Scripps researchers find the key culprits lupus

The more than 1.5 million Americans of systemic lupus erythematosus (or lupus) suffer from a variety of symptoms, and the intercept term, often painful or swollen joints, extreme fatigue, rash, fever, and problems kidney. Researchers from the Scripps Research Institute have now the main triggers for the development of this disease.

Lupus is one of many autoimmune diseases, including immune system against parts of the body, destroying cells and tissues is to protect. In a study published in the morning edition of the Proceedings of the National Academy of Sciences (PNAS) the week of June 29, Scripps Research professor of immunology and microbial science Dwight Kono and his colleagues show that the names of three proteins of Toll-like receptors (TLRs) are in favor of this Autodestruction occur. TLRs can be effective targets for the development of new treatments for lupus, as well as other autoimmune diseases.

In response to infection, a good immune system produces antibodies - proteins, combat and destroy the penetration of pathogens such as viruses, bacteria and other foreign bodies to avoid. Lupus But something goes wrong with the chain of events, production of antibodies. Accordingly, the immune system produces auto-antibodies against some of the body of molecules, cells and tissues.

TLRs are proteins in the immune cells that normally help the immune system response to pathogens. 10 persons have different types of TLRs. Some of them rely on the surface of immune cells and molecules, on the surface of bacteria and viruses. Other TLRs - TLR-3, TLR7, (TLR-8 in humans but not mice) and TLR 9 - residing in the immune cells in a department endolysosome, where bits of foreign material, usually at the end.

If bacteria or viruses into the human body, some cells of the immune system has collapsed and humiliated by the endolysosome. In this area, residing TLRs on bacterial and viral debris. These TLRs recognize specifically the genetic material of pathogens - viral DNA, viral RNA, DNA and bacteria - and to stimulate the cells of the immune system to produce antibodies against these molecules.

But the production of antibodies against the under-DNA and RNA which appears to be particularly vulnerable to errors. Most types of auto-antibodies of patients with Lupus are the body's own genetic material - DNA and RNA, which within the cell center or the base. Consequently, physicians are often tested on the presence of anti-nuclear antibodies for diagnosis Lupus.

"This is the Achilles heel," said Kono. "This endolysosomal that TLRs, viral and bacterial immunity, but the possibility, even reactivity."

Scientists are unsure how to develop anti-nuclear, but for some time in the suspicion that TLRs could be included. With engineered mice that lack of TLR 7 and TLR9 scientists have demonstrated that these TLRs may play a role in the disease.

"Previous studies had strongly suggested that TLRs endolysosomal important, but if you eliminate one or the other are not a very big impact," said Kono. "That's why we asked," What if you rid of all endolysosomal detection of nucleic acids TLRs at once?''

To answer this question, Kono and colleagues have used strains of laboratory mice prone to Lupus. These mice spontaneously develop many signs and symptoms, such as those of the disease. The next step to TLR 3, TLR 7 and TLR 9 in mice Lupus vulnerable.

But how to get three proteins at once? Kono and colleagues know that TLRs must be transferred to the endolysosome function. She knew that a protein called UNC-93B, a gene called Unc93b1 serves an important "Taxi" service. The protein UNC-93B is measured by TLR 3, TLR 7 and TLR 9 and facilitates the transport of the material in the cell, where they endolysosome.

With genetic tools, Kono and colleagues, technically vulnerable lupus in mice a gene inactive Unc93b1. Vulnerable to Lupus-mouse works with Unc93b1 gene, mice with the mutation Unc93b1 less anti-nuclear and less serious Lupus.

Another consideration, and Mr. Kono mutant mice treated with a substance that stimulates TLR 4 - stimulation of TLR-4 is to promote the production of auto-antibodies. But also to stimulate TLR-4, mice without a TLR 3, TLR 7 and TLR 9, no development lupus.

"It seems that these TLRs are essential for optimal use of auto-antibody production," said Kono. "This is a finding that is based on the results of other groups."

The results "suggest that the three endosomal TLRs or UNC-93B also be good targets for therapy," Kono said, adding that more tests are needed before these results are in treatment for patients. "We are certainly closer to understanding the etiology of these autoimmune disease."