Two Proteins Have Unexpected Effects on Autoimmune Diseases Such as Lupus

Blocking the effect of individual immune system proteins that normally recognize viruses and bacteria produces surprisingly different effects on the severity of autoimmune diseases such as Lupus, researchers at Yale School of Medicine report in the September issue of Immunity. Drugs that target these proteins could be important therapies for autoimmunity.

Blocking the effect of individual immune system proteins that normally recognize viruses and bacteria produces surprisingly different effects on the severity of autoimmune diseases such as Lupus, researchers at Yale School of Medicine report in the September issue of Immunity. Drugs that target these proteins could be important therapies for autoimmunity.

Led by Mark Shlomchik, M.D., professor of laboratory medicine and immunobiology at Yale, the researchers examined the effect on disease when two similar Toll-like receptors (TLRs) were removed from mice in the study.

“These data showed that TLRs do indeed modulate overall autoimmune disease but not always in the expected way,” said Shlomchik. “These are the first findings to show a definitive effect of TLR9 on anti-chromatin antibodies and are also the first to show the effect of TLR7 deficiency on autoantibodies and disease.”

“We also found that mice without TLR9 lacked antibodies to DNA and that mice deficient in TLR7 lacked antibodies to RNA-associated antigens,” said Shlomchik. “When we examined the effect on disease, we were surprised to find that the two TLRs had very different effects. Mice deficient in TLR9 had worse disease, despite lacking anti-DNA antibodies, while TLR7-deficient mice had a milder form of disease.”

Shlomchik said the study supports the idea that drugs that block TLR7 in particular could be promising as therapies, but he cautions against just blocking TLR9, a strategy he said some biotech/pharmaceutical companies may have already begun.

The study increases understanding of how the immune system and B cells in particular are activated by ‘self’ antigens, putting direct focus on the TLR family of receptors. B cells make autoantibodies and may also stimulate the T lymphocytes that destroy tissues.

Shlomchik and his co-authors plan to explore why TLR7 and TLR9 had different effects on disease. “We were very surprised because these two receptors are very similar to each other, generate signals in the same way and are expressed in the same cell types,” he said. “We need to make mice deficient in both receptors to determine if TLR7 and TLR9 interact with each other and if blocking both inhibits disease even more effectively than blocking TLR7 alone.”

Other authors on the study included Sean R. Christensen, Jonathan Shupe, Kevin Nickerson, Michael Kashgarian, and Richard Flavell.

The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases.

Citation: Immunity, Vol. 25, 417-428 (September 2006)

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Karen N. Peart: karen.peart@yale.edu, 203-980-2222