Two Proteins Found to Have Unexpected Effects on Lupus

Systemic lupus erythematosus (lupus) is a chronic, inflammatory systemic disease where the skin, joints, heart, blood elements, lungs, kidneys and/or brain may be affected. Lupus is also an autoimmune disease, which means the body’s immune system mistakenly produces antibodies to components of its own cells. While the mechanisms of this aberrant immune response are not well understood, researchers are finding clues in two immune system proteins called Toll-like receptor 7 (TLR7) and Toll-like receptor 9 (TLR9).

A new study supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) shows that these proteins, which normally recognize viruses and bacteria and activate immune cell responses against them, play an important role in autoimmunity. Furthermore, it shows that blocking the effects of these proteins �?in mice with a lupus-like disease �?produces different and unexpected effects on disease severity, suggesting these proteins might be new targets for lupus treatment.

"For a while we thought all Toll-like receptors (TLRs) could only react with things that were foreign," says study co-author Mark Shlomchik, M.D., Ph.D., professor of laboratory medicine and immunobiology at Yale University School of Medicine. "But in more recent years, TLR-7 and TLR9 were discovered and scientists found what they bound to: TLR7 to RNA, and TLR9 to DNA. We know that every living thing �?including the bacteria, viruses and other microorganisms that these TLRs are designed to fight �?has DNA and RNA in it."

Because many of the autoantibodies in a person with lupus target that person’s own RNA and DNA, the scientists theorized that in autoimmune disease these Toll-like receptors were recognizing self-DNA and self-RNA instead of the DNA and RNA of bacteria, says Dr. Shlomchik. To test this theory, the scientists crossed mice without these receptors with mice genetically prone to develop a lupus-like disease. Their study produced both expected and surprising results. As expected, the mice lacking TLR9 did not make antibodies to DNA. However, instead of getting better, as the researchers had expected, the lupus-like disease was worse in these mice. Also as expected, the mice lacking TLR7 did not make antibodies to RNA and, unlike the TLR9-deficient mice, their lupus was less severe.

Dr. Shlomchik says the study supports the idea that drugs to block TLR7 could be useful treatments for a disease that has few good treatments. Current lupus treatments work by suppressing the entire immune system and leave the body vulnerable to serious infections, he says. These new findings suggest that TLR7 may be a specific target for treatment rather than the blanket immune system suppression of current therapies. It also provides evidence that blocking just TLR9 �?which would seem to make sense �?could actually do more harm than good.

"What is nice about the work is that we found a very specific target and we found what it does �?at least in terms of antibodies," says Dr. Shlomchik. The scientists are continuing to study these proteins and their role in autoimmune diseases such as lupus. "We need to understand why blocking TLR9 has the opposite effect of what we thought," he says. "We need to find out if blocking TLR9 and TLR7 together somehow will cause more of a remission. Those kinds of studies are things we are working on in the lab now."

The mission of NIAMS, a part of the Department of Health and Human Services�?National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

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Christensen SR, et al. Toll-like Receptor 7 and TLR9 dictate autoimmunity specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 2006;25(9):417-428.