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!
Laser activated gold pyramids could deliver drugs, DNA into cells without harm
24.03.2017 | Harvard John A. Paulson School of Engineering and Applied Sciences
What does congenital Zika syndrome look like?
24.03.2017 | University of California - San Diego
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy