology not yet provides the required accuracy, the Fraunhofer Institute for Laser Technology ILT is collaborating with four renowned industry partners in the INSPIRE project to develop inline sensors with a new accuracy class. Funded by the German Federal Ministry of Education and Research (BMBF), the project is scheduled to run until the end of 2019.

New Manufacturing Technologies for New Products

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

A new technique isolates neuronal activity during memory consolidation

22.06.2017 | Life Sciences

Plant inspiration could lead to flexible electronics

22.06.2017 | Materials Sciences

A rhodium-based catalyst for making organosilicon using less precious metal

22.06.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>