TLR7, TLR9 proteins could be culprit behind lupus patients' resistance to steroid treatments: Scientists

Jul 13 2010

Findings Could Lead to Lower Doses of Medication for Lupus Patients, Reducing Serious Side Effects

Two immune system proteins could be the culprit behind many lupus patients' resistance to widely used steroid treatments, scientists with the Baylor Research Institute (BRI) in Dallas announced today. It is estimated that more than 5 million people suffer from lupus worldwide.

Currently, those with lupus and other autoimmune diseases, commonly treat the condition with corticosteroids to suppress their overactive immune system and prevent it from attacking healthy tissues which can result in symptoms such as inflammation, pain and organ damage.

These steroid treatments work by killing certain immune system cells, including plasmacytoid dendritic cells (PDCs) that overproduce type 1 interferons, an immune system substance that contributes to lupus and other autoimmune diseases. However, unlike other conditions, steroid treatments are not as effective against these cells in those with lupus.

By largely studying children with systemic lupus erythematosus (SLE), BRI scientists in collaboration with scientists at Dynavax in Berkeley, CA, were able to solve the mystery behind the resistance. They determined that two immune system proteins known as toll-receptor 7 (TLR7) and toll-receptor 9 (TLR9), cause an activation of PDCs—the very cells steroids target—negating the effects of treatment. BRI scientists reported their findings in the June issue of the journal Nature.

"We have long known that these receptors played a critical role in lupus, but until now, we didn't know they were directly interfering with the effects of steroid treatments," says Virginia Pascual, M.D., one of the principal investigators of the study and a researcher at Baylor Institute for Immunology Research, a component of BRI. "By blocking TLR7 and TLR9 function, we may have found a safer way to treat this debilitating disease."

Currently, large doses of corticosteroids are required to treat lupus, but can cause serious damage to the organs and create other side effects such as weight gain, cataracts, hypertension, brittle bones and thin skin. In children, corticosteroids can also cause stunted growth. In addition, patients must take other strong immunosuppressants which can leave them vulnerable to infections.

"The ultimate goal is to reduce the amount of steroids these patients take because they carry a risk of serious side effects. Our work suggests that if we can somehow block these proteins from carrying out their mission, steroid treatments will be more effective and we may be able to significantly lower the doses," explains Dr. Pascual.

While Dr. Pascual's research focused mainly on children, she says there is no reason to believe these findings would not be true for adults with lupus as well.

"There are limited treatment options for this disease and the ones that do exist are very hard on the body. It is a complicated condition that is difficult to treat so there is an urgent need for this type of research," says Michael Ramsay, M.D., president of BRI. "Not only have Dr. Pascual and her team made a huge contribution to medical research, but they have given hope to the millions of people who suffer from lupus."

Dr. Ramsay adds that blocking agents for TLR7 and TLR9 are already in development and could be ready for clinical studies soon.